Clinical trial NCT03266588
Conditions: Migraine, With or Without Aura
Sponsor: Pfizer
Start date: 2017-08-30; Completion date: 2019-07-15
Enrollment: 3019 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The purpose of this study is to evaluate safety and tolerability of BHV-3000 (rimegepant).

Detailed description:

Arms: arm 1: None
Interventions: intervention 1: Rimegepant
Intervention descriptions: intervention 1: 75 mg oral tablet

Protocol documents:
Prot_000.pdf: 
Protocol BHV3000-201  
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DRUG: 
BHV-3000 (rimegepant) 
 
STUDY NUMBER(S): 
BHV3000-201 
 
PROTOCOL(S) TITLE: 
BHV3000-201: A Multicenter, Open Label Long-
Term Safety Study of BHV-3000 in the Acute 
Treatment of Migraine  
IND NUMBER: 
109886 
 
SPONSOR: 
Biohaven Pharmaceutical Holding Company 
Limited 
 
ORIGINAL PROTOCOL 
DATE: 
19 May 2017 
 
VERSION NUMBER: 
V05 
 
VERSION DATE: 
22 June 2018 




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Name and Title 
Signature Approval 
Date 
PPD


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SUMMARY OF CHANGES 
Change 
Section(s)  
Affected 
Summary 
1. Add group of 
subjects with 
history of 4-14 
moderate to 
severe 
migraines/month. 
Synopsis, Target Population;, 
Synopsis, Study Design; Section 
1.4.1 Study Design Rationale; 
Section 4.1 Study Design and 
Duration; Section 4.3.2 Long 
Term Treatment Phase; Section 
4.3.3 End of Treatment; Section 
7.2.2 Selection and Timing of 
Dose and Administration 
 
Add new group of subjects with a history 
of 4-14 moderate to severe 
migraines/month who will dose every 
other day for 12 weeks. Subjects in this 
group can take a tablet of rimegepant on 
non-dosing days to treat a migraine of 
mild to severe intensity. 
2. Clarify the 
number of 
subjects to be 
screened and 
assigned 
rimegepant. 
Synopsis, Number of Subjects; 
Section 4.3.1 Screening visit / 
Observation Phase; Section 5, 
Population 
 
Clarified the targeted number of subjects 
to be screened and assigned treatment.  
 
3. Added study 
schema for 4-14 
moderate to 
severe 
migraines/month 
group 
Study Schematic 
Added a separate schematic for 12 weeks 
of treatment for subjects in the 4-14 
moderate to severe migraines/month 
group. 
4. Clarify Table 1, 
Schedule of 
assessments for 
separate patient 
groups 
Schedule of Assessments 
Added a new schedule of assessments for 
subjects in the 4-14 moderate to severe 
migraines/month, every other day dosing 
group.  
5. Clarify 
prophylactic 
migraine 
medication 
Section 5.2 Inclusion Criteria, 
Inclusion criterion 2f; Section 5.5 
Standard of Care and 
Clarified that prophylactic migraine 
medication regimen should not change 
during the course of the study. 


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Prophylactic Migraine 
Medication  
6. Added exclusion 
criteria 
Section 5.3 Exclusion Criteria: 
Exclusions l and m 
Added exclusion of BMI > 30 kg/m2 and 
exclusion of history of gallstones or 
cholecystectomy 
7. Modified 
exclusion criterion 
Section 5.3 Exclusion Criteria: 
Exclusion i 
Modified HbA1c to exclude those with 
HbA1c > 6.5%. 
8. Modified 
prohibited 
medications 
Section 5.4, Prohibited 
Concomitant Medications 
Further clarified that Depakene and 
valproate are both prohibited 
medications. Added new prohibited 
medication of Lamictal (lamotrigine) 
9. Clarified 
prophylactic and 
standard of care 
migraine 
medications 
Section 5.5, Prophylactic and 
Standard of Care Medications 
Clarified that if a patient takes a tablet of 
study drug and experiences a migraine 
later that day, after dosing with study 
drug for the day, the patient should take 
their standard of care migraine 
medication as described in this section of 
the protocol. Patients are not allowed to 
take more than one tablet of study 
medication per calendar day. 
10. Clarified 
discontinuation 
rule for specific S-
STS scores 
Section 6.5 Early Discontinuation 
From the Study 
Added criterion for early termination 
from study due to scores on the Sheehan-
Suicidality Tracking Scale per Section 
6.2.5 
11. Added definitions 
for terms mild, 
Section 8.1.1, Definitions for 
Serious Adverse Events 
Added definition of terms for mild, 
moderate and severe adverse events. 


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moderate and 
severe 
12. Updated sample 
size calculations 
Section 9.2, Sample Size 
Updated sample size of the subpopulation 
and corresponding sample size 
calculations. 
13. Included 
references to 
Table 2 
Various 
Added references to Table 2, when 
discussion study procedures, etc. 
 


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BHV3000-201 
BHV3000-201: A Multicenter, Open Label, Long-Term Safety 
Study of BHV-3000 in in the Acute Treatment of Migraine 
CONFIDENTIALITY AND INVESTIGATOR STATEMENT 
The information contained in this protocol and all other information relevant to BHV-
3000 (rimegepant) are the confidential and proprietary information of Biohaven 
Pharmaceutical Holding Company Limited, and except as may be required by federal, 
state or local laws or regulation, may not be disclosed to others without prior written 
permission of Biohaven Pharmaceutical Holding Company Limited. 
I have read the protocol, including all appendices, and I agree that it contains all of the 
necessary information for me and my staff to conduct this study as described. I will 
conduct this study as outlined herein, in accordance with the regulations stated in the 
Federal Code of Regulations for Good Clinical Practices and International Conference on 
Harmonization guidelines, and will make a reasonable effort to complete the study within 
the time designated. 
I will provide all study personnel under my supervision copies of the protocol and any 
amendments, and access to all information provided by Biohaven Pharmaceutical 
Holding Company Limited or specified designees. I will discuss the material with them to 
ensure that they are fully informed about BHV-3000 and the study. 
 
 
 
 
Principal Investigator Name (printed) 
Signature 
 
___________ ___________ 
Date 
 
Site Number 


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STUDY SUMMARY (SYNOPSIS) 
Title:  
A Multicenter, Open Label, Long-Term Safety Study of BHV-3000 in the 
Acute Treatment of Migraine  
Rationale:  
Rimegepant is being developed for the treatment of migraine, with a 
specific focus on acute treatment. Effectiveness against migraine was 
demonstrated in a Phase 2b double-blind, randomized, placebo-controlled, 
dose-ranging study where rimegepant at 75 mg showed efficacy on all four 
traditional endpoints: pain, nausea, photophobia and phonophobia [1].  
This study is being conducted to further characterize the safety and 
tolerability of rimegepant during longer term treatment of patients with 
migraine.  
Target 
Population: 
The study will recruit male and female patients, 18 years of age or older 
with at least a one-year history of migraine (with or without aura) 
consistent with a diagnosis according to the International Classification of 
Headache Disorders, 3rd edition, beta version [2]. Patients must have 
migraine onset prior to age 50, migraine attacks that last 4-72 hours (if not 
treated) and have had 2-14 migraine attacks of moderate to severe intensity 
per month within the 3 months prior to the screening visit. A separate 
group of patients with a history of 4-14 moderate to severe 
migraines/month during the 3 months prior to the screening visit, will be 
enrolled and will dose with one tablet of study drug every other day for 12 
weeks. After a 30-day observation period of standard of care, up to 
approximately 2000 eligible patients will be assigned to receive 
rimegepant. Patients who have participated in BHV3000-301, BHV3000-
302 or BHV3000-303 (or another clinical trial with rimegepant) may be 
considered for participation in this long term safety study if all eligibility 
criteria are met, however participation in this study is not guaranteed. 
Enrollment into this study will initially be open to patients with 2-8 
moderate to severe migraine attacks per month (primarily  the patients 
from BHV-3000-301 and BHV-3000-302) for approximately three months. 
After approximately three months, study enrollment will open for patients 
with a history of 9-14 migraine attacks of moderate to severe intensity per 
month within the 3 months prior to the screening visit. Lastly, study 
enrollment will open for subjects in the every other day dosing group who 
have a history of 4-14 moderate to severe migraines/month during the 3 
months prior to the screening visit.  
Number of 
Subjects: 
Approximately 2800 patients will be screened to assign up to 
approximately 2000 patients to rimegepant.  
Of the 2000 patients assigned to rimegepant, up to approximately: 


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- 
1200 will have a history of 2-8 moderate to severe migraine attacks 
per month,   
- 
600 will have a history of 9-14 moderate to severe migraine attacks 
per month, and  
- 
200 will have a history of 4-14 moderate to severe migraine attacks 
per month in the every other day dosing group.  
Objectives:  
Primary Objective: To evaluate the safety and tolerability of rimegepant.  
Secondary Objectives: 
• To evaluate the frequency of ALT or AST > 3x ULN with 
concurrent elevations in bilirubin > 2x ULN in subjects treated with 
rimegepant. 
• To evaluate the frequency and severity of hepatic-related adverse 
events and the frequency of hepatic-related treatment 
discontinuations.  
Exploratory Objectives: 
• To evaluate the frequency of subjects with elevated liver function 
tests (AST, ALT or total bilirubin).   
• To evaluate the frequency of subjects with ALT or AST elevations 
> 3x ULN in temporal association with nausea, vomiting, anorexia, 
abdominal pain or fatigue. 
• To explore the contributions of gender, age and exposure to 
rimegepant to abnormalities in AST, ALT, or bilirubin. 
• To investigate the time on treatment and cumulative exposure 
associated with: (1) hepatic related SAEs and treatment 
discontinuations; (2) elevations in ALT or AST > 3x ULN with 
concurrent elevations in bilirubin > 2x ULN. 


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• To evaluate the number of headache days and severity of migraine 
attacks while subjects are treated with rimegepant relative to the 
observational period. 
• To evaluate the effect of rimegepant treatment compared to 
baseline on the 20-Item Migraine-Specific Quality of Life 
Questionnaire v 2.1 (MSQoL). 
• To evaluate the effect of rimegepant treatment compared to 
baseline on the Migraine Preference of Medication (PoM). 
• To examine the scores on the Sheehan Suicidality Tracking Scale. 
• To evaluate the effect of rimegepant treatment compared to 
baseline on the Satisfaction with Medication survey. 
• To evaluate the effect of rimegepant treatment compared to 
baseline on the Migraine Disability Assessment (MIDAS) 
• To evaluate the effect of rimegepant treatment compared to 
baseline on the Clinical Global Impression – change (CGI-c) scale. 
Study 
Design: 
This is a multicenter, open-label study to assess the safety and tolerability 
of long term use of rimegepant, taken up to one tablet per calendar day, in 
patients with migraine. 
The Screening phase includes a screening visit and a 30 day Observation 
Period. For subjects to be eligible for the study, they must have 2-14 
migraine attacks of moderate to severe intensity per month in the 3 months 
prior to the Screening Visit. Patients enrolled in the every other day dosing 
group must have had 4-14 migraine attacks of moderate to severe intensity 
per month during the 3 months prior to the screening visit. Enrollment into 
this study will initially be open to patients with 2-8 moderate to severe 
migraine attacks per month (primarily the patients from BHV-3000-301 
and BHV-3000-302) for approximately three months. After approximately 
three months, study enrollment will open for patients with a history of 9-14 
migraine attacks of moderate to severe intensity per month within the 3 
months prior to the screening visit. Lastly, study enrollment will open for 
subjects in the every other day dosing group (4-14 moderate to severe 
migraines/month). 


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Upon the completion of the screening visit, patients will be provided an 
electronic diary (eDiary) to document each day of the 30 day Observation 
Period if a migraine occurred, the migraine intensity and if the migraine 
was treated. Patients will record the standard of care migraine treatment 
received on a paper diary. After completing the 30 day Observational 
Period, the patient will return to the clinic with both diaries for the 
Baseline Visit. At the Baseline Visit, eligibility for continued participation 
in the study will be assessed before study medication will be dispensed. 
After the investigator reviews the results of the baseline laboratory 
assessments and determines the patient’s continued eligibility, the site staff 
will inform the patient whether or not they are eligible to start dosing in the 
Long Term Treatment phase. If eligible for the Long Term Treatment 
Phase, patients will be instructed that they can take study medication at the 
onset of a migraine (of mild to severe intensity). Patients in the 2-8 or 9-14 
moderate to severe migraines/month groups will be instructed that they can 
take a maximum of one tablet of rimegepant per calendar day during the 52 
week Long Term Treatment phase at the onset of a migraine (of mild to 
severe intensity).  
Patients in the every other day dosing group (history of 4-14 moderate to 
severe migraines/month) will be instructed that they must take one tablet of 
rimegepant every other calendar day. If patients in this group have a 
migraine on a day that they are not scheduled to dose with rimegepant, 
they may take a rimegepant tablet to treat a migraine of mild, moderate or 
severe intensity. Therefore, patients in this group can take a maximum of 
one tablet of rimegepant per calendar day for 12 weeks.  
Patients are required to record their migraine occurrence and severity and 
all study medication doses in the eDiary. Patients are also required to 
continue to record the standard of care migraine treatment taken on a paper 
diary. Patients will also use the eDiary to complete the Preference of 
Medication (PoM) questionnaire and the Satisfaction with Medication 
(SM) questionnaire at specified study timepoints. 
At select study visits, patients will complete or will be administered the 
Migraine-specified Quality-of-Life Questionnaire v 2.1 (MQoLQ), the 
Migraine Disability Assessment (MIDAS), Clinical Global Impression – 
change (CGI-c) scale, and the Sheehan Suicidality Tracking Scale (S-STS) 
on paper forms, at specified study visits.  
Additional assessments and visit schedule are outlined in the procedural 
table in Section 4.3. Procedures include study personnel review of the 
eDiary and paper diary with the patient, assessment of study medication 
compliance, monitoring of tolerability and safety (including vital signs, 
laboratory tests, and electrocardiography). Study visits will be 


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approximately every two weeks during the first month and then every 4 
weeks until Week 52 for subjects in the 2-8 moderate to severe 
migraine/month group or the 9-14 moderate to severe migraine/month 
group.  
Study visits will be approximately every two weeks during the first month 
and then every 4 weeks until Week 12 for subjects in the every other day 
dosing group (those with history of 4-14 moderate to severe 
migraines/month). 
Patients will return to the study site at the end of Week 52 (or Week 12 for 
subjects in the every other day dosing group (history of 4-14 moderate to 
severe migraines/month)) (+/- 7 days) for the End of Treatment Visit. 
There is a Follow-up Visit 14 days (+/- 2 days) after the Week 12/52/EOT 
Visit. 
To closely monitor for potential drug induced liver injury, guidance on 
reporting potential drug-induced liver injury (DILI) events is provided in 
the protocol. Lab results that meet predefined LFT abnormality criteria as 
DILI should be reported as a serious adverse event (SAE). See Section 
8.1.5, Potential Drug Induced Liver Injury (DILI). 
Primary 
Endpoint:  
The frequency and severity of adverse events that occur in at least 5% of 
treated subjects, the frequency of serious adverse events, adverse events 
leading to discontinuation and clinically significant laboratory 
abnormalities during the treatment period will be assessed. The frequency 
of AEs, SAEs, AEs leading to discontinuation are determined from case 
report forms, and are tabulated based on the number of unique subjects. 
The frequency of clinically significant laboratory abnormalities are 
determined from laboratory data, and are also tabulated based on the 
number unique subjects. 
Secondary 
Endpoints: 
The frequency of AST or ALT elevations > 3x ULN, concurrently with 
bilirubin elevations > 2x ULN, will be assessed by tabulating the number 
of unique subjects with this pairing of events.  
The frequency of hepatic-related adverse events and hepatic-related 
treatment discontinuations will be tabulated from case report forms and 
will be based on unique subjects reporting such events. Severity will be 
assessed as the worst severity observed while the subject is on treatment.    


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STUDY SCHEMATIC (up to 52 weeks of treatment 2-8 and 9-14 
moderate to severe migraines/month groups) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  


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STUDY SCHEMATIC (up to 12 weeks of treatment for the 4-14 
moderate to severe migraines/month, every other day dosing 
group) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 


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TABLE OF CONTENTS 
CLINICAL PROTOCOL APPROVAL FORM ............................................................... 2 
SUMMARY OF CHANGES ................................................................................................ 4 
CONFIDENTIALITY AND INVESTIGATOR STATEMENT..................................... 7 
STUDY SUMMARY (SYNOPSIS) ..................................................................................... 8 
TABLE OF CONTENTS .................................................................................................... 15 
LIST OF TABLES ............................................................................................................... 18 
LIST OF FIGURES ............................................................................................................. 18 
1 
INTRODUCTION AND RATIONALE .................................................................... 22 
1.1 
BACKGROUND ...................................................................................................... 22 
1.2 
CGRP’S ROLE IN MIGRAINE ........................................................................... 22 
1.3 
PRODUCT DEVELOPMENT BACKGROUND ............................................... 23 
1.3.1 
NON-CLINICAL STUDIES ............................................................................ 23 
1.3.1.1 
NON-CLINICAL PHARMACOKINETICS AND 
PHARMACODYNAMICS ........................................................................ 23 
1.3.1.2 
NON-CLINICAL TOXICOLOGY .......................................................... 23 
1.3.4 
CLINICAL ADVERSE EVENT PROFILE.................................................. 29 
1.4 
STUDY RATIONALE ............................................................................................ 30 
1.4.1 
STUDY DESIGN RATIONALE ..................................................................... 32 
1.4.2 
DOSE SELECTION RATIONALE ............................................................... 32 
1.4.3 
OTHER RATIONALE RELATED TO THE 
COMPOUND/STUDY ...................................................................................... 33 
1.5 
RESEARCH HYPOTHESIS ................................................................................. 33 
2 
STUDY OBJECTIVE .................................................................................................. 34 
2.1 
PRIMARY ................................................................................................................ 34 
2.2 
SECONDARY .......................................................................................................... 34 
3 
STUDY ENDPOINTS .................................................................................................. 36 
CCI


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3.1 
PRIMARY ................................................................................................................ 36 
3.2 
SECONDARY .......................................................................................................... 36 
3.3 
MEASURES OF INTEREST ................................................................................ 36 
4 
STUDY PLAN ............................................................................................................... 37 
4.1 
STUDY DESIGN AND DURATION .................................................................... 37 
4.2 
STUDY SCHEMATIC ............................................................................................ 39 
4.3 
SCHEDULE OF ASSESSMENTS ........................................................................ 40 
4.3.1 
SCREENING VISIT / OBSERVATION PERIOD (30 DAYS).................. 53 
4.3.2 
LONG TERM TREATMENT PHASE (12 WEEKS OR 52 
WEEKS) .............................................................................................................. 53 
4.3.3 
END OF TREATMENT (WEEKS 12 OR 52) .............................................. 54 
4.3.4 
FOLLOW UP SAFETY VISIT ....................................................................... 55 
4.4 
POST STUDY ACCESS TO THERAPY (IF APPLICABLE) ......................... 55 
5 
POPULATION .............................................................................................................. 56 
5.1 
NUMBER OF SUBJECTS ..................................................................................... 56 
5.2 
INCLUSION CRITERIA ....................................................................................... 56 
5.3 
EXCLUSION CRITERIA ...................................................................................... 58 
5.4 
PROHIBITED CONCOMITANT MEDICATION ........................................... 62 
5.5 
PROPHYLACTIC AND STANDARD OF CARE MIGRAINE 
MEDICATIONS ...................................................................................................... 63 
5.6 
WOMEN OF CHILDBEARING POTENTIAL ................................................. 64 
5.7 
OTHER RESTRICTIONS AND PRECAUTIONS (IF APPLICABLE) ........ 64 
5.8 
DEVIATION FROM INCLUSION/EXCLUSION CRITERIA AND 
STUDY PROCEDURES ......................................................................................... 65 
6 
STUDY CONDUCT AND DESCRIPTION OF STUDY PROCEDURES.......... 66 
6.1 
STUDY MATERIALS ............................................................................................ 66 
6.2 
SAFETY ASSESSMENTS ..................................................................................... 67 
6.2.1 
VITAL SIGNS AND PHYSICAL MEASUREMENTS (HEIGHT 
AND WEIGHT) ................................................................................................. 67 
6.2.2 
ELECTROCARDIOGRAM (ECG) ............................................................... 67 
6.2.3 
PHYSICAL EXAM ........................................................................................... 68 
6.2.4 
LABORATORY ASSESSMENTS.................................................................. 68 
6.2.4.1 
SAFETY LABORATORY TESTING ..................................................... 68 
6.2.4.2 
PREGNANCY TESTING .......................................................................... 69 
6.2.5 
SHEEHAN SUICIDALITY TRACKING SCALE ...................................... 69 
6.3 
EFFICACY ASSESSMENTS ................................................................................ 69 
6.4 
OTHER ASSESSMENTS....................................................................................... 70 
6.4.1 
DAILY MIGRAINE ASSESSMENT OF 
SEVERITY/FREQUENCY ............................................................................. 70 
6.4.2 
MIGRAINE QUALITY OF LIFE QUESTIONNAIRE.............................. 70 
6.4.3 
MIGRAINE PREFERENCE OF MEDICINE ............................................. 70 
6.4.4 
SATISFACTION WITH MEDICATION QUESTIONNAIRE ................. 70 
6.4.5 
MIGRAINE DISABILITY ASSESSMENT TEST (MIDAS)..................... 70 
6.4.6 
CLINICAL GLOBAL IMPRESSION – CHANGE (CGI-C) ..................... 71 
6.5 
EARLY DISCONTINUATION FROM THE STUDY ...................................... 71 


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7 
STUDY DRUG MANAGEMENT.............................................................................. 73 
7.1 
DESCRIPTION OF STUDY DRUG .................................................................... 73 
7.1.1 
INVESTIGATIONAL PRODUCT ................................................................. 73 
7.1.2 
NON-INVESTIGATIONAL PRODUCT ...................................................... 73 
7.1.3 
PACKAGING, SHIPMENT AND STORAGE............................................. 73 
7.2 
DOSE AND ADMINISTRATION ........................................................................ 74 
7.2.1 
METHOD OF ASSIGNING PATIENT IDENTIFICATION .................... 74 
7.2.2 
SELECTION AND TIMING OF DOSE AND 
ADMINISTRATION ........................................................................................ 74 
7.2.3 
DOSE MODIFICATIONS ............................................................................... 74 
7.2.4 
DOSE INTERRUPTIONS ............................................................................... 75 
7.3 
BLINDING AND UNBLINDING ......................................................................... 75 
7.4 
TREATMENT COMPLIANCE ............................................................................ 75 
7.5 
DESTRUCTION AND RETURN OF STUDY DRUG ...................................... 76 
8 
ADVERSE EVENTS .................................................................................................... 77 
8.1 
SERIOUS ADVERSE EVENT .............................................................................. 77 
8.1.1 
DEFINITION OF SERIOUS ADVERSE EVENT (SAE) ........................... 77 
8.1.2 
COLLECTION AND REPORTING SERIOUS ADVERSE 
EVENTS .............................................................................................................. 79 
8.1.3 
OVERDOSE ....................................................................................................... 80 
8.1.4 
PREGNANCY .................................................................................................... 81 
8.1.5 
POTENTIAL DRUG INDUCED LIVER INJURY (DILI) ........................ 82 
8.2 
NON-SERIOUS ADVERSE EVENTS ................................................................. 82 
8.2.1 
COLLECTION AND REPORTING OF NON-SERIOUS 
ADVERSE EVENTS ......................................................................................... 82 
8.2.2 
LABORATORY TEST ABNORMALITIES ................................................ 83 
9 
STATISTICS ................................................................................................................. 84 
9.1 
GENERAL PROCEDURES .................................................................................. 84 
9.2 
SAMPLE SIZE ......................................................................................................... 84 
9.3 
STATISTICAL METHODS .................................................................................. 84 
9.3.1 
PRIMARY ENDPOINT(S) .............................................................................. 84 
9.3.2 
SECONDARY ENDPOINT(S) ........................................................................ 85 
9.3.3 
DEMOGRAPHIC AND BASELINE CHARACTERISTICS .................... 85 
9.4 
INTERIM ANALYSIS ............................................................................................ 85 
10 ETHICS AND RESPONSIBILITIES........................................................................ 86 
10.1 
GOOD CLINICAL PRACTICE ........................................................................... 86 
10.2 
DATA AND SAFETY MONITORING COMMITTEE.................................... 86 
10.3 
INSTITUTIONAL REVIEW BOARD/INDEPENDENT ETHICS 
COMMITTEE .......................................................................................................... 86 
10.4 
INFORMED CONSENT ........................................................................................ 87 
10.5 
CASE REPORT FORMS ....................................................................................... 88 
10.6 
RECORDS MANAGEMENT AND RETENTION............................................ 88 
10.7 
SOURCE DOCUMENTATION ............................................................................ 89 
10.8 
STUDY FILES AND RECORD RETENTION .................................................. 89 
11 AMENDMENTS ........................................................................................................... 91 


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12 STUDY REPORT AND PUBLICATIONS .............................................................. 92 
13 STUDY DISCONTINUATION .................................................................................. 93 
14 CONFIDENTIALITY .................................................................................................. 94 
15 APPENDICES ............................................................................................................... 95 
15.2 
APPENDIX 2 - DECLARATION OF HELSINKI ............................................. 96 
15.3 
APPENDIX 3 - STRONG CYP3A4 INHIBITORS AND INDUCERS 
(NOT ALL-INCLUSIVE)..................................................................................... 101 
16 REFERENCES............................................................................................................ 102 
 
LIST OF TABLES 
Table 1: 
 Schedule of Assessments (for 2-8 moderate to severe and 9-14 
moderate to severe migraines /month group) ......................................... 40 
Table 2:  
Schedule of Assessments (for 4-14 moderate to severe 
migraines/month (every other day dosing) group) ................................ 47 
 
LIST OF FIGURES 
Figure 1:  
Phase 2b Primary Endpoint: Rimegepant Pain Freedom at 2 hours 
Post Dose (+/- 95% Confidence)................................................................ 28 
Figure 2:  
Study Schematic (Up to 52 Weeks Treatment for 2-8 and 9-14 
moderate to severe migraines/month groups) ........................................ 39 
Figure 3:  
Study Schematic  (Up to 12 Weeks Treatment for the 4-14 moderate 
to severe migraines/month, every other day dosing group).................. 39 
PPD


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LIST OF ABBREVIATIONS 
AE 
Adverse Event 
ALT 
Alanine Aminotransferase 
AST 
Aspartate Aminotransferase 
AUC 
Area Under the Curve 
bid 
Twice Daily 
BP 
Blood Pressure 
BUN 
Blood Urea Nitrogen 
CGI-c 
Clinical Global Impressions- change scale 
Cmax 
Maximum Plasma Concentration 
CONMED 
Concomitant Medication 
CRF 
Case Report Form 
CV 
Coefficient of Variation 
DILI 
Drug-Induced Liver Injury 
DSMC 
Data and Safety Monitoring Committee 
DSM-V 
Diagnostic and Statistical manual of Mental Disorders Fifth edition 
ECG 
Electrocardiogram 
FSH 
Follicle Stimulating Hormone 
GCP 
Good Clinical Practice 
HIV 
Human Immunodeficiency Virus 
HR 
Heart Rate 
ICF 
Informed Consent Form 
IB 
Investigator’s Brochure 
ICH 
International Conference on Harmonization 


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ICF 
Informed Consent Form 
IEC 
Independent Ethics Committee 
HIS 
International Headache Society 
INR 
International Normalized Ratio 
IRB 
Institutional Review Board 
IV 
Intravenous 
IWRS 
Interactive Web Response System 
kBq 
Kilobecquerel 
kg 
Kilogram 
L 
Liters 
LFTs 
Liver Function Tests 
MBq 
Megabecquerel 
mg 
Milligram 
MIDAS 
Migraine Disability Assessment 
MQoLQ 
Migraine Quality of Life Questionnaire 
min 
Minute 
mmHg 
Millimeters Mercury 
NOEL 
No Observed Effect Level 
NOAEL 
No Observed Adverse Event Level 
PK 
Pharmacokinetic 
Po 
By Mouth, Orally 
QD 
Once Daily 
QTc 
Interval between Q-wave and T-wave in the cardiac cycle 
SAE 
Serious Adverse Event 


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S-SST 
Sheehan Suicidality Tracking scale 
ULN 
Upper Limit of Normal 
WBC 
White Blood Cell 
WHO 
World Health Organization 
WOCBP 
Women of Childbearing Potential 
 


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1 INTRODUCTION AND RATIONALE 
1.1 
Background 
BHV-3000 (rimegepant, /rih-MEJ-eh-pant/) is a calcitonin gene-related peptide (CGRP) 
receptor antagonist in development for the acute treatment of migraine. A comprehensive 
and durable efficacy profile for rimegepant was demonstrated in an 812 patient Phase 2b 
double-blind, randomized, placebo controlled, dose-ranging trial where migraine 
sufferers received either placebo, sumatriptan (100 mg) or rimegepant (10, 25, 75, 150, 
300 or 600 mg) (Study CN170003)[1]. A dose of 75 mg was selected as the optimal dose 
for Phase 3 clinical trials, given that larger doses showed a similar efficacy profile and 
there was negligible benefit identified with higher doses. Rimegepant at 75 mg showed 
statistically significant comprehensive efficacy across all four traditional endpoints at 2 
hr (pain, nausea, photophobia and phonophobia) which was durable as evidenced by the 
presence of pain freedom and pain relief which persisted through 24 hr and 48 hr 
showing significant difference from placebo on the corresponding 2-24 and 2-48 hr pain 
endpoints. 
1.2 
CGRP’s Role in 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 
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. 


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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 to the study are presented below.  
1.3.1 
Non-clinical Studies 
1.3.1.1 
Non-clinical Pharmacokinetics and Pharmacodynamics 
A series of in vitro and in vivo pharmacokinetic (PK) and metabolism studies were 
conducted with rimegepant in rats, dogs, and monkeys. In addition, rimegepant was 
compared with two different triptans to assess potential to contract coronary vessels.  
While sumatriptan and zolmitriptan exhibited progressive contraction of human coronary 
vessels at increasing concentrations, the CGRP receptor antagonist compounds leading 
up to identification of rimegepant did not induce any changes in the baseline tension in 
human coronary vessels even at very high (10 uM) concentrations.  Rimegepant was 
tested using the identical protocols in dog coronary artery (when viable human tissues 
were not available) and no vessel contraction was observed, in contrast to the triptans 
which again showed progressive concentration-dependent constriction. These data 
provide direct evidence that rimegepant acts without the undesirable effect of active 
vasoconstriction associated with treatment by triptans. Please refer to the most current 
version of the Investigator Brochure for further details. 
1.3.1.2 
Non-clinical Toxicology 
The nonclinical toxicity of rimegepant was comprehensively evaluated in a series of 
single- and repeat-dose oral toxicity, genetic toxicity, phototoxicity, and safety 
pharmacology studies. Rimegepant is not genotoxic or phototoxic and has a low potential 
for off-target receptor interactions or adverse effects on the cardiovascular, respiratory, 
and central nervous (CNS) systems. Please refer to the most current version of the 
Investigator Brochure for further details.  
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1.3.2.7.1 
CN170003 
Study CN170003 [3] was a double-blind, randomized, placebo-controlled, dose-ranging 
trial of rimegepant for the acute treatment of migraine.  The primary objective was to 
evaluate the efficacy of rimegepant compared with placebo in the acute treatment of 
migraine as measured by pain freedom (head pain intensity level reported as “no pain”) at 
2 hours post-dose using a four point rating scale (no pain, mild pain, moderate pain, 
severe pain) while identifying an optimal dose to support the Phase 3 clinical trials. 
Subjects were randomized to receive placebo, sumatriptan 100 mg or rimegepant (10 mg, 
25 mg, 75 mg, 150 mg, 300 mg, or 600 mg).  Randomization made use of an adaptive 
design, whereby one quarter of subjects were assigned placebo and one-eighth were 
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assigned sumatriptan; the remainder were assigned to one of six rimegepant groups based 
on a Bayesian analysis of the observed response rates. Subjects were instructed to treat 
one migraine of moderate or severe pain intensity and then return to the clinic within 7 
days.  
A total of 885 subjects were randomized and 812 completed the study. 
A broad and durable efficacy profile for rimegepant was demonstrated to be fully present 
at 75 mg [1].  This dose was selected as the optimal dose to support Phase 3 clinical 
trials, given that larger doses showed a similar efficacy profile and there was negligible 
benefit identified with larger doses, consistent with previously published migraine studies 
characterizing the dose-response profiles of acute treatments for migraine [8].   
Rimegepant at 75 mg showed statistically significant efficacy across all four traditional 
endpoints at 2 hr (pain, nausea, photophobia and phonophobia) which was durable and 
persisted through 24 hr.  At 2 hr following a single oral dose of 75 mg, patients who 
previously were experiencing moderate-to-severe migraine pain had no-pain (31.4% p < 
0.0018) or mild-to-no-pain (72.1% = < 0.0007) as compared to placebo (15.2% and 
51.2%, respectively) (Figure 1).   
Figure 1:  
Phase 2b Primary Endpoint: Rimegepant Pain Freedom at 2 
hours Post Dose (+/- 95% Confidence) 
 
In conclusion, Study CN170003 [3] demonstrated that rimegepant is superior to placebo 
in the acute treatment of migraines. The selection of 75 mg rimegepant as the dose for the 
Phase 3 pivotal efficacy studies is based on reliably demonstrated efficacy on the key 
primary outcome measure, Pain Freedom at 2 hours (31.4% vs 15.3% placebo; p = 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
  
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 


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0.0018), durability of effect as well as benefit on secondary outcome measures as 
presented above (see also Section 1.4.2).   
1.3.4 
Clinical Adverse Event Profile 
To date, 7 clinical studies have been completed in healthy volunteers and migraineurs 
that inform PK, metabolic interactions, safety, tolerability and efficacy. In total, the 
current data suggests a favorable benefit-risk profile for rimegepant in the acute treatment 
of migraine attacks.  Efficacy was established in Study CN170003, and the overall 
database suggests a favorable safety profile. Clinical experience with rimegepant has also 
allowed the characterization of safety and tolerability at substantial multiples of the 
intended therapeutic exposure and intended frequency of use. Rimegepant has been 
assessed in single doses up to 1500 mg and in multiple doses from 75 mg to 600 mg with 
14-days of dosing (including 300 mg twice daily), where the higher doses yielded 
exposures more than 60 times greater in AUC and 30 times higher in Cmax as compared 
to the mean therapeutic exposure of a single 75 mg dose.  These high exposure multiples 
were generally well tolerated and safe. 
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Rimegepant appears to be generally safe and well tolerated in humans when given as 
single oral doses up to the maximum dose of 1500 mg and multiple oral doses up to the 
maximum daily dose of 600 mg for 14 days. Please refer to the Investigators Brochure for 
a summary of the clinical safety profile.  
The primary identified AE of interest is potential change in liver function tests. 
Investigators must carefully monitor routine liver function tests (ALT, AST, total 
bilirubin, and ALP) and potentially liver related symptoms and signs. Clinicians should  
also monitor changes in hematology and other laboratory measures. Please refer to the 
current Investigators Brochure for further information regarding the clinical safety profile 
of rimegepant. 
1.4 
Study Rationale 
Migraine is a chronic and debilitating disorder characterized by recurrent attacks lasting 
four to 72 hours with multiple symptoms, including typically one-sided, pulsating 
headaches of moderate or severe pain intensity that are associated with nausea or 
vomiting, and/or sensitivity to sound (phonophobia) and sensitivity to light 
(photophobia). The World Health Organization’s (WHO) Global Burden of Disease 
Study ranks migraine as the third most prevalent disease worldwide [9] and the Global 
Burden of Disease Survey 2010 rates migraine as the seventh highest specific cause of 
disability worldwide.  Annually, migraines affect approximately 15% of the adult 
population in the United States [10], comprising approximately 33 million adults.  
Approximately 62% of migraineurs have one or more attack per month, and 
approximately 25% have one or more per week [11].  Approximately 80% of individuals 
are unable to work or function normally during a migraine attack, with 53% reporting 
severe impairment and/or requiring bedrest [12, 13]. Comorbid conditions associated 
with migraine include depression, anxiety and cardiovascular disease [14].  
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While there are multiple classes of medications for the acute treatment of migraine, 
considerable unmet need remains, as evidenced by migraines being the seventh leading 
cause of disability worldwide [9].  In part, this burden is attributed to limitations of 
current standard-of-care pharmacotherapies, which are contraindicated for use in over 2.6 
million American migraine sufferers with known cardiovascular disease as well as many 
others with multiple cardiovascular (CV) risk factors.  The US Prescribing Information 
(USPI) for triptans includes warnings and precautions for migraine patients with risk 
factors for cardiovascular disease and states that high risk patients, including those with 
increased age, diabetes, hypertension, smoking, obesity or a strong family history of 
coronary artery disease, should be evaluated prior to receiving the first dose of a triptan. 
Triptans are contraindicated in patients with a history of ischemic heart disease, coronary 
artery vasospasm, history of stroke, peripheral vascular disease or uncontrolled 
hypertension. Even in patients who have a negative cardiovascular evaluation, product 
labeling for triptans recommends that consideration be given to administration of the first 
dose in a medically-supervised setting and performing an electrocardiogram immediately 
following administration. Additionally, periodic cardiovascular evaluation should be 
considered for long-term users of triptans who have cardiovascular risk factors. 
According to a recent study published in the journal Headache, an estimated 2.6 million 
migraine sufferers in the United States have a cardiovascular event, condition or 
procedure that limits the potential of triptans as a treatment option. Thus, there remains a 
significant unmet medical need for a novel migraine-specific medication that does not 
increase the risk of cardiovascular liability. 
Biohaven is developing a small molecule CGRP receptor antagonist, rimegepant, for the 
acute treatment of migraine that is expected to address these cardiovascular limitations.  
As discussed in Section 1.3.1.1, nonclinical studies show that rimegepant is not 
associated with adverse vasoconstrictive properties that are thought to cause the serious 
cardiovascular adverse events of the triptan class and does not share a mechanism with 
other agents of cardiovascular concern such as non-steroidal anti-inflammatories 
(NSAIDs) and ergotamine derivatives.  A completed Phase 2 trial [3] demonstrated the 
efficacy of rimegepant in the acute treatment of migraine, with and without aura, at doses 
of 75 mg and above.   Doses above 75 mg were not associated with clinically significant 
differences in efficacy and therefore 75 mg is the selected dose for Phase 3.   
The open label, long-term safety study proposed herein will further assess the safety of 
rimegepant (75 mg) for the acute treatment of migraine. This study is being conducted to 
further characterize the safety and tolerability of rimegepant during longer term treatment 
of patients with migraine. Importantly, it will help define the safety profile of rimegepant 
dosing on an as needed (up to daily basis for a period up to 1 year. Approximately 200 
subjects will dose at least every other day, but not more than once per calendar day, for a 
period of approximately 12 weeks.  


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1.4.1 
Study Design Rationale 
This is a multicenter, open label evaluation of the safety and tolerability of long term use 
of rimegepant 75 mg tablet taken as needed (up to one 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 study will also evaluate at least every other day dosing in 
approximately 200 patients for up to 12 weeks. Up to approximately 2000 patients will be 
assigned treatment, in this study.  
1.4.2 
Dose Selection Rationale 
Study CN170003 was a double-blind, randomized, placebo-controlled, dose-ranging trial 
of rimegepant for the acute treatment of migraine [1].  The primary objective was to 
evaluate the efficacy of rimegepant compared with placebo in the acute treatment of 
migraine as measured by pain freedom (head pain intensity level reported as “no pain”) at 
2 hours post-dose using a four point rating scale (no pain, mild pain, moderate pain, 
severe pain) while identifying an optimal dose to support the Phase 3 clinical trials. 
Subjects were randomized to receive placebo, sumatriptan 100 mg or rimegepant (10, 25, 
75, 150, 300, or 600 mg).  Randomization made use of an adaptive design, whereby one 
quarter of subjects were assigned placebo and one-eighth were assigned sumatriptan; the 
remainder were assigned to one of the six rimegepant groups based on a Bayesian 
analysis of the observed response rates. Subjects were instructed to treat one migraine of 
moderate or severe pain intensity and return to the clinic within 7 days.  
A total of 885 subjects were randomized and 812 completed the study.  Key entry criteria 
were very similar to those chosen for this clinical trial. 
A comprehensive and durable efficacy profile for rimegepant was demonstrated to be 
fully present at 75 mg but not at lower doses (i.e., 10 mg or 25 mg). This dose was 
selected as the optimal dose to support Phase 3 clinical trials, given that larger doses (150 
mg, 300 mg, 600 mg) showed a similar efficacy profile and there was no pattern of added 
benefit in dosing higher, consistent with previously published migraine studies [8].  
rimegepant at 75 mg showed statistically significant broad efficacy across all four 
traditional endpoints at 2 hr (pain, nausea, photophobia and phonophobia) which was 
durable and persisted through 24 hr.  At 2 hr following a single oral dose of 75 mg, 
patients who previously were experiencing moderate-to-severe migraine pain had no-pain 
(31.4% p = 0.0018) or mild-to-no-pain (72.1%) as compared to placebo (15.3% and 
51.2%, respectively). For the 75 mg dose at 2 hr, patients also showed significant 
freedom from nausea (67.4%, p = 0.0074) freedom from phonophobia (52.3%, p = 
0.0001) and freedom from photophobia (41.9%, p = 0.0023) vs. placebo (51.2%, 28.1% 
and 24.1%, respectively).  The lasting nature of these beneficial anti-migraine effects 
were evidenced by a comparatively similar efficacy profile in the 2-24 hr measures, 
where rimegepant at 75 mg produced significant 2-24 hr sustained pain freedom (27.9%, 
p < 0.0001) and 2-24 hr sustained pain relief (69.8%, p < 0.0001) vs. placebo (7.4% and 
42.4%, respectively).   


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1.4.3 
Other Rationale related to the compound/study 
Prior to initiation of Phase 3, a Phase 1 crossover study to assess the safety, tolerability 
and pharmacokinetics of a single dose of the rimegepant tablet in healthy volunteers will 
be conducted to ensure PK comparability with the previously studied capsule (rimegepant  
free-base). The Investigator Brochure will be updated to include these study results when 
available.  
1.5 
Research Hypothesis 
Long term treatment dosing with rimegepant, up to one tablet per day, is safe and well 
tolerated in the acute treatment of migraine.  


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2 STUDY OBJECTIVE 
2.1 
Primary 
To evaluate the safety and tolerability of rimegepant. 
2.2 
Secondary 
Secondary Objectives: 
• To evaluate the frequency of elevations in ALT or AST > 3x ULN with 
concurrent elevations in bilirubin > 2x ULN in subjects treated with rimegepant. 
• To evaluate the frequency and severity of hepatic-related adverse events and the 
frequency of hepatic-related treatment discontinuations.  
Exploratory Objectives: 
• To evaluate the frequency of subjects with elevated liver function tests (AST, 
ALT or total bilirubin).   
• To evaluate the frequency of subjects with ALT or AST elevations > 3x ULN in 
temporal association with nausea, vomiting, anorexia, abdominal pain or fatigue. 
• To explore the contributions of gender, age and exposure to rimegepant to 
abnormalities in AST, ALT, or bilirubin. 
• To investigate the time on treatment and cumulative exposure associated with: (1) 
hepatic related SAEs and treatment discontinuations; (2) elevations in ALT or 
AST > 3x ULN with concurrent elevations in bilirubin > 2x ULN. 
• To evaluate the number of headache days and severity of migraine attacks while 
subjects are treated with rimegepant relative to the observational period. 
• To evaluate the effect of rimegepant treatment compared to baseline on the 20-
Item Migraine-Specific Quality of Life Questionnaire v 2.1 (MSQoL). 
• To evaluate the effect of rimegepant treatment compared to baseline on the 
Migraine Preference of Medication (PoM). 


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• To examine the scores on the Sheehan Suicidality Tracking Scale. 
• To evaluate the effect of rimegepant treatment compared to baseline on the 
Satisfaction with Medication survey. 
• To evaluate the effect of rimegepant treatment compared to baseline on the 
Migraine Disability Assessment (MIDAS) 
• To evaluate the effect of rimegepant treatment compared to baseline on the 
Clinical Global Impression – change (CGI-c) scale. 
 
 


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3 STUDY ENDPOINTS  
3.1 
Primary 
The frequency and severity of adverse events that occur in at least 5% of treated subjects, 
the frequency of serious adverse events, adverse events leading to discontinuation and 
clinically significant laboratory abnormalities during the treatment period will be 
assessed. The frequency of AEs and SAEs are determined from case report forms, and are 
tabulated based on the number of unique subjects. The frequency of clinically significant 
laboratory abnormalities are determined from laboratory data, and are also tabulated 
based on the number unique subjects. 
3.2 
Secondary 
The frequency of AST or ALT elevations above 3x ULN, concurrently with bilirubin 
elevations above 2x ULN, will be assessed by tabulating the number of unique subjects 
with this pairing of events.    
The frequency of hepatic related adverse events and hepatic related treatment 
discontinuations will be tabulated from case report forms and will be based on unique 
subjects reporting such events. 
3.3 
Measures of Interest 
Not Applicable 
 


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4 STUDY PLAN 
4.1 
Study Design and Duration 
This is a multicenter, open-label study to assess the safety and tolerability of long term 
use of rimegepant, taken up to one tablet per calendar day, in patients with migraine. 
The Screening phase includes a screening visit and a 30 day Observation Period. For 
subjects to be eligible for the study, they must have 2-14 migraine attacks of moderate to 
severe intensity per month in the 3 months prior to the Screening Visit. Patients enrolled 
in the every other day dosing group must have had 4-14 migraine attacks of moderate to 
severe intensity per month within the 3 months prior to the screening visit.  Enrollment 
into this study will initially be open to patients with 2-8 moderate to severe migraine 
attacks per month (primarily the patients from BHV-3000-301 and BHV-3000-302) for 
approximately three months. After approximately three months, study enrollment will 
open for patients with a history of 9-14 migraine attacks of moderate to severe intensity 
per month within the 3 months prior to the screening visit. Lastly, study enrollment will 
open for subjects in the every other day dosing group (4-14 moderate to severe 
migraines/month). 
Upon completion of the screening visit, patients will be provided an eDiary to document 
on each day of the 30 day Observation Period if a migraine occurred, the migraine 
intensity and if the migraine was treated. Patients will record the standard of care 
migraine treatment received on a paper diary. After completing the 30 day Observational 
Period, the patient will return to the clinic with both diaries for the Baseline Visit. At the 
Baseline Visit, eligibility for continued participation in the study will be assessed before 
study medication will be dispensed. After the investigator reviews the results of the 
baseline laboratory assessments and determines continued eligibility, the site staff will 
inform the patient whether or not they are eligible to start dosing in the Long Term 
Treatment phase. If eligible for the Long Term Treatment Phase, in the 2-8 or 9-14 
moderate to severe migraines/month groups, patients will be instructed that they can take 
study medication at the onset of a migraine (of mild to severe intensity). Patients can take 
a maximum of one tablet of rimegepant per day during the 52 week Long Term 
Treatment phase at the onset of a migraine (mild, moderate or severe intensity).  
Patients in the every other day dosing group (history of 4-14 moderate to severe 
migraines/month) will be instructed that they must take one tablet of rimegepant every 
other calendar day, regardless of whether or not the patient has a migraine. If patients in 
this group have a migraine on a day that they are not scheduled to dose with rimegepant, 
they may take a rimegepant tablet to treat a migraine of mild, moderate or severe 
intensity. Therefore, patients in this group can take a maximum of one tablet of 
rimegepant per calendar day for up to 12 weeks.  
Patients are required to record their migraine occurrence and severity and all study 
medication doses in the eDiary and are required to continue to record the standard of care 
migraine treatment taken on a paper diary. Patients will also use the eDiary to complete 


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the Preference of Medication (PoM) questionnaire and the Satisfaction with Medication 
(SM) questionnaire at specified study timepoints. 
At select study visits, patients will complete or will be administered the Migraine-
specified Quality-of-Life Questionnaire v 2.1 (MQoLQ), the Migraine Disability 
Assessment (MIDAS), Clinical Global Impressions-change (CGI-c) scale, and the 
Sheehan Suicidality Tracking Scale (S-STS) on paper forms, at specified study visits.   
Additional assessments and visit schedule are outlined in the procedural table in Section 
4.3. Procedures include study personnel review of the eDiary and paper diary with the 
patient, assessment of study medication compliance, monitoring of tolerability and safety 
(including vital signs, laboratory tests, and electrocardiography). Study visits will be 
approximately every two weeks during the first month and then every 4 weeks until 
Week 52 for subjects in the 2-8 moderate to severe migraine/month group or the 9-14 
moderate to severe migraine/month group.  
Study visits will be approximately every two weeks during the first month and then every 
4 weeks until Week 12 for subjects in the every other day dosing group (those with 
history of 4-14 moderate to severe migraines/month). 
Patients will return to the study site at the end of Week 52 (or Week 12 for subjects in the 
every other day dosing group (history of 4-14 moderate to severe migraines/month)) (+/- 
7 days) for the End of Treatment Visit. There is a Follow-up Visit 14 days (+/- 2 days) 
after the Week 12/52/EOT Visit. 
To closely monitor for potential drug induced liver injury, guidance on reporting 
potential drug-induced liver injury (DILI) events is provided in the protocol. Lab results 
that meet predefined LFT abnormality criteria as DILI should be reported as a serious 
adverse event (SAE). See Section 8.1.5, Potential Drug Induced Liver Injury (DILI). 


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4.2 
Study Schematic 
Figure 2:  
Study Schematic (Up to 52 Weeks Treatment for 2-8 and 9-14 
moderate to severe migraines/month groups)  
 
 
Figure 3:  
Study Schematic  (Up to 12 Weeks Treatment for the 4-14 
moderate to severe migraines/month, every other day dosing 
group) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 






 
 
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Procedure 
 
Screening 
Visit 
Observational 
Period 
(30 days, +/- 2 
days) 
Baseline 
Visit 
(Day 1) 
Phone visit to 
confirm 
eligibility 
based on 
laboratory 
criteria1 
Week 2 
(Day 15 
+/- 2 
days) 
Week 4 
(Day 
29 +/- 2 
days) 
Weeks 8, 12, 
16, 20, 24, 
28, 32, 36, 
40, 44, 48, 52 
(or Early 
Termination) 
(all visits +/- 
7 days) 
Week 2 
Follow-up 
Safety Visit 
(14 days 
after EOT  
visit +/- 2 
days) 
only) 
Liver function tests (LFTs)  
X7 
 
X 
 
X 
X 
X 
X 
Lipid panel 
 
 
X 
 
 
 
X (Weeks 24 
and 52/early 
termination 
only) 
 
ECG 
X 
 
X 
 
 
X 
X (Weeks 24 
and 52/early 
termination 
only) 
X 
Urinalysis 
 
 
X 
 
 
 
X (Week 
52/early 
termination 
only) 
 
                                                          
7 If the end of treatment laboratory tests from BHV-3000-301/-302 were done within 2 weeks of the screening visit for BHV-3000-201, the labs do not need to be 
completed at screening.  






 
 
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Procedure 
 
Screening 
Visit 
Observational 
Period 
(30 days, +/- 2 
days) 
Baseline 
Visit 
(Day 1) 
Phone visit to 
confirm 
eligibility 
based on 
laboratory 
criteria1 
Week 2 
(Day 15 
+/- 2 
days) 
Week 4 
(Day 
29 +/- 2 
days) 
Weeks 8, 12, 
16, 20, 24, 
28, 32, 36, 
40, 44, 48, 52 
(or Early 
Termination) 
(all visits +/- 
7 days) 
Week 2 
Follow-up 
Safety Visit 
(14 days 
after EOT  
visit +/- 2 
days) 
Daily report of migraine 
occurrence and severity  
reported by patient in eDiary15  
 
 
X 
X 
 
X 
X 
X 
 
 
 Migraine Specified Quality of 
Life Questionnaire (MQoLQ) 
v 2.1 
 
 
X 
 
 
 
X (Weeks 12, 
24, 36 and 
52/early 
termination 
only) 
 
Preference of Medication 
(PoM) 
 
 
 
 
 
 
 
 
X (Weeks 24 
and 52/early 
termination 
only) 
 
Satisfaction with Medication 
(SM) Survey 
 
 
 
 
 
 
X (Weeks 24 
and 52/early 
termination 
only) 
 
                                                          
15 The electronic patient diary will be dispensed at the Screening Visit, after all Screening Procedures are completed. The patient will be trained on the use of the 
eDiary. The patient will use the eDiary every day during the Observation Phase and Long Term Treatment Phase to report migraine occurrence, migraine severity 
and if the patient treated the migraine. 
 


 
 
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Procedure 
 
Screening 
Visit 
Observational 
Period 
(30 days, +/- 2 
days) 
Baseline 
Visit 
(Day 1) 
Phone visit to 
confirm 
eligibility 
based on 
laboratory 
criteria1 
Week 2 
(Day 15 
+/- 2 
days) 
Week 4 
(Day 
29 +/- 2 
days) 
Weeks 8, 12, 
16, 20, 24, 
28, 32, 36, 
40, 44, 48, 52 
(or Early 
Termination) 
(all visits +/- 
7 days) 
Week 2 
Follow-up 
Safety Visit 
(14 days 
after EOT  
visit +/- 2 
days) 
Clinical Global Impression – 
change (CGI-c)  
 
 
 
 
 
 
X (Weeks 12, 
24, 36 and 
52/early 
termination 
only) 
 
Migraine Disability 
Assessment (MIDAS) 
 
 
X 
 
 
 
X (Weeks 12, 
24, 36 and 
52/early 
termination 
only) 
 
 
 
 
 
 
 
 
 
 
 


 
 
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Table 2:  
Schedule of Assessments (for 4-14 moderate to severe migraines/month (every other day dosing) 
group) 
Procedure 
Screening 
Visit 
Observational 
Period (30 
days, +/- 2 
days) 
Baseline 
Visit 
(Day 1) 
Phone visit to 
confirm 
eligibility based 
on laboratory 
criteria 
Week 2 
(Day 15 +/- 
2 days) 
Week 4 
(Day 29 
+/- 2 
days) 
Weeks 8 and 
12 (or Early 
Termination) 
(all visits +/- 7 
days) 
Week 2 
Follow up 
Safety 
Visit (14 
days after 
EOT visit 
+/- 2 days) 
Eligibility Assessments 
 
 
 
 
 
 
 
 
Informed Consent 
X 
 
 
 
 
 
 
 
Inclusion/Exclusion Criteria 
X 
 
X 
X 
 
 
 
 
Medical History 
X 
 
 
 
 
 
 
 
Migraine History 
(signs/symptoms/prior 
treatment/frequency/intensity) 
 
X 
 
 
 
 
 
 
 
 
Prophylactic and standard of 
care migraine medication 
recorded on paper diary/ 
Concomitant Medication16 
X 
X 
X 
 
X 
X 
X 
X17 
Safety Assessments 
 
 
 
 
 
 
 
 
Physical Examination 
X18 
 
X 
 
 
X 
X (Week 12 
/early 
 
                                                          
16 Concomitant medication, including prophylactic and standard of care migraine medication, taken during the Observational Period and Long term treatment 
phase should be recorded the patient’s paper diary and reviewed by the study personnel at each study visit 
17 Collect if treatment with conmed is required for an AE or if conmed is considered related to AE 
18 If the end of treatment physical exam from BHV-3000-303 was done within 4 weeks of the screening visit for BHV-3000-201, it does not need to be 
completed at screening. 


 
 
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Procedure 
Screening 
Visit 
Observational 
Period (30 
days, +/- 2 
days) 
Baseline 
Visit 
(Day 1) 
Phone visit to 
confirm 
eligibility based 
on laboratory 
criteria 
Week 2 
(Day 15 +/- 
2 days) 
Week 4 
(Day 29 
+/- 2 
days) 
Weeks 8 and 
12 (or Early 
Termination) 
(all visits +/- 7 
days) 
Week 2 
Follow up 
Safety 
Visit (14 
days after 
EOT visit 
+/- 2 days) 
termination 
only) 
Vital Signs19/Physical 
Measurements20 
X 
 
X 
 
 
X 
X 
X 
Clinical Safety Laboratory 
Testing 
X 
 
X 
 
 
X 
 
X (Week 
12/early 
termination 
only) 
 
Liver function tests (LFTs)  
X 
 
X 
 
X 
X 
X 
X 
Lipid panel 
 
 
X 
 
 
 
X (Week 
12/early 
termination 
only) 
 
ECG 
X 
 
X 
 
 
X 
X (Week 
12/early 
termination 
only) 
X 
                                                          
19 If the end of treatment vital signs from BHV3000-303 were done on the same day of the screening visit for BHV3000-201, the vitals do not need to be 
completed at screening. 
20 Height measured at the Screening Visit only. 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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Procedure 
Screening 
Visit 
Observational 
Period (30 
days, +/- 2 
days) 
Baseline 
Visit 
(Day 1) 
Phone visit to 
confirm 
eligibility based 
on laboratory 
criteria 
Week 2 
(Day 15 +/- 
2 days) 
Week 4 
(Day 29 
+/- 2 
days) 
Weeks 8 and 
12 (or Early 
Termination) 
(all visits +/- 7 
days) 
Week 2 
Follow up 
Safety 
Visit (14 
days after 
EOT visit 
+/- 2 days) 
Urinalysis 
 
 
X 
 
 
 
X (Week 
12/early 
termination 
only) 
 
Urine Drug Screen for drugs 
of abuse21 
X 
 
 
 
 
 
 
 
FSH, if applicable, to 
determine WOCBP status22 
X 
 
 
 
 
 
 
 
 
Pregnancy Test 
X (urine) 
 
X (urine 
and 
serum) 
 
 
X (urine) 
X (urine) 
X (urine) 
 
AE and SAE assessment23 
X 
 
X 
 
X 
X 
X 
 
X 
Sheehan Suicidality 
Tracking Scale24 
X 
 
X 
 
X 
X 
X 
X 
Clinical Drug 
 
 
 
 
 
 
 
 
                                                          
21 If the end of treatment urine drug screen from BHV3000-303 was done on the same day of the screening visit for BHV3000-201, the urine drug screen does 
not need to be completed at screening 
22 If WOCBP status was determined in BHV-3000-303, the patient is considered to have the same status in BHV-3000-201. 
23 SAEs and AEs must be reported after patient signs informed consent.  
24 If the end of treatment Sheehan Suicidality Tracking Scale from BHV3000-303 was done on the same day of the screening visit for BHV3000-201, the 
Sheehan Suicidality Tracking Scale does not need to be completed at screening 


 
 
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Procedure 
Screening 
Visit 
Observational 
Period (30 
days, +/- 2 
days) 
Baseline 
Visit 
(Day 1) 
Phone visit to 
confirm 
eligibility based 
on laboratory 
criteria 
Week 2 
(Day 15 +/- 
2 days) 
Week 4 
(Day 29 
+/- 2 
days) 
Weeks 8 and 
12 (or Early 
Termination) 
(all visits +/- 7 
days) 
Week 2 
Follow up 
Safety 
Visit (14 
days after 
EOT visit 
+/- 2 days) 
Supplies/Study Supplies 
Dispense Study 
Medication25 
 
 
X 
 
 
X 
X 
 
Administer study 
medication26  
 
 
 
X 
X 
X 
X 
 
Enter use of study 
medication in eDiary 
 
 
 
X 
X 
X 
X 
 
Return unused study 
medication to site for 
compliance check 
 
 
 
 
X 
X 
X 
 
Electronic Diary Dispensed 
X 
 
 
 
 
 
 
 
Electronic Diary 
returned/reviewed for 
completeness27 
 
 
X 
 
X 
X 
X 
 
                                                          
25 Patients should finish a bottle of study medication before starting a new bottle. Study drug will be dispensed at monthly study visits. Unscheduled visits to 
dispense study medication may be scheduled as needed. 
26 Patients in the 4-14 moderate to severe migraines/month group will be instructed that they must take their study medication every other day, regardless of 
whether or not they have a migraine. If patients in this group have a migraine on a day that they are not scheduled to take a tablet of rimegepant, they may take a 
rimegepant tablet to treat a migraine of mild to severe intensity. Therefore, patients can take a maximum of one tablet of rimegepant per calendar day. Patients 
must report each tablet they take in the eDiary. 
27 Subjects with 6 or more missed evening diary reports per month, for 2 months (sequential or non-sequential months), should be discontinued for lack of study 
compliance. 


 
 
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Procedure 
Screening 
Visit 
Observational 
Period (30 
days, +/- 2 
days) 
Baseline 
Visit 
(Day 1) 
Phone visit to 
confirm 
eligibility based 
on laboratory 
criteria 
Week 2 
(Day 15 +/- 
2 days) 
Week 4 
(Day 29 
+/- 2 
days) 
Weeks 8 and 
12 (or Early 
Termination) 
(all visits +/- 7 
days) 
Week 2 
Follow up 
Safety 
Visit (14 
days after 
EOT visit 
+/- 2 days) 
Other Assessments 
 
 
 
 
 
 
 
 
Daily report of migraine 
occurrence and severity  
reported by patient in 
eDiary28  
 
 
X 
X 
 
X 
X 
X 
 
 
 Migraine Specified Quality 
of Life Questionnaire 
(MQoLQ) v 2.1 
 
 
X 
 
 
 
X (Week 
12/early 
termination 
only) 
 
Preference of Medication 
(PoM) 
 
 
 
 
 
 
 
 
X (Week 
12/early 
termination 
only) 
 
Satisfaction with Medication 
(SM) Survey 
 
 
 
 
 
 
X (Week 
12/early 
termination 
only) 
 
                                                          
28 The electronic patient diary will be dispensed at the Screening Visit, after all Screening Procedures are completed. The patient will be trained on the use of the 
eDiary. The patient will use the eDiary every day during the Observation Phase and Long Term Treatment Phase to report migraine occurrence, migraine severity 
and if the patient treated the migraine. 
 


 
 
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Procedure 
Screening 
Visit 
Observational 
Period (30 
days, +/- 2 
days) 
Baseline 
Visit 
(Day 1) 
Phone visit to 
confirm 
eligibility based 
on laboratory 
criteria 
Week 2 
(Day 15 +/- 
2 days) 
Week 4 
(Day 29 
+/- 2 
days) 
Weeks 8 and 
12 (or Early 
Termination) 
(all visits +/- 7 
days) 
Week 2 
Follow up 
Safety 
Visit (14 
days after 
EOT visit 
+/- 2 days) 
Clinical Global Impression – 
change (CGI-c)  
 
 
 
 
 
 
X (Week 
12/early 
termination 
only) 
 
Migraine Disability 
Assessment (MIDAS) 
 
 
X 
 
 
 
X (Week 
12/early 
termination 
only) 
 
 
 
 
 
 


 
 
 
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4.3.1 
Screening Visit / Observation Period (30 days) 
Approximately 2800 patients will be screened to assign up to approximately 2000 patients to 
rimegepant.  
Before any study procedures are performed, patients must sign informed consent. After 
informed consent, patients will be enrolled in the IWRS system. The patient’s migraine history 
and medical history will be collected at the Screening Visit.  All patients will continue to use 
their migraine prophylactic or standard of care medications during the 30 day observation 
period.  Patients will undergo all screening procedures as detailed in Table 1 and Table 2, after 
which they will be provided an eDiary to document each day during the 30 day Observation 
Phase the occurrence and severity of migraines and if the migraine was treated. Patients will 
also record all migraine standard of care treatments taken during the Observation Phase on a 
paper diary. After completing the 30 day Observation Phase, patients will return to the clinic, 
and both their eDiary and paper diary will be reviewed for completeness.   
If the patient meets inclusion/exclusion criteria, they may enter the Long Term Treatment 
Phase.  
4.3.2 
Long Term Treatment Phase (12 weeks or 52 Weeks) 
Once completing the Screening/Observational Period, patients will return to the study site for 
the Baseline Visit. Patients who continue to meet all inclusion/exclusion criteria and have been 
compliant with the eDiary may enter the Long Term Treatment Phase. At the Baseline Visit, 
patients will be dispensed study medication and will be instructed they cannot take study 
medication until baseline laboratory results confirm study eligibility. After the investigator 
reviews the results of the baseline laboratory assessments and determines the patient’s 
continued eligibility, the site staff will inform the patient whether or not they are eligible to 
start dosing in the Long Term Treatment phase. This contact with the patient must be 
documented in the patient’s medical record.  
There are two different dosing schedules in this study. If eligible, patients in the 2-8 moderate 
to severe migrains/month and 9-14 moderate to severe migraines month groups will be 
instructed that they can take study medication at the onset of a migraine (of mild to severe 
intensity). Patients will also be instructed that they can take a maximum of one tablet of 


 
 
 
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rimegepant per calendar day during the Long Term Treatment Phase at the onset of a migraine 
(mild, moderate or severe intensity).  
Patients in the 4-14 moderate to severe migraines/month group will be instructed that they must 
take one tablet of study drug every other calendar day, regardless of whether they have a 
migraine on that day or not. If patients in this group have a migraine on a day that they are not 
scheduled to dose with rimegepant, they may take a rimegepant tablet to treat a migraine of 
mild, moderate or severe intensity. Therefore, patients can take a maximum of one tablet of 
rimegepant per calendar day for 12 weeks. 
The electronic patient diary will be completed by patients to capture dosing of study medication 
and the frequency and severity of migraines during the Treatment Phase.  
Patients will also use the eDiary to complete the Preference of Medication (PoM) and 
Satisfaction with Medication (SM) questionnaire. The Migraine-Specified Quality of Life 
questionnaire v 2.1 (MSQoL), The Sheehan Suicidality Tracking Scale (S-STS), Migraine 
Assessment Disability (MIDAS) and Clinical Global Impression (CGI-c) will be completed, or 
administered by the investigator, on paper at specified study visits (Table 1 and Table 2).  
Study visits will be approximately every two weeks during the first month and then every 4 
weeks, until Week 52 (Table 1). At each visit the eDiary will be reviewed by site staff for 
completeness and compliance. Study drug compliance and concomitant medication use will be 
reviewed (and compared to the eDiary and paper diary entries) and patient will be dispensed 
additional study drug as needed. Additional safety (including laboratory tests and ECGs) will 
be performed per the schedule outlined in Table 1 and Table 2.  
4.3.3 
End of Treatment (Weeks 12 or 52)  
Patients will return to the study at the end of Week 12 or 52 (+/- 7 days) for review of the 
electronic diary, assessment of medication compliance, assessment of tolerability and safety 
(including vital signs, laboratory tests,  and  electrocardiography) (Table 1 and Table 2). 
Patients will return the unused study medication and electronic patient diary to the study site. 


 
 
 
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4.3.4 
Follow up Safety Visit 
Patients will return to the study site 14 days after the Week 12/52/EOT Visit (+/- 2 days) to 
collect laboratory tests, vital signs, electrocardiography, and AEs. Investigators should assess 
patients for AEs consistent with drug dependency or withdrawal effects and report as 
appropriate (see Section 7.4). 
4.4 
Post Study Access to Therapy (if applicable)  
At the end of the study the sponsor will not continue to supply study drug to patients or 
investigators. The investigator should ensure that the subject receives appropriate standard of 
care to treat the condition under study.  
 
 


 
 
 
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5 POPULATION 
Of the approximately 2000 patients assigned to treatment in this study, approximately:  
- 
1200 will have a history of 2-8 moderate to severe migraine attacks per month,  
- 
600 will have a history of 9-14 moderate to severe migraine attacks per month, and  
- 
200 will have a history of 4-14 moderate to severe migraine attacks per month (every 
other day dosing group). 
5.1 
Number of Subjects 
It is anticipated that up to approximately 2800 patients may be screened in order to assign up to 
approximately 2000 patients to rimegepant.   
5.2 
Inclusion Criteria 
1. Signed Written Informed Consent 
 
a) Written informed consent must be obtained from the patient in accordance with 
requirements of the study center’s institutional review board (IRB) or ethics 
committee, prior to the initiation of any protocol-required procedures. 
2. Target Population 
Patient 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 Edition, beta version 
[2], including the following: 
a) Age of onset of migraines prior to 50 years of age 
b) Migraine attacks, on average, lasting 4 - 72 hours if untreated 
c) 2-14 migraine attacks of moderate or severe intensity per month within the last 
3 months prior to the Screening Visit  


 
 
 
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(participants in the every other dosing group must have a history of 4-14 
moderate to severe migraines/month within the last 3 months prior to the 
Screening Visit in the every other day dosing group) 
d) 2 or more migraine days requiring treatment during Observation Phase  
e) Ability to distinguish migraine attacks from tension/cluster headaches 
f) Patients on prophylactic migraine medication are permitted to remain on 
therapy if the dose has been stable dose for at least 2 months prior to the Baseline 
Visit, and the regimen should not change during the course of the study. 
g) Patients with contraindications for use of triptans may be included provided 
they meet all other study entry criteria 
3. Age and Reproductive Status 
a) Male and female patients ≥ 18 years  
b) Women of childbearing potential (WOCBP) and non-sterile men must be using 
two acceptable methods of contraception to avoid pregnancy throughout the study 
in such a manner that the risk of pregnancy is minimized. See Section 5.6 for the 
definition of WOCBP. Males with vasectomy are considered surgically sterile 
provided the procedure occurred greater than 6 months prior to study 
participation. 
c) At the Baseline Visit, WOCBP must have a negative pregnancy test (minimum 
sensitivity 25 IU/L or equivalent units of HCG) before dosing with study drug 
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 


 
 
 
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interfere with the study procedures (not including exclusion criteria listed in 
Section 5 below) 
5.3 
Exclusion Criteria 
1. Target Disease Exclusion 
a) Patient has a history of basilar migraine or hemiplegic migraine 
2. Medical History and Concurrent Diseases 
a) Patient history of HIV disease 
b) Patient history with current evidence of uncontrolled, unstable or recently 
diagnosed cardiovascular disease, such as ischemic heart disease, coronary 
artery vasospasm, and cerebral ischemia. Patients with myocardial infarction 
(MI), acute coronary syndrome (ACS), percutaneous coronary intervention 
(PCI), cardiac surgery, stroke or transient ischemic attack (TIA) during 6 months 
prior to screening.  
c) Uncontrolled hypertension or uncontrolled diabetes (however, patients can be 
included who have stable hypertension and /or diabetes for 3 months prior to 
screening). Blood pressure greater than 150 mm Hg systolic or 100 mm Hg 
diastolic after 10 minutes of rest is exclusionary. 
d) Patient has a current diagnosis of major depressive disorder or has had a major 
depressive episode within the last 12 months, other pain syndromes, psychiatric 
conditions, dementia, or significant neurological disorders (other than migraine) 
that, in the Investigator’s opinion, might interfere with study assessments 
e) Patient has a history of gastric, or small intestinal surgery, or has a disease that 
causes malabsorption 
f) 
Patients has a history or diagnosis of Gilbert’s Syndrome or any other active 
hepatic or biliary disorder 


 
 
 
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g) The patient has a history or current evidence of any unstable medical conditions 
(e.g., history of congenital heart disease or arrhythmia, known or suspected 
infection, hepatitis B or C, or cancer) that, in the investigator’s opinion, would 
expose them to undue risk of a significant adverse event (AE) or interfere with 
assessments of safety or efficacy during the course of the trial 
h) History of, treatment for, or evidence of, alcohol or drug abuse within the past 12 
months or patients who have met DSM-V criteria [15] for any significant 
substance use disorder within the past 12 months from the date of the screening 
visit 
i) 
Patients should be excluded if they have a positive drug screen for drugs of abuse 
that in the investigator’s judgment is medically significant, in that it would 
impact the safety of the patient or the interpretation of the study results. In 
addition: 
i. 
Detectable levels of cocaine, amphetamine and phencyclidine (PCP) in 
the drug screen are exclusionary. Patients who are positive for 
amphetamines on the urine drug screen may have their urine samples 
evaluated for further analysis at the investigator’s discretion to rule out a 
false positive result 
ii. 
Detectable levels of marijuana in the drug screen are not exclusionary, if 
in the investigator’s documented opinion the patient does not meet DSM-
V  criteria [15] for substance abuse or dependence; in the investigator’s 
documented opinion, the positive test does not signal a clinical condition 
that would impact the safety of the patient or interpretation of the study 
results. 
j) Hematologic or solid malignancy diagnosis within 5 years prior to screening. 
Subjects with a history of localized basal cell or squamous cell skin cancer are 
eligible for the study if they are cancer-free prior to the screening visit in this 
study. 


 
 
 
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k) Patient has current diagnosis of schizophrenia, major depressive disorder 
requiring treatment with atypical antipsychotics, bipolar disorder, or borderline 
personality disorder 
l) Body mass index > 30 kg/m2 
m) History of gallstones or cholecystectomy  
3. Allergies and Adverse Drug Reactions 
a) History of drug or other allergy which, in the opinion of the investigator, makes 
the subject unsuitable for participation in the study 
4. Sex and Reproductive Status 
a) WOCBP who are unwilling or unable to use an acceptable contraceptive method 
or abstinence to avoid pregnancy for the entire study period and for up to 8 weeks 
after last dose of study medication 
b) Women who are pregnant or breastfeeding.  
c) Women with a positive pregnancy test at screening or prior to study drug 
administration 
5. ECG and Laboratory Test Findings 
a) Estimated glomerular filtration rate (eGFR) according to the re-expressed 
abbreviated (four-variable) Modification of Diet in Renal Disease (MDRD) Study 
equation ≤ 40 ml/min/1.73m
2 
 
b) Corrected QT interval > 470 msec (QTc by method of Frederica), at Screening 
c) Left Bundle Branch block 
d) Right Bundle Branch Block with a QRS duration ≥ 150 msec. 
e) Intraventricular Conduction Defect with a QRS duration ≥ 150 msec. 
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f) Serum bilirubin (Total, Direct or Indirect) bilirubin > 1 x ULN (Only abnormal 
values of between 1-1.5x ULN may be repeated once for assessment of eligibility 
during the screening period.)  
g) Neutrophil count ≤ 1000/µL (or equivalent). 
h) AST or ALT > 1 x ULN (Only abnormal values of between 1-1.5x ULN may be 
repeated once for assessment of eligibility during screening period.) 
i) HbA1c > 6.5% 
6. Other Exclusion Criteria 
a) Prisoners or subjects who are involuntarily incarcerated 
b) Subjects who are compulsorily detained for treatment of either a psychiatric or 
physical (e.g., infectious disease) illness 
c) Non-compliance with or inability to complete eDiary during Observation Period. 
Non-compliance is more than 4 missed evening reports during the Observation 
Period. 
d) Exposure to non-biological investigational agents (other than rimegepant) within 
the 30 days prior to Screening visit. 
e) Exposure to biological investigational agents within the 90 days prior to 
Screening visit.  
f) Score of > 0 on the Sheehan Suicidality Tracking Scale (See Section 6.2.5) for the 
period of 30 days prior to screening.  
g) Previous enrollment in study BHV3000-201.  
h) Participation in any other investigational clinical trial while participating in this 
clinical trial.  
Please see Section 5.4  for Prohibited medications and Section 5.5 for allowable migraine 
Medications 
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5.4 
Prohibited Concomitant Medication  
The medications listed below are prohibited starting at the Baseline visit and during the course 
of this study or as specified.  
1. St. John’s Wort should not be taken 14 days prior to the Baseline visit and throughout 
the study.  
2. Butterbur root or extracts should not be taken 14 days prior to the Baseline visit and 
throughout the study. 
3. History of use of ergotamine medications on > 10 days per month on a regular basis 
for > 3 months 
4. Use of narcotic medication, such as opioids (e.g. morphine, codeine, oxycodone and 
hydrocodone) for at least 2 days prior to baseline visit.  
5. Use of acetaminophen or acetaminophen containing products for non-migraine 
indications after the Baseline visit is prohibited. Any use of acetaminophen or 
acetaminophen containing products for non-migraine indications during the 
Observation Phase must be stopped at least 2 days prior to baseline visit. 
Acetaminophen as a standard of care migraine medication as described in Section 5.5 
is allowed during the Long-Term Treatment phase.  
6. Use of triptans is prohibited during the Long Term Treatment phase.  
7. Use of marijuana is prohibited during the study.  
8. Concomitant use of strong CYP3A4 inhibitors with rimegepant is prohibited during 
the study. If use of a 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 the strong CYP3A4 inhibitor. Please see Appendix 3. 
9. Concomitant use of strong CYP3A4 inducers with rimegepant is prohibited during the 
-
-


 
 
 
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study. If use of a strong CYP3A4 inducer is required, such as use of carbamazepine, 
phenytoin, or rifampin, dosing with rimegepant should be stopped and should not start 
again until 14 days after the last dose of the strong CYP3A4 inducer. Please see 
Appendix 3. 
10. Concomitant use of atypical antipsychotics such as Abilify (aripiprazole), Zyprexa 
(olanzapine), Seroquel (quetiapine), Geodon (ziprasidone), or Risperdal (risperidone) 
or Depakote/Depakene (valproic acid/valproate) during the long-term treatment phase. 
11. Concomitant use of LAMICTAL (lamotrigine) is prohibited during the study. 
5.5 
Prophylactic and Standard of Care Migraine Medications 
Patients on prophylactic migraine medication are permitted to remain on therapy if the dose has 
been stable for at least 2 months prior to the Baseline Visit, and the regimen should not change 
during the course of the study.  
Patients may take their previously prescribed standard of care medications: aspirin, ibuprofen, 
acetaminophen up to 1000 mg/day for a maximum of 2 consecutive days at a time (this 
includes Excedrin Migraine), naprosyn (or any other type of non-steroidal anti-inflammatory 
(NSAID)), antiemetics (e.g. metoclopramide or promethazine) or muscle relaxants for standard 
of care during the course of the study (Observation Period and Long Term Treatment Phase).   
Use of triptans by patients without a contraindication to their use is allowed during the 
Observation Phase but must be discontinued at the baseline visit. As described above, use of 
triptans is prohibited during the Long Term Treatment phase. With the exception of triptans and 
acetaminophen as described in this section, patients are allowed to take standard of care 
migraine treatment, if needed, during the course of the study. 
If a patient takes a tablet of study drug and experiences a migraine later that day, after dosing 
with study drug for the day, the patient should take their standard of care migraine medication 
as described in this section of the protocol. Patients are not allowed to take more than one tablet 
of study medication per calendar day. 


 
 
 
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Use of standard of care medication during Observation Period and Long Term Treatment 
Phase, will be recorded by the patient on a paper diary and reported to the site.  
5.6 
Women of Childbearing Potential 
Women of childbearing potential (WOCBP) include 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. Post 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 > 35mIU/mL at 
screening) or 
2. Woman with irregular menstrual periods and a documented serum follicle 
stimulating hormone (FSH) level > 35mIU/mL (at screening) or 
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 
3. Woman on hormone replacement therapy (HRT) 
Women of childbearing potential (WOCBP) and men must be using two acceptable methods of 
contraception to avoid pregnancy throughout the study and for up to 56 days after the last dose 
of investigational product in such a manner that risk of pregnancy is minimized. It is required 
that all WOCBP use two methods of contraception for the duration of the study (i.e. beginning 
at first treatment to 56 days after the last dose of study drug). The two methods should include 
one barrier method (ex. condom with spermicidal gel, intrauterine devices, cervical cap etc.) 
and one other method. The other method could include hormonal contraceptives or another 
barrier method. 
WOCBP will complete a pregnancy test at Screening, Baseline, Week 4, Week 8 and at study 
visits every 4 weeks through the Week 52/end of treatment visit and at the follow up visit. If a 
WOCBP suspects that she might be pregnant she should immediately contact the study doctor. 
5.7 
Other Restrictions and Precautions (if applicable) 
Not Applicable 


 
 
 
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5.8 
Deviation from Inclusion/Exclusion Criteria and Study Procedures 
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/EC at the frequency required by your IRB/EC. There will be no protocol exceptions 
granted by the Sponsor for Inclusion/Exclusion criteria. 


 
 
 
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6 STUDY CONDUCT AND DESCRIPTION OF STUDY PROCEDURES 
6.1 
 Study Materials  
The following study materials will be provided at the study start: 
• Investigator File/Regulatory Binder 
• Pharmacy Binder 
• Drug Accountability Logs 
• Sample source documents, where applicable 
• Investigator Brochure 
• Interactive Web-based Response System (IWRS) 
• Electronic Case Report Form (eCRF) instructions 
• Electronic Diary: hand held electronic device (1 will be given to each patient) 
• Instructions for the  eDiary device and access to the portal 
• Paper diary to record standard of care migraine medications 
• Laboratory Kits and Laboratory Manual 
• ECG Machine and Instructions 
• Serious Adverse Event (SAE) forms 
• Pregnancy Surveillance Forms 
• Sheehan Suicidality Tracking Scale (S-STS) forms 


 
 
 
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• MIDAS forms 
• CGI-c forms 
All sites will use an Electronic Data Capture (EDC) tool to submit study data to the CRO. 
Electronic Case Report Forms (eCRFs) will be prepared for all data collection fields including 
Serious Adverse Events (SAE) Reporting. SAE data (including queries) will be submitted to 
the CRO using eCRFs.  
The eDiary will be used to record all study medication dosing, to complete select patient-rated 
scales, and record migraine occurrence and severity. Any assessment completed by the patient 
in the eDiary will be transferred from the site/patient to the vendor and from the vendor to the 
CRO and Sponsor. No additional source documents are required for scales and assessments 
completed by the patient on the eDiary. 
Safety laboratory, plasma, serum, instructions for all specimens collected will be provided by a 
designated central laboratory. ECG equipment, supplies, instructions and training materials will 
be supplied by a centralized ECG vendor. 
6.2 
Safety Assessments 
6.2.1 
Vital Signs and Physical Measurements (Height and Weight) 
Vital signs, body weight and height will be  recorded  at  the  scheduled  visits  as  outlined  in  
Table 1 and Table 2 
6.2.2 
Electrocardiogram (ECG) 
A standard 12-lead ECG will be recorded during the Screening Phase and at all scheduled visits 
as outlined in Table 1 and Table 2. A central ECG service will be utilized for reading all ECGs.  
The over read from the central ECG vendor should be used to determine eligibility for the 
study. The investigator will determine if any ECG abnormalities are clinically significant or 
not. 


 
 
 
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6.2.3 
Physical Exam 
Patients will undergo a routine physical examination during the Screening Phase and at  all 
scheduled visits as outlined in Table 1 and Table 2. PE to include examination of heart, 
abdomen and lungs, with review of any other system to be guided by symptoms. 
6.2.4 
Laboratory Assessments 
6.2.4.1 
Safety Laboratory Testing 
Blood and urine samples will be obtained as outlined in Table 1 or Table 2 for clinical 
laboratory evaluations. A central laboratory vendor will be utilized for this study and a 
laboratory manual will be provided to each site. If possible, patients should be fasting for a 
minimum of 8 hours before labs at Baseline, Weeks 4, 24 and 52/EoT (or Week 12/EoT in 
the 4-14 moderate to severe migraines/month, every other day dosing group). However, if 
a patient is not fasting at a given visit, the blood draw should still be performed, and the non-
fasting status should be documented. 
1. Clinical safety labs:  
Hematology: Hemoglobin, hematocrit, red blood cell count, white blood cell count 
with differential, and platelets;  
Chemistry: Sodium, potassium, chloride, bicarbonate, calcium; glucose, HbA1c, 
BUN (urea), serum creatinine, uric acid, LDH, total protein, albumin, CPK (with 
local lab fractionation, if central lab CK result is > 1.5 x ULN);  
eGFR using the estimated MDRD formula (calculated at central lab); 
2. LFTs: AST, ALT, Alkaline Phosphatase and Bilirubin (Total, Direct, Indirect) 
3. Lipid panel: Cholesterol, LDL, HDL, triglycerides  
4. Urinalysis: pH, specific gravity, ketones, nitrites, urobilinogen, leukocyte esterase, 
protein, glucose, and blood. If blood, protein or leukocytes are positive, reflex to 


 
 
 
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microscopic examination. 
5. Urine Drug Screen: For drugs of abuse 
6. FSH: For WOCBP at screening, to determine WOCBP status 
6.2.4.2 
Pregnancy Testing 
WOCBP will complete pregnancy tests (serum or urine) at specified study visits, prior to taking 
study medication, and as outlined in Table 1 or Table 2. 
6.2.5 
Sheehan Suicidality Tracking Scale   
 
The Sheehan STS (S-STS) is a prospective, patient self-reported or clinician administered 
rating scale that contains 16 questions to track both treatment-emergent suicidal ideation and 
behaviors[16, 17]. The S-STS will be completed on a paper form at the site. At the screening 
visit, the recall period for completing the S-STS is 30 days prior; at all other visits, the recall 
period for completing the S-STS is since the last visit. Any responses other than 0 must be 
immediately evaluated by the investigator. If the investigator determines that a subject is at risk 
of suicide or 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. Any subject with a 
response greater than 0 to any question, excluding Question 2, must be immediately 
be discontinued from the study. Subjects with a response of 1 (“a little”) to Question 2 will be 
discontinued per the investigator’s assessment or if the response persists. Subjects with a 
response greater than 1 on Question 2 will be discontinued from the study immediately. 
 
6.3 
Efficacy Assessments 
Not applicable. 


 
 
 
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6.4 
Other Assessments  
6.4.1 
Daily Migraine Assessment of Severity/Frequency  
The number of headache days and severity of migraine attacks during the period that subjects 
are treated with rimegepant relative to the observational period will be analyzed. 
6.4.2 
Migraine Quality of Life Questionnaire 
Impact of treatment on patient-reported quality of life will be assessed using The Migraine 
Quality of Life Questionnaire (MQoLQ) version 2.1. The MQoLQ is a 15-item instrument that 
has been validated in migraine patients to measure the impact of treatment (within past 4 
weeks) on migraine-specific domains: work, social function, energy, vitality, feelings, 
concerns, and migraine symptoms.[26]    
6.4.3 
Migraine Preference of Medicine 
The Preference of Medication Scale (PoM) is a brief scale that captures the patients' perception 
of whether the medication they are taking has had a greater benefit compared with previous 
medications to treat their pain. The eDiary will be used to evaluate the Preference of 
Medication Scale. 
6.4.4 
Satisfaction with Medication Questionnaire 
The Satisfaction with Medication (SM) Questionnaire is a brief questionnaire that captures the 
patients’ perception of whether they are satisfied with their headache medication. The eDiary 
will be used to evaluate the Satisfaction with Medication Questionnaire.  
6.4.5 
Migraine Disability Assessment Test (MIDAS) 
The Migraine Disability Assessment questionnaire is a retrospective patient self-reported scale 
of 5 questions that measures headache-related disability as lost time due to headache from paid 
work or school, household work and nonwork activities. The MIDAS will be completed on a 
paper form at the site [18]. 


 
 
 
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6.4.6 
Clinical Global Impression – Change (CGI-c) 
The Clinical Global Impression-change scale is a brief observer-rated scale that rates patient 
total improvement relative to the investigator’s past experience with other patients with the 
same diagnosis, with or without collateral information [19].  The CGI-c will be administered by 
the investigator or designee who has been trained on administration and will be completed on a 
paper form, at the site. 
6.5 
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) 
• Any clinical adverse event (AE), laboratory abnormality or intercurrent illness which, in the 
opinion of the investigator, indicates that continued participation in the study is not in the 
best interest of the subject 
• Pregnancy 
• Termination of the study by Biohaven Pharmaceuticals 
• 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 
• No migraine treated with study medication prior to Week 8 visit of Long-Term Treatment 
Phase. 
• Poor compliance with study procedures and visits, including poor completion compliance 
with evening reports in eDiary. Subjects with 6 or more missed evening reports per month, 
in 2 (sequential or non-sequential) months, should be discontinued from the study for poor 
compliance, after discussion with Sponsor.  
• Please see section 6.2.5 for guidance on study discontinuation based on results from the S-
STS. 


 
 
 
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All subjects who discontinue should comply with protocol specified End of Treatment 
procedures as outlined in Table 1 or Table 2. The only exception to this requirement is when a 
subject withdraws consent for all study procedures or loses the ability to consent freely (i.e., is 
imprisoned or involuntarily incarcerated for the treatment of either a psychiatric or physical 
illness


 
 
 
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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 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 rimegepant 75 mg tablet.  
7.1.2 
Non-investigational Product 
Other medications used as support or rescue medication for preventative, diagnostic, or 
therapeutic reasons, as components of the standard of care for a given diagnosis, may be 
considered as non-investigational products. 
In this protocol, non-investigational product(s) is/are: standard of care for migraine treatment. 
7.1.3 
Packaging, Shipment and Storage 
The product storage manager should ensure that the study drug is stored in accordance with the 
environmental conditions (temperature, light, and humidity) as determined by the sponsor. 
Please see the Pharmacy Manual 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. 


 
 
 
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7.2 
Dose and Administration 
7.2.1 
Method of Assigning Patient Identification 
Immediately after written informed consent is obtained and before performing any study-related 
procedures, the site staff must contact the IWRS to enter each subject into the IWRS. Each 
subject will be assigned an unique sequential 4-digit subject number through the IWRS (0001, 
0002, 0003, etc.). This subject number must not be reused for any other participant in the study. 
Patients will maintain their subject number assigned at screening throughout the trial.  
After confirming patient eligibility, registering a subject for Baseline will trigger a container 
number for the study medication. The study drug will be dispensed at baseline and as needed at 
the monthly study visits.  
7.2.2 
Selection and Timing of Dose and Administration 
Study medication (rimegepant) will be assigned via the IWRS. There are no dose adjustments in 
this study and patients will receive 30 tablets of rimegepant in a bottle.  Patients will be 
dispensed study medication at the Baseline Visit, and the patients in the 2-8 and 9-14 moderate 
to severe migraines per month groups will be instructed that they can take the one tablet of 
study medication per calendar day at the onset of a migraine of mild to severe intensity. Patients 
in the in the 2-8 and 9-14 moderate to severe migraines per month groups will dose for up to 52 
weeks. 
Patients in the 4-14 moderate to severe migraine group will also be dispensed study medication 
at the Baseline Visit and will be instructed to dose with one rimegepant tablet every other 
calendar day, regardless of whether they have a migraine on that day or not. If the patients in 
this group have a migraine (mild to severe intensity) on a non-dosing day, they may take a 
rimegepant tablet, for a maximum of one tablet per calendar day. Patients in the 4-14 moderate 
to severe migraines per month group will dose for up to 12 weeks.  
Dosing of study medication is not to occur until after eligibility is confirmed based on the 
subject’s baseline laboratory tests.  
7.2.3 
Dose Modifications 
There will be no dose adjustments in this study. 


 
 
 
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7.2.4 
Dose Interruptions 
If a patient experiences an AE that requires interruption in study medication, the investigator 
should consult with the Sponsor medical monitor to evaluate the need for any additional tests 
prior to re-starting study medication.  
7.3 
Blinding and Unblinding  
Not applicable. 
7.4 
Treatment Compliance 
Responsible study personnel will dispense the study drug.  Patients should finish a bottle of 
study medication before starting a new bottle. Accountability and compliance verification 
should be documented in the patient’s study records.   
Patients must be counseled on the importance of taking the study drug as directed (see Section 
7.2.2). Treatment compliance, review of study medication doses reported in the eDiary and 
through review of returned study medication, should be assessed by site staff at each study visit. 
Discrepancies between doses reported in the eDiary, review of study medication and 
information provided by patient must be documented in the source record. Incorrect or missing 
dosing data and migraine data that are reported in the eDiary will be corrected through either a 
Data Clarification Record or a Medication Reconciliation Form. Investigators, should inform 
study participants that involuntary termination from the study will occur in cases where non-
compliance is identified. Study staff should contact a patient in between the monthly study 
visits if the patient demonstrates non-compliance with the eDiary and document the contact in 
the source, to identify potential lost to follow up patients as early as possible.  
Investigators must monitor patients for possible cases of abuse of study medication (patients 
taking study drug for non-therapeutic purposes, e.g. for psychoactive effects such as high or 
euphoria). Investigators should also assess study drug accountability discrepancies (e.g. missing 
study medication, loss of drug, or non-compliance cases in which more study medication was 
used, as compared to expected). Investigators should obtain more information and explanation 
from patients when there are study drug accountability discrepancies. See Section 8.1.1. 
Cases of potential study medication abuse or overdose (including cases of non-compliance with 
study medication dosing instructions or patients who discontinue treatment without returning 
study medication) should be documented in the source record and reported as an AE or SAE as 
appropriate. Dosing errors (e.g. accidentally taking 2 tablets in one calendar day) should be 
reported as deviations.  


 
 
 
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7.5 
Destruction and Return of Study Drug 
If the study drug (those supplied by the sponsor or sourced by the investigator) are to be 
destroyed 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 BHV Study monitor or the sponsor’s designee 
unless this is against institutional policy.  
All unused and/or partially used study drug may be destroyed on site providing the site has an 
applicable standard operating procedure on file.  


 
 
 
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8 ADVERSE EVENTS 
An Adverse Event (AE) is defined as any new untoward medical occurrence or worsening of a 
pre-existing medical condition in a patient or clinical investigation patient 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.  
Adverse events can be spontaneously reported or elicited during an open-ended questioning, 
examination, or evaluation of a patient.  In order to prevent reporting bias, patients should not 
be questioned regarding the specific occurrence of one or more AEs. 
There are two types of adverse events, Serious Adverse Events (SAE) and Non-Serious Adverse 
Events (AEs).  
8.1 
SERIOUS ADVERSE EVENT 
8.1.1 
Definition of Serious Adverse Event (SAE) 
An SAE is any event that meets any of the following criteria at any dose: 
• Death 
• Life-threatening 
• Inpatient hospitalization or prolongation of existing hospitalization 
• Persistent or significant disability/incapacity 
• Congenital anomaly/birth defect in the offspring of a subject who received rimegepant 
• Other: Important medical events that may not result in death, be life-threatening, or require 
hospitalization, may be considered an SAE when, based upon appropriate medical 
judgment, 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): 
o Intensive treatment in an emergency room or at home for allergic bronchospasm 


 
 
 
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o Blood dyscrasias or convulsions that do not result in inpatient hospitalization 
o Development of drug dependency or drug abuse 
o Potential drug induced liver injury (see Section 8.1.5) 
o Abuse or Overdose of medication 
 Potential study medication abuse (including cases of excessive non-compliance with 
study medication dosing instructions or patients who discontinue treatment without 
returning study medication) should be documented in the source record and reported 
as an AE or SAE as appropriate. Investigators must monitor patients for possible 
cases of abuse of study medication (patients taking study drug for non-therapeutic 
purposes, e.g. for psychoactive effects such as high or euphoria). Investigators 
should obtain more information and explanation from patients when there are study 
drug accountability discrepancies 
 Potential study medication overdose is defined in Section 8.1.3 
Definition of Terms 
 
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 
required 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 


 
 
 
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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. 
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 BHV clinical studies (but may be 
considered non-serious AEs): 
1. 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); 
2. Elective surgery, planned prior to signing consent; 
3. Admissions as per protocol for a planned medical/surgical procedure; 
4. Routine health assessment requiring admission (i.e., routine colonoscopy); 
5. 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 patient’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 during the screening 
period and up to and including the EOT visit. The investigator should report any SAE occurring 
after these time periods that is believed to be related to study drug or protocol-specific 
procedures.   
An SAE report should be completed for any event  where doubt exists regarding its status of 
seriousness.   






 
 
 
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8.1.5 
Potential Drug Induced Liver Injury (DILI) 
Wherever possible, timely confirmation of the initial liver-related laboratory abnormalities 
should occur prior to the reporting of a potential DILI event.  All occurrences of potential 
DILIs, meeting the defined criteria, must be reported as SAEs as per Section 8.1.2.  
Potential drug induced liver injury is defined as:  
1. ALT or AST elevation > 3 times the upper limit of normal (ULN) 
AND 
2. Total bilirubin > 2 times ULN, without initial findings of cholestasis (elevated serum 
alkaline phosphatase) 
AND 
3. No other immediately apparent possible causes of ALT or AST elevation and 
hyperbilirubinemia, including but not limited to, viral hepatitis, pre-existing chronic or 
acute liver disease, or the administration of other drug(s) known to be hepatotoxic.  
If any potential DILI is identified and meets the criteria above, the Biohaven Medical 
Monitor (or designee) should immediately be contacted for further instruction and whether 
the patient must discontinue from the trial and appropriate follow up requirements.  
8.2 
Non-serious Adverse Events 
A non-serious adverse event is an AE not classified as serious.  
8.2.1 
Collection and Reporting of Non-Serious Adverse Events 
The collection of non-serious AE information should begin at the initiation of study drug.  Non-
serious AE information should also be collected from the start of a placebo lead-in phase or 
other observational period intended to establish a baseline status for a patient.  
Non-serious adverse events should be followed until conclusion or stabilization, ore 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.  


 
 
 
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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 patient to have the study drug 
discontinued or interrupted; 
3. Any laboratory abnormality that required the patient to receive specific corrective 
therapy. 
 
 


 
 
 
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9 STATISTICS 
9.1 
General Procedures 
Categorical variables are tabulated with counts and percentages. Continuous variables are 
summarized with univariate statistics (e.g., n, mean, standard error, median, minimum and 
maximum).   
For the calculation of descriptive statistics of observed data, subjects must have a baseline value 
to be evaluable for endpoints based on values and changes from baseline over time. 
Tabulations of the following endpoints present the number of unique subjects with an event: 
protocol deviations; interruptions of study therapy; non-study medications; adverse events; and 
laboratory abnormalities. Thus, for these endpoints, multiple occurrences of the same event are 
counted only once per subject. 
9.2 
Sample Size 
With a sample size of roughly 2000 subjects, and with no events observed, the upper bound of a 
one-sided, 95% confidence interval for zero observations is roughly 0.0015. Hence, this sample 
size is large enough to rule out adverse events that occur at rates greater than 15 cases per 
10,000 patients.  
This study has a subpopulation of approximately 800 subjects with more frequent migraines that 
is expected to have a greater exposure to the study drug. With this sample size, and no events 
observed, the upper bound of a one-sided, 95% confidence interval for zero observations is 
roughly 0.00375. Hence, this sample size is large enough to rule out adverse events that occur at 
rates greater than 37.5 cases per 10,000 patients. 
9.3 
Statistical Methods 
9.3.1 
Primary Endpoint(s) 
The investigators will determine the intensity of adverse events (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 to the analyst. AEs will be presented by system organ class and preferred term. If a 
subject had an adverse event with different intensities over time, then only the greatest intensity 
will be reported.  Tabulations will be made for adverse events that occur in at least 5% of 


 
 
 
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treated subjects,  serious adverse events and adverse events leading to discontinuation. Other 
safety analyses will be described in the statistical analysis plan. 
Laboratory abnormalities will be identified from on-treatment laboratory data using a pre-
defined list of clinically significant abnormalities. The number of unique subjects with each 
abnormality will be tabulated. 
9.3.2 
Secondary Endpoint(s) 
The frequency of subjects that have confirmed values of ALT or AST that exceed 3x the ULN 
concurrently with confirmed total bilirubin that exceeds 2x the ULN will be tabulated and 
presented with descriptive statistics and exact confidence intervals.  
Both hepatic related AEs and hepatic related AEs leading to discontinuation will be summarized 
in a manner similar to that described for the primary endpoint. 
9.3.3 
Demographic and Baseline Characteristics 
Tabulations of demographic and baseline characteristics are made for treated subjects. A 
separate set of tabulations will be made for subjects enrolled but not treated.  
9.4 
Interim Analysis 
This is an open label study, single-arm, study designed to evaluate the safety and tolerability of 
rimegepant. As such, safety monitoring the primary concern. There is little concern, or 
opportunity, for inflation of type I (false-positive) error. During the course of the study 
laboratory, safety and exposure data will be monitored on an on-going basis. Summaries of 
these data will be produced roughly every 2 months for review by the sponsor and CRO. In 
addition, data may be locked, analyses conducted, and reports produced as required to support 
safety monitoring, administrative concerns, and regulatory requirements.  A clinical study 
report will be produced after last patient last visit. 
 
 


 
 
 
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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) and all applicable regulations, including the Federal Food, 
Drug and Cosmetic Act, U.S. applicable Code of Federal Regulations (title 21), any 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, with 
the exception that registration of such Phase 1 trials in a publicly accessible database is not 
mandatory.  
This study will be conducted in compliance with the protocol. The protocol and any 
amendments and the patient informed consent will receive Institutional Review 
Board/Independent Ethics Committee (IRB/IEC) approval/favorable opinion prior to initiation 
of the study.    
All serious breaches must be reported to Biohaven (or designee) immediately.  A Serious breach 
is a breach of the conditions and principles of GCP in connection with the stud or protocol, 
which is likely to affect, to a significant degree, the safety or physical or mental integrity of the 
patients of the study or the scientific value of the study.  
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., lose of medical licensure, debarment).  
10.2 Data and Safety Monitoring Committee 
This study will not make use of a Data Safety Monitoring Committee (DMC). The study 
medication rimegepant has been tested and found to be well tolerated.  Safety will be closely 
monitored via oversight by the investigators, Sponsor and CRO/designee. Summaries of LFTs 
and AEs will be reviewed roughly every 2 months by Sponsor/CRO.  
10.3 Institutional Review Board/Independent Ethics Committee 
The Investigators agree to provide the IEC with all appropriate documents, including a copy of 
the protocol/amendments, ICFs, advertising text (if any), Investigator’s brochure and any other 
written information provided to study subjects. The trial will not begin until the Investigators 


 
 
 
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have obtained the IEC favorable written approvals for the above-mentioned study documents. A 
properly executed written ICF shall be read, signed, and dated by each subject prior to entering 
the trial or prior to performing any study procedure. The original signed and dated ICF will be 
kept at the Investigator site and a copy will be given to the subject.  
In the event that the protocol is amended, the revised protocol must be approved by the IEC 
prior to its implementation, unless the changes involve only logistical or administrative aspects 
of the trial. 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 IEC, prior to subsequently 
obtaining each subject’s consent.  
The Principal investigator and the Sponsor’s representative must sign the protocol and its 
amendments (if any) before initiating the study.  
It is the Sponsor’s responsibility to submit the protocol and its amendments (if any), and the 
ICFs to regulatory authorities when necessary.  
10.4 Informed Consent 
Investigators must ensure that patients, or, in those situations where consent cannot be given by 
patients, 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.  
Biohaven (or designee) will provide the investigator with an appropriate (i.e., Global or Local) 
sample informed consent form which will include all elements required by  
ICH, GCP and applicable regulatory requirements.  The sample informed consent form will 
adhere to the ethical principles that have their origin in the Declaration of Helsinki. 
Before the potential subject has undergone any study-related screening procedures, the nature of 
the study and the potential risks associated with it will be explained to the subject, and the 
subject will be given an opportunity to ask questions to his or her satisfaction. After the 
questions are answered, but before proceeding further, the subject must read and sign a written 
informed consent form. This signed informed consent form will be reviewed and approved by 
an IRB/IEC, revisions to the protocol and informed consent form will be reviewed and 
approved by the IRB/IEC, a copy retained in the Study Master File, and the date and time the 
subject signed the form will be entered in his or her CRF. The subject will be provided with a 
copy of his or her signed and dated informed consent form.   


 
 
 
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If informed consent is initially given by a patient’s legal guardian or legally acceptable 
representative, and the patient subsequently becomes capable of making and communicating 
their informed consent during the study, then the consent must additionally be obtained from the 
patient.  
The informed consent form must also include a statement that Biohaven and its representatives 
and regulatory authorities may have direct access to patient records.  
The rights, safety, and well-being of study patients are the most important considerations and 
should prevail over interests of science and society.  
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 
patient. 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 collections fields when EDC is being used.    
The confidentiality of records that could identify patients 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 Records Management and Retention 
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 must retain all study records and source documents for the maximum 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 must contact the Sponsor prior 
to destroying any records associated with this study.  
Biohaven will notify the Investigators when the study files for this study are no longer needed.  


 
 
 
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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 Biohaven.  
It is the responsibility of the Investigator to ensure that the current disposition record of 
investigational product (those 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: 
1. amount of study drug received and placed in storage area 
2. label ID number or batch number or Kit number as specified for the protocol 
3. amount dispensed to and returned from each patient 
4. amount transferred to another area or site for dispensing or storage if applicable 
5. amount of drug lost or wasted 
6. amount destroyed at the site if applicable 
7. amount returned to sponsor, if applicable 
8. retain sampled for bioavailability/bioequivalence, if applicable 
9. record of dates and initials of personnel responsible for IM dispensing and 
accountability   
10.7 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 record for each patient for verification of data points.   
Unless otherwise instructed by the Sponsor or designee to enter data directly on the eCRF.  
10.8 Study Files and Record Retention 
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 


 
 
 
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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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11 AMENDMENTS 
Protocol modifications, except those intended to reduce immediate risk to study subjects, may 
be made only by Biohaven. A protocol change intended to eliminate an apparent immediate 
hazard to subjects may be implemented immediately, provided the IRB/IEC is notified within 5 
days. 
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. Biohaven will submit protocol amendments to the appropriate 
regulatory authorities for approval. 
If in the judgment of the IRB/IEC, the investigator, and/or Biohaven, 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 participant, the currently approved 
written informed consent form will require similar modification. In such cases, informed 
consent will be renewed for subjects enrolled in the study before continued participation. 
 


 
 
 
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12 STUDY REPORT AND PUBLICATIONS 
Biohaven is responsible for preparing and providing the appropriate regulatory authorities with 
clinical study reports according to the applicable regulatory requirements. 
The publication policy of Biohaven is discussed in the investigator's Clinical Research 
Agreement. 
 


 
 
 
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13 STUDY DISCONTINUATION  
Both Biohaven and the Principal Investigator reserve the right to terminate the study at the 
investigator’s site at any time. Should this be necessary, Biohaven or a specified designee will 
inform the appropriate regulatory authorities of the termination of the study if needed and the 
reasons for its termination, and the Principal Investigator will inform the IRB/IEC of the same. 
In terminating the study, Biohaven and the Principal Investigator will assure that adequate 
consideration is given to the protection of the subjects’ interests. 
 


 
 
 
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14 CONFIDENTIALITY 
All information generated in this study is considered highly confidential and must not be 
disclosed to any person or entity not directly involved with the study unless prior written 
consent is gained from Biohaven. However, authorized regulatory officials, IRB/IEC personnel, 
Biohaven and its authorized representatives are allowed full access to the records. 
Identification of subjects and eCRFs shall be by initials, subject numbers only. Only if required 
by law, the subject's full name may be made known to an authorized regulatory agency or other 
authorized official. 


 
 
 
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15 APPENDICES 
PPD


 
 
 
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15.2 APPENDIX 2 - Declaration of Helsinki 
WORLD MEDICAL ASSOCIATION DECLARATION OF HELSINKI 
Ethical Principles 
for 
Medical Research Involving Human Subjects 
 
Adopted by the 18th WMA General Assembly 
Helsinki, Finland, June 1964 
and amended by the 
29th WMA General Assembly, Tokyo, Japan, October 1975 
35th WMA General Assembly, Venice, Italy, October 1983 
41st WMA General Assembly, Hong Kong, September 1989 
48th WMA General Assembly, Somerset West, Republic of South Africa, October 1996 
and the 
52nd WMA General Assembly, Edinburgh, Scotland, October 2000 
 
A. 
INTRODUCTION 
The World Medical Association has developed the Declaration of Helsinki as a statement of 
ethical principles to provide guidance to physicians and other participants in medical research 
involving human subjects. Medical research involving human subjects includes research on 
identifiable human material or identifiable data. 
It is the duty of the physician to promote and safeguard the health of the people. The 
physician’s knowledge and conscience are dedicated to the fulfillment of this duty. 
The Declaration of Geneva of the World Medical Association binds the physician with the 
words, "The health of my subject will be my first consideration," and the International Code of 
Medical Ethics declares that, "A physician shall act only in the subject's interest when providing 
medical care which might have the effect of weakening the physical and mental condition of the 
subject." 
Medical progress is based on research, which ultimately must rest in part on experimentation 
involving human subjects. 
In medical research on human subjects, considerations related to the well-being of the human 
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The primary purpose of medical research involving human subjects is to improve prophylactic, 
diagnostic and therapeutic procedures and the understanding of the etiology and pathogenesis of 
disease. Even the best-proven prophylactic, diagnostic, and therapeutic methods must 
continuously be challenged through research for their effectiveness, efficiency, accessibility and 
quality. 
In current medical practice and in medical research, most prophylactic, diagnostic and 
therapeutic procedures involve risks and burdens. 
Medical research is subject to ethical standards that promote respect for all human beings and 
protect their health and rights. Some research populations are vulnerable and need special 
protection. The particular needs of the economically and medically disadvantaged must be 
recognized. Special attention is also required for those who cannot give or refuse consent for 
themselves, for those who may be subject to giving consent under duress, for those who will not 
benefit personally from the research and for those for whom the research is combined with care. 
Research investigators should be aware of the ethical, legal and regulatory requirements for 
research on human subjects in their own countries as well as applicable international 
requirements. No national ethical, legal or regulatory requirement should be allowed to reduce 
or eliminate any of the protections for human subjects set forth in this Declaration. 
B. 
BASIC PRINCIPLES FOR ALL MEDICAL RESEARCH 
It is the duty of the physician in medical research to protect the life, health, privacy, and dignity 
of the human subject. 
Medical research involving human subjects must conform to generally accepted scientific 
principles, be based on a thorough knowledge of the scientific literature, other relevant sources 
of information, and on adequate laboratory and, where appropriate, animal experimentation. 
Appropriate caution must be exercised in the conduct of research, which may affect the 
environment, and the welfare of animals used for research must be respected. 
The design and performance of each experimental procedure involving human subjects should 
be clearly formulated in an experimental protocol. This protocol should be submitted for 
consideration, comment, guidance, and where appropriate, approval to a specially appointed 
ethical review committee, which must be independent of the investigator, the Sponsor or any 
other kind of undue influence. This independent committee should be in conformity with the 
laws and regulations of the country in which the research experiment is performed. The 
committee has the right to monitor ongoing trials. The researcher has the obligation to provide 


 
 
 
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monitoring information to the committee, especially any SAEs. The researcher should also 
submit to the committee, for review, information regarding funding, Sponsors, institutional 
affiliations, other potential conflicts of interest and incentives for subjects. 
The research protocol should always contain a statement of the ethical considerations involved 
and should indicate that there is compliance with the principles enunciated in this Declaration.  
Medical research involving human subjects should be conducted only by scientifically qualified 
persons and under the supervision of a clinically competent medical person. The responsibility 
for the human subject must always rest with a subject of the research, even though the subject 
has given consent. 
Every medical research project involving human subjects should be preceded by careful 
assessment of predictable risks and burdens in comparison with foreseeable benefits to the 
subject or to others. This does not preclude the participation of healthy volunteers in medical 
research. The design of all studies should be publicly available. 
Physicians should abstain from engaging in research projects involving human subjects unless 
they are confident that the risks involved have been adequately assessed and can be 
satisfactorily managed. Physicians should cease any investigation if the risks are found to 
outweigh the potential benefits or if there is conclusive proof of positive and beneficial results. 
Medical research involving human subjects should only be conducted if the importance of the 
objective outweighs the inherent risks and burdens to the subject. This is especially important 
when the human subjects are healthy volunteers. 
Medical research is only justified if there is a reasonable likelihood that the populations in 
which the research is carried out stand to benefit from the results of the research. 
The subjects must be volunteers and informed participants in the research project. 
The right of research subjects to safeguard their integrity must always be respected. Every 
precaution should be taken to respect the privacy of the subject, the confidentiality of the 
subject’s information and to minimize the impact of the study on the subject's physical and 
mental integrity and on the personality of the subject. 
In any research on human beings, each potential subject must be adequately informed of the 
aims, methods, sources of funding, any possible conflicts of interest, institutional affiliations of 
the researcher, the anticipated benefits and potential risks of the study and the discomfort it may 
entail. The subject should be informed of the right to abstain from participation in the study or 


 
 
 
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to withdraw consent to participate at any time without reprisal. After ensuring that the subject 
has understood the information, the physician should then obtain the subject's freely-given 
informed consent, preferably in writing. If the consent cannot be obtained in writing, the non-
written consent must be formally documented and witnessed. 
When obtaining informed consent for the research project the physician should be particularly 
cautious if the subject is in a dependent relationship with the physician or may consent under 
duress. In that case the informed consent should be obtained by a well-informed physician who 
is not engaged in the investigation and who is completely independent of this relationship. 
For a research subject who is legally incompetent, physically or mentally incapable of giving 
consent or is a legally incompetent minor, the investigator must obtain informed consent from 
the legally authorized representative in accordance with applicable law. These groups should 
not be included in research unless the research is necessary to promote the health of the 
population represented and this research cannot instead be performed on legally competent 
persons. 
When a subject deemed legally incompetent, such as a minor child, is able to give assent to 
decisions about participation in research, the investigator must obtain that assent in addition to 
the consent of the legally authorized representative. 
Research on individuals from whom it is not possible to obtain consent, including proxy or 
advance consent, should be done only if the physical/mental condition that prevents obtaining 
informed consent is a necessary characteristic of the research population. The specific reasons 
for involving research subjects with a condition that renders them unable to give informed 
consent should be stated in the experimental protocol for consideration and approval of the 
review committee. The protocol should state that consent to remain in the research should be 
obtained as soon as possible from the individual or a legally authorized surrogate. 
Both authors and publishers have ethical obligations. In publication of the results of research, 
the investigators are obliged to preserve the accuracy of the results. Negative as well as positive 
results should be published or otherwise publicly available. Sources of funding, institutional 
affiliations and any possible conflicts of interest should be declared in the publication. Reports 
of experimentation not in accordance with the principles laid down in this Declaration should 
not be accepted for publication. 
C. 
ADDITIONAL PRINCIPLES FOR MEDICAL RESEARCH COMBINED WITH 
MEDICAL CARE 


 
 
 
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The physician may combine medical research with medical care, only to the extent that the 
research is justified by its potential prophylactic, diagnostic or therapeutic value. When medical 
research is combined with medical care, additional standards apply to protect the subjects who 
are research subjects. 
The benefits, risks, burdens and effectiveness of a new method should be tested against those of 
the best current prophylactic, diagnostic, and therapeutic methods. This does not exclude the 
use of placebo, or no treatment, in studies where no proven prophylactic, diagnostic or 
therapeutic method exists. 
At the conclusion of the study, every subject entered into the study should be assured of access 
to the best-proven prophylactic, diagnostic and therapeutic methods identified by the study. 
The physician should fully inform the subject which aspects of the care are related to the 
research. The refusal of a subject to participate in a study must never interfere with the subject-
physician relationship. 
In the treatment of a subject, where proven prophylactic, diagnostic and therapeutic methods do 
not exist or have been ineffective, the physician, with informed consent from the subject, must 
be free to use unproven or new prophylactic, diagnostic and therapeutic measures, if in the 
physician’s judgment it offers hope of saving life, re-establishing health or alleviating suffering. 
Where possible, these measures should be made the object of research, designed to evaluate 
their safety and efficacy. In all cases, new information should be recorded and, where 
appropriate, published. The other relevant guidelines of this Declaration should be followed. 
 
 


 
 
 
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15.3 APPENDIX 3 - Strong CYP3A4 Inhibitors and Inducers (Not all-inclusive) 
The following medications and medication combinations are some of the strong inhibitors of 
CYP3A4. This list should not be considered all-inclusive. As described in the study protocol, 
concomitant use of potent CYP3A inhibitors is prohibited. Individual drug labels should be 
reviewed for specific information on propensity to inhibit CYP3A4 for a specific compound.  
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 
 
The following medications and supplements are some of the strong inducers of CYP3A4. The 
list should not be considered all-inclusive. As described in the study protocol, concomitant use 
of potent CYP3A inducers is prohibited. Individual product labels should be reviewed for 
specific information on propensity to induce CYP3A4 for a specific compound. 
Carbamazepine, phenytoin, rifampin, St. John’s wort 
Resources:  
https://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/DrugInterac
tionsLabeling/ucm093664.htm#table3-2 
 
https://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/DrugInterac
tionsLabeling/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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1. 
Marcus, R., et al., BMS-927711 for the acute treatment of migraine: a double-blind, 
randomized, placebo controlled, dose-ranging trial. Cephalalgia, 2014. 34(2): p. 114-25. 
2. 
IHS, International Classificaton of Headache Disorders, 3rd edition beta version. 2013. 
3. 
CN170003, A Phase 2b, adaptive, double-blind, randomized, multi-center outpatient, 
dose-ranging trial to evaluate the efficacy and safety of BHV-92771 for the acute 
treatment of moderate or severe migraine. Bristol-Myers Squibb Company 
4. 
CN170002, Effect of BMS-927711 on the Pharmacokinetics of a Combined Oral 
Contraceptive Containing Ethinyl Estradiol and Norgestimate in Healthy Female 
Subjects. 2012, Bristol-Myers Squibb Company. 
5. 
CN170004, Phase 1 open-label, randomized single sequence study with two dose groups 
to compare the pharmacokinetics of BMS-927711 in migraine subjects during an acute 
migraine attack and during nonmigraine period. 2012, Bristol-Myers Squibb Company 
6. 
CN170006, Phase 1 Mass Balance Recovery Study - Rimegepant oral dosing and 
infusion. Bristol-Myers Squibb Company 
7. 
CN170007, DDI with Midazolam (CYP3A4 substrate) to study the changes of 
midazoloam pharmacokinetics with or without BMS-92771. Bristol-Myers Squibb 
Company 
8. 
Hougaard, A. and P. Tfelt-Hansen, Review of dose-response curves for acute 
antimigraine drugs: triptans, 5-HT1F agonists and CGRP antagonists. Expert Opin Drug 
Metab Toxicol, 2015. 11(9): p. 1409-18. 
9. 
Vos, T., et al., Years lived with disability (YLDs) for 1160 sequelae of 289 diseases and 
injuries 1990-2010: a systematic analysis for the Global Burden of Disease Study 2010. 
Lancet, 2012. 380(9859): p. 2163-96. 
10. 
Burch, R.C., et al., The prevalence and burden of migraine and severe headache in the 
United States: updated statistics from government health surveillance studies. Headache, 
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Lipton, R.B., et al., Migraine in the United States: epidemiology and patterns of health 
care use. Neurology, 2002. 58(6): p. 885-94. 
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Lipton, R.B., W.F. Stewart, and P.J. Goadsby, Headache-related disability in the 
management of migraine. Neurology, 2001. 56(6 Suppl 1): p. S1-3. 
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Brandes, J.L., Global trends in migraine care: results from the MAZE survey. CNS 
Drugs, 2002. 16 Suppl 1: p. 13-8. 
14. 
Buse, D.C., M.F. Rupnow, and R.B. Lipton, Assessing and managing all aspects of 
migraine: migraine attacks, migraine-related functional impairment, common 
comorbidities, and quality of life. Mayo Clin Proc, 2009. 84(5): p. 422-35. 
15. 
APA, Diagnostic and Statistical Manual of Mental Disorders, 5th Edition: DSM-5 5th 
Edition. 5th ed, ed. A.P. Association. 2013: American Psychiatric Publishing. 
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Sheehan, D.V., et al., Comparative Validation of the S-STS, the ISST-Plus, and the C-
SSRS for Assessing the Suicidal Thinking and Behavior FDA 2012 Suicidality Categories. 
Innov Clin Neurosci, 2014. 11(9-10): p. 32-46. 
17. 
Sheehan, D.V., J.M. Giddens, and I.S. Sheehan, Status Update on the Sheehan-
Suicidality Tracking Scale (S-STS) 2014. Innov Clin Neurosci, 2014. 11(9-10): p. 93-140. 


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18. 
Lipton, R.B., et al., Clinical utility of an instrument assessing migraine disability: the 
Migraine Disability Assessment (MIDAS) questionnaire. Headache, 2001. 41(9): p. 854-
61. 
19. 
Guy, W., ECDEU Assessment Manual for psychopharmacology. 1976, Rockville, Md. : 
U.S. Dept. of Health, Education, and Welfare, Public Health Service, Alcohol, Drug 
Abuse, and Mental Health Administration, National Institute of Mental Health, 
Psychopharmacology Research Branch, Division of Extramural Research Programs. 
 

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