BHV3000-301: Phase 3: Double-Blind, Randomized, Placebo-Controlled, Safety and Efficacy Trial of BHV-3000 (Rimegepant) for the Acute Treatment of Migraine
Phase: PHASE3
Conditions: Migraine, With or Without Aura
Sponsor: Pfizer

 
 
 
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DRUG: 
BHV-3000 (rimegepant) 
 
STUDY NUMBER(S): 
BHV3000-301 
 
PROTOCOL(S) TITLE: 
BHV3000-301: Phase 3: Double-Blind, 
Randomized, Placebo Controlled, Safety and 
Efficacy, Trial of BHV-3000 (rimegepant) for the 
Acute Treatment of Migraine  
IND NUMBER: 
109886 
SPONSOR: 
Biohaven Pharmaceutical Holding Company 
Limited 
 
ORIGINAL PROTOCOL 
DATE: 
April 12, 2017  
 
VERSION NUMBER: 
V 4.0 (Incorporates Administrative Letter 3) 
 
VERSION DATE: 
23-January-2018 

 
 
 
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Name and Title 
Signature Approval 
Date 
 
PPD

 
 
 
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SUMMARY OF CHANGES1 
Change 
Page(s)  
Affected 
Summary 
1. 6.2.4.1 Safety Laboratory 
Testing 
 
52 
Requirements for addressing 
elevated CPK results have been 
revised:  
 
Currently written: 
Blood chemistry/electrolyte: 
Sodium, potassium, chloride, 
bicarbonate, calcium; glucose, 
BUN (urea), serum creatinine, 
uric acid, ALT, AST, alkaline 
phosphatase, LDH, total protein, 
albumin, total bilirubin, direct 
bilirubin, indirect bilirubin, CPK 
(with local lab fractionation, if 
elevated); 
  
Should be written: 
 
Blood chemistry/electrolyte: 
Sodium, potassium, chloride, 
bicarbonate, calcium; glucose, 
BUN (urea), serum creatinine, 
uric acid, ALT, AST, alkaline 
phosphatase, LDH, total protein, 
albumin, total bilirubin, direct 
bilirubin, indirect bilirubin, CPK 
(with local lab fractionation, if 
central lab CK result is > 1.5 x 
ULN); 
                                                          
1 If higher than v1.0 

 
 
 
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Change 
Page(s)  
Affected 
Summary 
2. 8.1.2 Collection and 
Reporting Serious Adverse 
Events 
 
60 
The time period for reporting on-
study SAEs has been updated as 
follows: 
 
Currently written: 
  
Following the subject’s written 
consent to participate in the 
study, all SAEs, whether related 
or not related to study drug, must 
be collected, including those 
thought to be associated with 
protocol-specific procedures. All 
SAEs must be collected that 
occur during the screening 
period and within 30 days of 
discontinuation of dosing. The 
investigator should report any 
SAE occurring after these time 
periods that is believed to be 
related to study drug or protocol-
specific procedures.  
 
Should be written: 
  
Following the subject’s written 
consent to participate in the 
study, all SAEs, whether related 
or not related to study drug, must 
be collected, including those 
thought to be associated with 
protocol-specific procedures. All 
SAEs must be collected that 
occur during the screening 
period and throughout the 
course of the study up to and 
including the End of 
Treatment 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.  
 

 
 
 
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Change 
Page(s)  
Affected 
Summary 
3. 9.3 Populations for 
Analysis 
63 
The definition of the mITT 
population was adjusted to 
correspond with recent 
instructions from the FDA. The 
mITT population had been 
defined as all treated subjects. It 
is now defined as all treated 
subjects with a migraine of 
moderate to severe intensity and 
who provide at least one 
evaluable, post-baseline efficacy 
data point. 
4. 9.4.1 Primary 
Endpoints(s) 
64 
The analysis of the MBS had 
previously been stratified by use 
of prophylactic medication and 
MBS.  It is now stratified only 
by use of of prophylactic 
medication. 
The discussion of sensitivity 
analyses has been moved to 
statistical analysis plan. 
5. 9.4.2 Secondary Endpoints 
64 
The hierarchical testing order for 
the secondary endpoints has 
been changed.  
6. 9.4.3 Analysis of Safety 
64, 65 
Eliminated the phrase “and 
clinically relevant 
abnormalities” from the 
reporting of AEs. 
7. Minor administrative 
corrections 
Misc. 
In addition to the changes 
detailed above, several minor 
administrative edits have been 
made throughout the document 

 
 
 
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BHV-3000-301 
BHV3000-301: Phase 3: Double-Blind, Randomized, Placebo 
Controlled, Safety and Efficacy, Trial of BHV-3000 (rimegepant) 
for 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 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 Biohaven and the study. 
_____________________________  
_________________________ 
 
Principal Investigator Name (printed) 
Signature 
 
___________        ___________ 
Date 
                   Site Number 

 
 
 
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STUDY SUMMARY (SYNOPSIS) 
Title:  
BHV3000-301: Phase 3: Double-Blind, Randomized, Placebo Controlled, 
Safety and Efficacy, Trial of BHV-3000 (rimegepant) for 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. 
The data from this study will allow characterization of the relative safety, 
and efficacy of tablets of rimegepant versus placebo in the treatment of 
moderate or severe migraine measuring freedom from pain and freedom 
from most bothersome symptom (nausea, photophobia or phonophobia) 
reported at the onset of the treated migraine. Information regarding time to 
onset of action, the duration of action, and the sustainability of pain 
freedom in patients with an acute migraine will also be obtained. 
Target 
Population: 
The study will recruit male and female patients 18 years of age and older  
with at least a one-year history of migraines (with or without aura), 
consistent with a diagnosis according to the International Classification of 
Headache Disorders, 3rd edition beta version[1], including an age of onset 
prior to 50, migraine attacks that last about 4 - 72 hours, not more than 8 
attacks of moderate or severe intensity per month within the last 3 months 
and not less than 2 attacks per month. 
Number of 
Subjects: 
Approximately 1415 patients will be screened to randomize 1200 patients 
(approximately 600 per arm).  If, however, the targeted number of treated 
subjects (see Section 9.2 Sample Size) is reached first, the study may be 
closed. The subjects will be randomized in a 1:1 ratio to the rimegepant or 
placebo treatment groups. The randomization will be stratified by the use 
of prophylactic migraine medications (yes or no). 
Objectives:  
This is a double-blind, randomized, multicenter, outpatient evaluation of 
the safety and efficacy of rimegepant as compared to placebo in the 
treatment of moderate or severe migraine. The study drug will be 

 
 
 
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rimegepant presented in a 75 mg tablet or matching placebo.  
The study will randomize approximately 1200 patients. The subjects will 
be randomized in a 1:1 ratio to the rimegepant or placebo treatment 
groups. The randomization will be stratified by the use of prophylactic 
migraine medications (yes or no). 
A patient whose usual migraine attack results in headache pain of 
moderate or severe intensity and who is otherwise found acceptable for 
entry into this trial based on inclusion and exclusion criteria will first 
participate in the screening phase (3 - 28 day period). Patients on 
prophylactic migraine medication are permitted to remain on therapy 
provided they have been on a stable dose for at least 3 months prior to 
study entry.  
After randomization, the patient will be dispensed a single dose of the 
double-blind study medication that will be taken at the time a migraine 
attack reaches moderate or severe pain intensity (described below) on the 
numeric rating scale (NRS) as indicated in the electronic diary (eDiary). 
The patient will be instructed to take their study medication, as an 
outpatient, when (if) they have a migraine headache which reaches 
moderate or severe pain intensity and only after they have identified their 
most bothersome migraine-associated symptom (phonophobia, 
photophobia or nausea). The patient will complete an eDiary for up to 
forty-eight hours after taking study medication. The patient will telephone 
the study center immediately if a severe or serious adverse event occurs. 
Patients will record efficacy data in their eDiary. This includes the 
following: onset time of headache, intensity of the headache prior to and at 
time of taking study medication. The patient should record all headache 
intensity leading up to dosing, but should not dose with study medication 
until the headache reaches moderate or severe pain intensity. Headache 
severity will be recorded using a four-point numeric rating scale (no pain, 
mild pain, moderate pain, severe pain) at the onset of the migraine and 
after dosing at time points of 15, 30, 45, 60, and 90 minutes and 2, 3, 4, 6, 
8, 24 and 48 hours. The presence or absence of associated symptoms 
(nausea, photophobia, phonophobia) and ratings of functional disability 
(four-point scale: normal, mildly impaired, severely impaired, requires 
bedrest) will be recorded at the same time points as the headache severity 
ratings. Patients will also complete the migraine-specific quality-of-life 

 
 
 
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questionnaire and preference of medication (PoM) scale 24 hours after 
dosing. Patients who experience reduction of  headache pain to a mild 
intensity or pain free intensity level will be considered to have achieved 
pain relief. The patient who does not experience relief of their migraine 
headache at the end of two hours after dosing with study medication (and 
after the two hour assessments have been completed on the eDiary) will be 
permitted to use the following rescue medication: aspirin, ibuprofen, 
acetaminophen (up to 1000 mgs/day) naproxen (or any other type of 
nonsteroidal anti-inflammatory (NSAID)), antiemetics (e.g., 
metoclopramide or promethazine), or baclofen. These are the only 
medications allowed for rescue treatment after 2 hours post dose of study 
medication. If at the end of 48-hours after dosing with study medication 
(but before the End of Treatment Visit) patients are in need of migraine 
relief, they may take their prescribed standard of care medications, 
including triptans if not contraindicated, provided all of the assessments 
have been completed on the eDiary. Exclusionary rescue medication such 
as opioids, ergotamines, butalbital compounds, and muscle 
relaxants  (except baclofen as a rescue medication, see above) are not 
allowed on this study. Similarly, if the migraine is relieved by study 
medication at 2 hours after dosing but then recurs to a moderate or severe 
intensity level between two and forty-eight hours, the patient will be 
permitted to take the same rescue therapy as outlined above. In all 
circumstances, the patient will always continue to complete his or her 
eDiary for up to forty-eight hours after consuming the study medication. 
Patients will return to the study site within 7 days of study treatment for 
review of the eDiary, assessment of medication compliance, and 
monitoring of tolerability and safety (including vital signs, laboratory tests, 
and electrocardiography).  If a patient has  NOT experienced  a  migraine  
headache of sufficient severity within 45 days after randomization, he or 
she will be withdrawn from the trial and instructed to return the unused 
study medication and eDiary to the study center. 
 
 
 
 

 
 
 
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STUDY SCHEMATIC 
 
 
 
 
 
 
 
 
 
 
 
 
 
   
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 

 
 
 
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TABLE OF CONTENTS 
SUMMARY OF CHANGES .............................................................................................4 
STUDY SUMMARY (SYNOPSIS) ..................................................................................8 
STUDY SCHEMATIC ....................................................................................................11 
TABLE OF CONTENTS ................................................................................................12 
LIST OF ABBREVIATIONS .........................................................................................17 
1 
INTRODUCTION AND RATIONALE .................................................................19 
1.1 
THERAPEUTIC AREA BACKGROUND .......................................................19 
1.2 
CGRP’S ROLE IN MIGRAINE.........................................................................19 
1.3 
PRODUCT DEVELOPMENT BACKGROUND .............................................20 
1.3.1 
NON-CLINICAL PHARMACOLOGY.......................................................20 
1.3.1.1 
NONCLINICAL PHARMACOKINETICS AND 
PHARMACODYNAMICS......................................................................20 
1.3.1.2 
NONCLINICAL TOXICOLOGY ..........................................................20 
1.3.2 
CLINICAL EXPERIENCE ..........................................................................21 
1.3.2.8 
RCT DOSE-RANGING TRIAL OF RIMEGEPANT FOR 
ACUTE MIGRAINE (CN170003) ..........................................................25 
1.3.4 
CLINICAL ADVERSE EVENT PROFILE ................................................28 
1.4 
STUDY RATIONALE .........................................................................................29 
1.4.1 
STUDY DESIGN RATIONALE ..................................................................30 
1.4.2 
DOSE SELECTION RATIONALE .............................................................31 
1.4.3 
OTHER RATIONALE RELATED TO THE 
COMPOUND/STUDY ...................................................................................32 
1.5 
RESEARCH HYPOTHESIS ..............................................................................32 
CCI
CCI

 
 
 
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2 
STUDY OBJECTIVES ............................................................................................33 
2.1 
PRIMARY ............................................................................................................33 
2.2 
SECONDARY ......................................................................................................33 
2.3 
EXPLORATORY ................................................................................................34 
3 
STUDY ENDPOINTS ..............................................................................................35 
3.1 
PRIMARY ............................................................................................................35 
3.2 
SECONDARY ......................................................................................................35 
3.3 
MEASURES OF INTEREST..............................................................................36 
4 
STUDY PLAN ...........................................................................................................37 
4.1 
STUDY DESIGN AND DURATION .................................................................37 
4.2 
STUDY SCHEMATIC ........................................................................................37 
4.3 
SCHEDULE OF ASSESSMENTS .....................................................................38 
4.3.1 
SCREENING PHASE (3-28 DAYS).............................................................42 
4.3.2 
ACUTE (RANDOMIZATION) PHASE (45 DAYS) ..................................42 
4.3.3 
EXTENSION PHASE ....................................................................................43 
4.3.4 
END OF TREATMENT (7 DAYS AFTER TREATMENT) .....................43 
4.4 
POST STUDY ACCESS TO THERAPY (IF APPLICABLE) ........................43 
5 
POPULATION ..........................................................................................................44 
5.1 
NUMBER OF SUBJECTS ..................................................................................44 
5.2 
INCLUSION CRITERIA ....................................................................................44 
5.3 
EXCLUSION CRITERIA ...................................................................................45 
5.4 
PROHIBITED CONCOMITANT MEDICATION ..........................................47 
5.4.1 
RESCUE MEDICATIONS ...........................................................................48 
5.5 
WOMEN OF CHILDBEARING POTENTIAL ...............................................48 
5.6 
OTHER RESTRICTIONS AND PRECAUTIONS (IF APPLICABLE) ........49 
5.7 
DEVIATION FROM INCLUSION/EXCLUSION CRITERIA ......................49 
6 
STUDY CONDUCT AND DESCRIPTION OF STUDY PROCEDURES .........50 
6.1 
STUDY MATERIALS .........................................................................................50 
6.2 
SAFETY ASSESSMENTS ..................................................................................51 
6.2.1 
VITAL SIGNS AND PHYSICAL MEASUREMENTS (HEIGHT 
AND WEIGHT) .............................................................................................51 
6.2.2 
ELECTROCARDIOGRAM (ECG) .............................................................51 
6.2.3 
PHYSICAL EXAM ........................................................................................51 
6.2.4 
LABORATORY ASSESSMENTS ...............................................................51 
6.2.4.1 
SAFETY LABORATORY TESTING ...................................................51 
6.2.4.2 
PREGNANCY TESTING .......................................................................52 
6.2.5 
SHEEHAN SUICIDE TRACKING SCALE ...............................................52 
6.3 
EFFICACY ASSESSMENTS .............................................................................52 
6.3.1 
PAIN ................................................................................................................52 

 
 
 
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6.3.2 
NAUSEA, PHONOPHOBIA AND PHOTOPHOBIA ................................53 
6.3.3 
RESCUE MEDICATION .............................................................................53 
6.3.4 
FUNCTIONAL DISABILITY ......................................................................53 
6.3.5 
MIGRAINE QUALITY OF LIFE QUESTIONNAIRE .............................53 
6.3.6 
MIGRAINE PREFERENCE OF MEDICINE ............................................53 
6.4 
EARLY DISCONTINUATION FROM THE STUDY .....................................54 
7 
STUDY DRUG MANAGEMENT ...........................................................................55 
7.1 
DESCRIPTION OF STUDY DRUG ..................................................................55 
7.1.1 
INVESTIGATIONAL PRODUCT...............................................................55 
7.1.2 
NON-INVESTIGATIONAL PRODUCT ....................................................55 
7.1.3 
PACKAGING, SHIPMENT AND STORAGE ...........................................55 
7.2 
DOSE AND ADMINISTRATION .....................................................................55 
7.2.1 
METHOD OF ASSIGNING PATIENT IDENTIFICATION ...................55 
7.2.2 
SELECTION AND TIMING OF DOSE AND 
ADMINISTRATION .....................................................................................56 
7.2.3 
DOSE MODIFICATIONS ............................................................................56 
7.3 
BLINDING AND UNBLINDING .......................................................................56 
7.4 
TREATMENT COMPLIANCE .........................................................................57 
7.5 
DESTRUCTION AND RETURN OF STUDY DRUG .....................................57 
8 
ADVERSE EVENTS ................................................................................................58 
8.1 
SERIOUS ADVERSE EVENT ...........................................................................58 
8.1.1 
DEFINITION OF SERIOUS ADVERSE EVENT (SAE) ..........................58 
8.1.2 
COLLECTION AND REPORTING SERIOUS ADVERSE 
EVENTS..........................................................................................................59 
8.1.3 
OVERDOSE ...................................................................................................60 
8.1.4 
PREGNANCY ................................................................................................61 
8.1.5 
POTENTIAL DRUG INDUCED LIVER INJURY (DILI) .......................61 
8.2 
NON-SERIOUS ADVERSE EVENTS ...............................................................62 
8.2.1 
COLLECTION AND REPORTING OF NON-SERIOUS 
ADVERSE EVENTS .....................................................................................62 
8.2.2 
LABORATORY TEST ABNORMALITIES ..............................................62 
9 
STATISTICS .............................................................................................................63 
9.1 
GENERAL PROCEDURES ...............................................................................63 
9.2 
SAMPLE SIZE .....................................................................................................63 
9.3 
POPULATIONS FOR ANALYSIS ....................................................................63 
9.4 
STATISTICAL METHODS ...............................................................................64 
9.4.1 
PRIMARY ENDPOINT(S) ...........................................................................64 
9.4.2 
SECONDARY ENDPOINT(S) .....................................................................64 
9.4.3 
ANALYSIS OF SAFETY ..............................................................................64 

 
 
 
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9.4.4 
DEMOGRAPHIC AND BASELINE CHARACTERISTICS ...................65 
9.5 
INTERIM ANALYSIS ........................................................................................65 
10 ETHICS AND RESPONSIBILITIES .....................................................................66 
10.1 
GOOD CLINICAL PRACTICE ........................................................................66 
10.2 
DATA AND SAFETY MONITORING COMMITTEE ..................................66 
10.3 
INSTITUTIONAL REVIEW BOARD/INDEPENDENT ETHICS 
COMMITTEE ......................................................................................................66 
10.4 
INFORMED CONSENT .....................................................................................67 
10.5 
CASE REPORT FORMS ....................................................................................68 
10.6 
RECORDS MANAGEMENT AND RETENTION ..........................................68 
10.7 
SOURCE DOCUMENTATION .........................................................................69 
10.8 
STUDY FILES AND RECORD RETENTION ................................................69 
11 AMENDMENTS .......................................................................................................70 
12 STUDY REPORT AND PUBLICATIONS ............................................................71 
13 STUDY DISCONTINUATION ...............................................................................72 
14 CONFIDENTIALITY ..............................................................................................73 
APPENDICES ..................................................................................................................74 
 
APPENDIX II – DECLARATION OF HELSINKI .....................................................75 
WORLD MEDICAL ASSOCIATION DECLARATION OF HELSINKI ................75 
A. 
INTRODUCTION..........................................................................................75 
B. 
BASIC PRINCIPLES FOR ALL MEDICAL RESEARCH ......................76 
C. 
ADDITIONAL PRINCIPLES FOR MEDICAL RESEARCH 
COMBINED WITH MEDICAL CARE ......................................................78 
15 REFERENCES .........................................................................................................80 
 
 
 
PPD

 
 
 
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LIST OF TABLES 
Table 1:  
Schedule of Assessments ..........................................................................38 
 
 
 

 
 
 
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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 
Cmax 
Cmin 
CGRP 
Maximum Plasma Concentration 
Minimum Concentration 
Calcitonin gene-related peptide 
CONMED 
Concomitant Medication 
CV 
DILI 
Coefficient of Variation 
Drug induced liver injury 
DSMC 
DSM V 
Data and Safety Monitoring Committee 
Diagnostic and Statistical manual of mental Disorders Fifth edition 
ECG 
EC 
eCRF 
EDC 
eDiary 
ePRO 
FDA 
Electrocardiogram 
Ethics Committee 
Electronic case report forms 
Electronic Data Capture 
Electronic Diary 
Electronic Patient Reported Outcome 
Food and Drug Administration 
FSH 
Follicle Stimulating Hormone 
GCP 
HIV 
Good Clinical Practice 
Human Immunodeficiency Virus 
HR 
HRT 
Heart Rate 
Hormone Replacement Therapy 
ICF 
Informed Consent Form 
IB 
Investigator’s Brochure 

 
 
 
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ICH 
International Conference on Harmonization 
IEC 
IP 
Independent Ethics Committee 
Investigational Product 
IRB 
IHS 
Institutional Review Board 
International Headache Society 
Iv 
IWRS 
LDH 
LDL 
LOCF 
Intravenous 
Interactive Web Response System 
Lactate Dehydrogenase 
Low-density lipoprotein 
Last Observation Carried Forward 
kg 
Kilogram 
kBq 
mg 
Kilobecquerel 
Milligram 
Min 
MBq 
MBS 
MQoLQ 
Minute 
Megabecquerel 
Most bothersome Symptom 
Migraine-Specific Quality-of-Life Questionnaire  
msecs 
MTD 
Milliseconds 
Maximum tolerated dose 
PK 
Pharmacokinetic 
Qd 
QTc 
Once Daily 
Interval between Q-wave and T-wave in the cardiac cycle 
SAE 
Serious Adverse Event 
ULN 
WBC 
Upper Limit of Normal 
White Blood Cell 
WHO 
WOCBP 
World Health Organization 
Women of Childbearing Potential 
 

 
 
 
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1 INTRODUCTION AND RATIONALE 
1.1 
Therapeutic Area 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 821 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)[2]. 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 

 
 
 
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pathologic dilation of intracranial arteries without the unwanted effect of active 
vasoconstriction. 
Inhibiting Pain Transmission: Binding of CGRP receptor antagonists to CGRP 
receptors would suppress the transmission of pain by inhibiting the central relay 
of pain signals from the trigeminal nerve to the caudal trigeminal nucleus 
1.3 
Product Development Background 
Details of the clinical and preclinical studies are provided in the most current investigator 
brochure. A summary of the relevant date to the study are presented below.  
1.3.1 
Non-clinical Pharmacology 
1.3.1.1 
Nonclinical 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 
Nonclinical 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 
Clinical Experience 
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CCI

 
 
 
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CCI

 
 
 
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CCI

 
 
 
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1.3.2.8 
RCT Dose-ranging trial of rimegepant for acute migraine 
(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 [2].  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(Figure 1) 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).   

 
 
 
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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 Phase 3 
dose is based on reliably demonstrated efficacy on the key primary outcome measure, 
Pain Freedom at 2 hours (31.4% vs 15.3% placebo; p = 0.0018).   
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
  
 
 
  
  
 
  
 
 
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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 functions tests. 
Investigators must carefully monitor routine liver functions 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] .   
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 
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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 will address such cardiovascular limitations.  Clinical 
and 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 randomized controlled study proposed herein will further assess the efficacy and 
safety of rimegepant (75 mg) for the acute treatment of migraine.  As such, this study 
serves the broader objectives of the rimegepant clinical development program: to 
demonstrate the safety, tolerability, and efficacy of rimegepant in the acute treatment of 
migraine with or without aura in adults. 
1.4.1 
Study Design Rationale 
This is a double-blind, randomized, multicenter, outpatient evaluation of the safety and 
efficacy of rimegepant as compared to placebo in the treatment of moderate or severe 
migraine. The study drug will be rimegepant formulated in a 75 mg tablet or a matching 
placebo. The patient will be instructed to take their study medication, as an outpatient, 
when (if) they have a migraine headache which reaches moderate or severe intensity.  

 
 
 
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The study will randomize approximately 1200 patients. The subjects will be randomized 
in a 1:1 ratio to the rimegepant or placebo treatment groups. The randomization will be 
stratified by the use of prophylactic migraine medications (yes or no). 
This study design is utilized to confirm the efficacy and safety profiles observed in the 
Phase 2b study with rimegepant. Incorporation of placebo and use of appropriate rescue 
medications will permit enrollment of patients with a broad range of comorbidities, 
including cardiovascular conditions, representative of the potential treatment population. 
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 [2].  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% 

 
 
 
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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).   
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 
Rimegepant (75mg tablet) will have efficacy superior to placebo in the treatment of acute 
migraine with a favorable safety profile suitable for use by a broad patient population. 

 
 
 
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2 STUDY OBJECTIVES 
2.1 
Primary 
To evaluate the efficacy of rimegepant (75 mg tablet) compared with placebo in the acute 
treatment of migraine as measured by pain freedom and by freedom from the most 
bothersome symptom (MBS), associated with migraine, at two hours post dose.   
2.2 
Secondary 
• To evaluate rimegepant (75 mg tablet) compared to placebo on freedom from 
photophobia at 2 hours post-dose. 
• To evaluate rimegepant (75 mg tablet) compared to placebo on freedom from 
phonophobia at 2 hours post-dose. 
• To evaluate rimegepant (75 mg tablet) compared to placebo on pain relief at 2 hours 
post-dose. 
• To evaluate rimegepant (75 mg tablet) compared to placebo on freedom from 
nausea at 2 hours post-dose 
• To evaluate rimegepant (75 mg tablet) compared to placebo on the probability of 
requiring rescue medication within 24 hours of initial treatment. 
• To evaluate rimegepant (75 mg tablet) compared to placebo on sustained pain 
freedom from 2 to 24 hours post-dose 
• To evaluate rimegepant (75 mg tablet) compared to placebo on sustained pain relief 
from 2- 24 hours post-dose.   
• To evaluate rimegepant (75 mg tablet) compared to placebo on sustained pain 
freedom from 2- 48 hours post-dose..   
• To evaluate rimegepant (75 mg tablet) compared to placebo on sustained pain relief 
from 2- 48 hours post-dose.   
• To evaluate rimegepant (75 mg tablet) compared to placebo for the incidence of pain 
relapse from 2 to 48 hours post-dose 

 
 
 
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• To evaluate the effect of rimegepant (75 mg tablet) relative to placebo on the patients 
ability function at a “normal” level at 2 hrs post dose according to the Functional 
Disability scale. 
2.3 
Exploratory  
• To evaluate the effect of rimegepant (75 mg tablet) relative to placebo on the patients 
ability to work or function at 24 hrs post dose according to the Functional Disability 
scale.  
• To evaluate rimegepant (75 mg tablet) compared to placebo on pain relief at 90 
minutes post-dose. 
• To evaluate rimegepant (75 mg tablet) compared to placebo on pain relief at 60 
minutes post-dose. 
• To evaluate rimegepant (75 mg tablet) compared to placebo on pain relief at 30 
minutes post-dose. 
• To evaluate the effect of rimegepant (75 mg tablet) relative to placebo on the 
Migraine Preference of Medication (PoM) 
• To evaluate rimegepant (75 mg tablet) relative to placebo for pain relief on the 4 
point scale at all scheduled time points post dose 
• To evaluate the effect of rimegepant (75 mg tablet) relative to placebo on the 
Migraine Quality of Life (MQoLQ) 
• To evaluate the tolerability and safety of rimegepant (75 mg tablet) in the acute 
treatment of migraine as measured by the frequency of adverse events of at least 
moderate intensity, serious adverse events; and clinically relevant laboratory 
abnormalities. 
• To evaluate the effect of rimegepant (75 mg tablet) relative to placebo on the 
Sheehan Suicidality Tracking Scale. 

 
 
 
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3 STUDY ENDPOINTS  
3.1 
Primary 
Pain freedom will be assessed using the number of evaluable subjects that report no pain 
at 2 hours post-dose. Pain will be measured on a 4 point Likert scale (0=none, 1=mild, 
2=moderate, 3=severe).  
Freedom from the most bothersome symptom (MBS) will be assessed using the 
number of evaluable subjects that report the absence of their MBS at 2 hours post-dose.  
The MBS (nausea, phonophobia or photophobia) will measured using a binary scale 
(0=absent, 1=present). 
3.2 
Secondary 
• Freedom from Photophobia will be assessed by tabulating the number of subjects 
that report the absence of photophobia at 2 hours post-dose in the subset of subjects 
that reported the presence of photophobia at headache baseline. 
• Freedom from Phonophobia will be assessed by tabulating the number of subjects 
that report the absence of phonophobia at 2 hours post-dose in the subset of subjects 
that reported the presence of phonophobia at headache baseline. 
• Pain Relief  (aka “headache response” ), at 2 hours post-dose, will be assessed using 
the number of evaluable subjects that report a pain level of moderate or severe 
(responses of 2 or 3 on the 4 point Likert scale) at baseline and then report a pain 
level of none or mild (response of 0 or 1) at two hours post-dose. 
• Freedom from Nausea will be assessed by tabulating the number of subjects that 
report the absence of nausea at 2 hours post-dose in the subset of subjects that 
reported the presence of nausea at headache baseline. 
• The probability of requiring rescue medication will be assessed using the number of 
subjects that take rescue medication within 24 after administration of study 
medication (BHV3000 or placebo). 
• Sustained pain freedom, from 2 to 24 hours, will be assessed using the number of 
subjects that do not experience any headache pain through the time period of interest.  

 
 
 
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• Sustained pain relief, from 2 to 24 hours will be assessed using the number of 
subjects that do not use any rescue medications, and do not experience any moderate 
or severe headache pain through the time period of interest. 
• Sustained pain freedom, from 2 to 48 hours, will be assessed using the number of 
subjects that do not experience any headache pain through the time period of interest 
• Sustained pain relief from 2 to 48 hours, will be assessed using the number of 
subjects that do not use any rescue medications, and do not experience any moderate 
or severe headache pain through the time period of interest. 
• Pain relapse will be assessed using the number of subjects  that are pain free at 2 
hours post-dose and then have a headache of any severity (response of 1, 2 or 3 on the 
4 point scale) within 48 hours after administration of study medication (BHV3000 or 
placebo). 
• The proportion of subjects able to function normally, at 2 hours, will be assessed 
using the number of subjects that self-report as “normal” on the functional disability 
scale. 
3.3 
Measures of Interest 
Safety and Other assessments: 
• Adverse Events 
• ECG assessments 
• Vital Sign and Physical Measurements 
• Routine Laboratory Tests 
• Sheehan Suicidality Tracking Scale (S-SST) 
• Preference of Medication (PoM) 
• Assessment of Migraine Pain and Symptoms 
• Migraine Specified Quality of Life Questionnaire (MQoLQ) 

 
 
 
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4 STUDY PLAN 
4.1 
Study Design and Duration 
This is a double-blind, randomized, multicenter, outpatient evaluation of the safety and 
efficacy of rimegepant as compared to placebo in the treatment of moderate or severe 
migraine. Participants will be dispensed one dose of study medication consisting of a 
rimegepant 75 mg tablet or a matching placebo. The total duration of the study will be 
approximately 11 weeks.  This includes a 3-28 day Screening Period, an Acute Phase that 
can last up to 45 days or until the patient has a migraine that reaches moderate or severe 
intensity, followed by an End of Treatment Visit 7 days after the administration of the 
study medication.  
4.2 
Study Schematic 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
                               
 
 
 
 
 
 
 
 
 
 
 
 
  
   
 
 
 
 
 
 
 
 
 

 
 
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Procedure 
Screening 
Visit 
(3-28 
days)1 
 
Baseline Visit 
(Randomization)1 
Onset of 
moderate or 
severe 
migraine2 
During 
Treatment 15, 
30, 45, 60 and 
90 minutes 
Post-Dose 
During 
Treatment 
2, 3, 4, 6, 8 
hours 
Post- Dose 
During 
Treatment 
24 hours 
Post-Dose 
During 
Treatment 
48 hours 
Post- Dose 
End of 
Treatment 
Visit 
Assessment of Migraine 
Symptoms (photophobia, 
phonophobia, and nausea 
- eDiary)13 
 
 
 
 
X 
 
X 
 
X 
 
X 
 
X 
 
Functional Disability 
Scale13 
 
 
X 
X 
X 
X 
X 
 
MQoLQ (Migraine 
Specified Quality of Life 
Questionnaire)13 
 
 
 
 
 
 
 
X 
 
 
Preference of 
Medication13 
 
 
 
 
 
 
X 
 
 
 
1 Screening/Baseline Phase will be 3 - 28 days. The Baseline Visit may be scheduled but should only occur after all screening procedures are complete, patient meets 
inclusion/exclusion criteria, and lab test results have been received by the site. 
2 Patients will use eDiary to answer questions about their migraine symptoms upon experiencing a moderate/severe migraine headache. The patient will administer pre- 
dispensed study drug if 1) the headache remains moderate or severe; 2) the patient has completed all required migraine assessment questions in the eDiary, including their 
current most bothersome migraine symptom, and 3) the patient has not already taken prohibited medications (see protocol section 5.4). 
3 Patients should keep track of their concomitant medications throughout the study and report them to the study personnel at the End of Treatment Visit. Any medication 
taken for recurrent headache should be documented. Use of concomitant medications after randomization, including rescue medications, will be recorded by the patient on 
a paper diary and reported to the site. 
4 Height will only be captured at the Screening Visit. Weight body temperature, respiratory rate, blood pressure and heart rate will be collected at all time points where 
indicated. Sitting arterial systolic and diastolic blood pressure and pulse rate will be measured. 

 
 
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5 All Screening Visit laboratory test results must be received prior to Baseline Visit. 
6 A serum pregnancy test will be completed at Screening and End of Treatment Visits as part of the standard laboratory tests (if appropriate). Confirmatory urine 
pregnancy test for WOCBP should be completed on site at Baseline Visit and any subsequent visits for confirmation at the Investigator’s discretion. Home pregnancy test 
will be provided to WOCBP after completion of baseline visit. 
7 SAEs are reported from the time of informed consent and non-serious AEs are reported from baseline. All ongoing non-serious AEs and SAEs will be followed to 
resolution or until investigator deems there will be no further status change. SAE and AE’s that occur during the treatment period should be reported to the site. 
8 This scale will be clinician administered, completed on site, and will be in paper. The source document will be provided by Biohaven. The assessment period for 
completing the scale will be 30 days prior to Screening, and since the last visit for the remainder of the study. 
9 Patients will be randomized in the IWRS system at the Baseline Visit (Randomization Day 01) 
10 Patient should be instructed that the dose should be taken once the migraine attack reaches moderate or severe pain. 
11 Site staff to review and confirm entries with patients and confirm all data points are transferred to the system and reset eDiary for future patient use, PRIOR to the 
patient leaving the clinic. 
12 ± Windows for timeframe around efficacy assessments (15, 30, 45, 60, 90 min, 2, 3, 4, 6, 8, 24 and 48 hours) will be automated and captured in the eDiary. 
13 These scales will be captured in the eDiary. Patients will also be asked about their most bothersome symptom at the time of reporting and treating a qualifying migraine. 
14 Paper source document will be used to capture Migraine History. Patients will also be asked about their typical most bothersome symptom when having a migraine. 

 
 
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4.3.1 
Screening Phase (3-28 days) 
It is estimated that approximately 1415 patients will be screened to allow 1200 patients to be 
randomized at the Baseline visit. All patients who are screened into the study will be entered 
into the IWRS system. After obtaining informed consent, patients will undergo all screening 
procedures as detailed in Table 1. After all screening procedures are complete, patients will 
return 3-28 days from signing informed consent to be randomized at the Baseline visit if they 
meet all eligibility criteria. Patients on prophylactic migraine medication are permitted to 
remain on therapy provided they have been on a stable dose for at least 3 months prior to 
randomization.  
4.3.2 
Acute (Randomization) Phase (45 days) 
If the patient meets all eligibility criteria they will be randomized at the Baseline Visit via the 
IWRS system. The patients will be provided with an eDiary. The study personnel will instruct 
the patient on the proper use of the eDiary and ensure proper understanding and use of the tool, 
prior to the patient leaving the office. 
After randomization via the IWRS system, the patient will be dispensed a single dose of the 
double-blind study medication to take home for up to 45 days. This study medication is to be 
taken when a migraine attack reaches moderate or severe intensity on the numeric rating scale 
(NRS) as indicated in the eDiary. The patient will be instructed to take their study medication, 
as an outpatient, when (if) they have a migraine headache which reaches moderate or severe 
intensity after they answer eDiary questions about their current pain and symptoms and 
identify their currently most bothersome, migraine associated, symptom (phonophobia, 
photophobia or nausea). The patient will complete an eDiary for up to forty-eight hours after 
taking study medication. The patient will telephone the study center immediately if a severe or 
serious adverse event occurs. 
 
Patients will record efficacy data in their eDiary. This includes the following: onset time of 
headache, intensity of the headache prior to and at time of taking study medication. The patient 
should record all headache intensity leading up to dosing, but should not dose with study 
medication until the headache reaches moderate or severe intensity. Headache severity will be 
recorded using a four-point numeric rating scale (no pain, mild pain, moderate pain, severe 
pain) at the onset of the migraine and after dosing at time points of 15, 30, 45, 60, and 90 
minutes and 2, 3, 4, 6, 8, 24 and 48 hours. The presence or absence of associated symptoms 
(nausea, photophobia, phonophobia) and ratings of functional disability (four-point scale: 
normal, mildly impaired, severely impaired, requires bedrest) will be recorded at the same time 
points as the headache severity ratings. Patients will also identify their currently most 
bothersome symptom before taking study medication. Patients will record the date and time 
study therapy was taken in their eDiary. Patients will also complete the migraine-specific 
quality-of-life questionnaire (MQoLQ) and preference of medication (PoM) 24 hours after 

 
 
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dosing. Patients who have headache pain reduced to a mild intensity or pain free intensity level 
will be considered to have achieved pain relief.  
 
After dosing with study medication, all other headache medication is prohibited during the 2 
hours post dose. However, a patient who does not experience relief of their migraine headache 
at the end of two hours after dosing with study medication (and after the two hour assessments 
have been completed on the eDiary) will be permitted to use the following rescue medication: 
aspirin, ibuprofen, acetaminophen up to 1000mg/day (this includes Excedrin Migraine) 
naproxen (or any other type of nonsteroidal anti-inflammatory (NSAID)), antiemetics (e.g., 
metoclopramide or promethazine), or baclofen. These are the only medications allowed for 
rescue treatment after 2 hours post dose of study medication. However, if needed, after 48-
hours of administering the one dose of study medication (and before returning for the End of 
Treatment Visit) patients may take their prescribed standard of care medications for treatment 
of migraine, including triptans if not contraindicated, provided all of the assessments have 
been completed on the eDiary. Exclusionary rescue medication such as, opioids, ergotamines, 
butalbital compounds, and muscle relaxants  (except baclofen as a rescue medication, see 
above) are not allowed on this study. Similarly, if the migraine is relieved by study medication 
at 2 hours after dosing but then recurs to a moderate or severe intensity level between two and 
forty-eight hours, the patient will be permitted to take the same rescue therapy as outlined 
above.  In all circumstances, the patient will continue to complete his or her eDiary for up to 
forty-eight hours after consuming the study medication. 
4.3.3 
Extension Phase  
Not Applicable 
4.3.4 
End of Treatment (7 days after Treatment) 
Patients will return to the study site within 7 days of study treatment (+2 days)  for review of 
the eDiary assessment of medication compliance, and monitoring of tolerability and safety 
(including vital signs, laboratory tests,  and  electrocardiography).  If a patient  has  NOT  
experienced  a  migraine  headache of sufficient severity within 45 days after randomization, he 
or she will be withdrawn from the trial and instructed to return unused study medication and 
eDiary to the study center. 
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/investigators. The investigator should ensure that the subject receives the appropriate 
standard of care to treat the condition under study.  Alternatively, patients may be eligible  to 
receive study drug by participation in a rimegepant Long Term Safety study requiring approval 
by responsible health authorities and ethics committees.  

 
 
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5 POPULATION 
Individuals entered in this trial will be patients who suffer from migraines. The treatment 
setting for these patients may include clinics, institutions or private office practices. Patients 
may be recruited through a variety of sources, including referral from physicians and other 
health care professionals. 
5.1 
Number of Subjects 
It is anticipated that 1415 patients will need to be screened in order to randomize approximately 
1200 patients. If, however, the minimum number of treated subjects is reached first, the study 
may be closed. The subjects will be randomized in a 1:1 ratio to the rimegepant or placebo 
treatment groups.  It is anticipated that enrollment will occur at approximately 50 sites in the 
United States over a period of approximately 3 months during this trial. 
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 migraines (with or without aura) consistent with a 
diagnosis according to the International Classification of Headache Disorders, 3rd 
Edition, beta version[1], including the following: 
a) Migraine attacks present for more than 1 year with the age of onset prior to 50 
years of age 
b) Migraine attacks, on average, lasting about 4 - 72 hours if untreated 
c) Not more than 8 attacks of moderate or severe intensity per month within last 3 
months 
d) Patients must be able to distinguish migraine attacks from tension/cluster 
headaches.  
e) Consistent migraine headaches of at least 2 migraine headache attacks of 
moderate  or severe intensity in each of the 3 months prior to the Screening Visit 
and maintains this requirement during the Screening Period 
f) Less than 15 days with headache (migraine or non-migraine) per month in each of 
the 3 months prior to the Screening Visit and maintains this requirement during 
the Screening Period 
g) Patients on prophylactic migraine medication are permitted to remain on therapy 
provided they have been on a stable dose for at least 3 months prior to study entry. 
h) Patients with contraindications for use of triptans may be included provided they 

 
 
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meet all other study entry criteria. 
3. Age and Reproductive Status 
a) Male and Female patients ≥ 18 years and older 
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 5.5 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) 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 that the 
finding is not clinically significant and will not introduce additional risk factors 
and will not interfere with the study procedures 
d) At the Baseline Visit prior to dispensing Investigational Study Medication, 
WOCBP must have a negative serum or urine pregnancy test (minimum 
sensitivity 25 IU/L or equivalent units of HCG) 
e) Women must not be breastfeeding 
5.3 
Exclusion Criteria 
1. Disease Target 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 the 6 months 
prior to screening.  
c) Uncontrolled hypertension (high blood pressure), or uncontrolled diabetes 
(however patients can be included who have stable hypertension and/or diabetes 
for 3 months prior to being enrolled) 
d) Patient has a current diagnosis of major depression, other pain syndromes, 
psychiatric conditions (e.g., schizophrenia), 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 

 
 
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f) The patient has a history or current evidence of any significant and/or unstable 
medical conditions (e.g., history of congenital heart disease or arrhythmia, known 
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 
g) 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 
h) 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 use disorder, 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. 
3. Allergies and Adverse Drug Reactions 
a) History of drug or other allergy which, in the opinion of the principal investigator, 
makes the subject unsuitable for participation in the study 
4. Sex and Reproductive Status 
a) Females of child-bearing potential who are unwilling or unable to use an 
acceptable contraceptive method or abstinence to avoid pregnancy for the entire 
study period and for 56 days after the study. 
b) Women who are pregnant or breastfeeding. Women with a positive pregnancy test 
on enrollment 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/1.73m2 
b) Corrected QT interval > 470 msec (QTc by method of Frederica), during the 
Screening/Baseline Phase 
c) Left Bundle Branch block 
d) Right Bundle Branch Block with a QRS duration ≥ 150 msec. 

 
 
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e) Intraventricular Conduction Defect with a QRS duration ≥ 150 msec. 
f) Serum bilirubin (Total, Direct or Indirect) > 1 x ULN (Only abnormal values of 
between 1-1.5x ULN may be repeated once for confirmation during the screening 
period.)  
g) Neutrophil count ≤ 1000/µL (or equivalent). 
h) AST (SGOT) or ALT (SGPT) > 1 x ULN (Only abnormal values of between 1-1.5x 
ULN may be repeated once for confirmation during the screening period.) 
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) Exposure to non-biological investigational agents (other than rimegepant) within 
the 30 days prior to Baseline visit.  
d) Exposure to biological investigational agents within the 90 days prior to Baseline 
visit. 
e) Score of >0 on the Sheehan Suicidality Tracking Scale for the period of 30 days 
prior to Screening and during the study. 
7. Please see Section 5.4 for Prohibited medications and Section 5.4.1 for allowable Rescue 
Medications 
 
5.4 
Prohibited Concomitant Medication  
The below medications are prohibited prior to randomization and during the course of this 
study or as specified.  
1. St. John’s Wort should not be taken 14 days prior to randomization and throughout the 
study.  
2. Butterbur root or extracts should not be taken 14 days prior to randomization and 
throughout the study. 
3. History of use of ergotamine medications on greater than/equal 10 days per month  on 
a regular basis for greater than/equal 3 months 
4. History of non-narcotic analgesic intake on greater than/equal 15 days per month for 
greater than/equal 3 months 
5. Use of narcotic medication, such as barbiturates, heroin, opium in the form of 
morphine and codeine, oxycodone and hydrocodone for at least 2 days prior to 
randomization. 
6. Use of acetaminophen or acetaminophen containing products at daily dosing levels 
greater than 1000mg/day for at least two days prior to randomization.  
7. Use of marijuana is prohibited during the study. 

 
 
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Patients on prophylactic migraine medication are permitted to remain on therapy provided they 
have been on a stable dose for at least 3 months prior to study entry.  
5.4.1 
Rescue Medications 
After dosing with study medication, all other headache medication is prohibited during the 2 
hours post dose. However, a patient who does not experience relief of their migraine headache 
at the end of two hours after dosing with study medication (and after the two hour assessments 
have been completed on the eDiary), will be permitted to use the following rescue medication: 
aspirin, ibuprofen, acetaminophen up to 1000mg/day (this includes Excedrin Migraine) 
naprosyn (or any other type of non- steroidal anti-inflammatory (NSAID)), antiemetics (e.g., 
metoclopramide or promethazine), or baclofen. These are the only medications allowed for 
rescue treatment after 2 hours post dose of study medication. However, if needed, after 48-
hours of administering the one dose of study medication (and before coming in for the End of 
Treatment Visit) patients may take their prescribed standard of care medications for treatment 
of migraine (including triptans if not contraindicated, provided all of the assessments have 
been completed on the eDiary. Similarly, if the migraine is relieved by study medication at 2 
hours after dosing but then recurs to a moderate or severe intensity level between two and 
forty-eight hours, the patient will be permitted to take the same rescue therapy as outlined 
above. In all circumstances, the patient will always continue to complete his or her eDiary for 
up to forty-eight hours after consuming the study medication. Use of concomitant medication 
after randomization, including rescue medication, will be recorded by the patient on a paper 
diary and reported to the site. The site will record medications that were taken within 14 days 
of dosing with study medication (or until the End of Treatment Visit).  
5.5 
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 or 
2. Woman with irregular menstrual periods and a documented serum follicle stimulating 
hormone (FSH) level > 35mIU/mL 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 

 
 
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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 
before treatment with the 1 dose of study medication to 56 days after dosing). 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 oral contraceptives or 
another barrier method (Note an Intra Uterine Device is considered one method). 
Women who suspect that they have become or may have become pregnant despite using proper 
birth control methods, should use the home pregnancy test provided at Baseline Visit. Home 
pregnancy test should be administered prior to taking Investigational Study Drug. Patient 
should not take Investigational Study Drug if they are pregnant and patient should immediately 
contact Study Investigator.  
5.6 
Other Restrictions and Precautions (if applicable) 
Not Applicable 
5.7 
Deviation from Inclusion/Exclusion Criteria 
Any significant event that does not comply with the inclusion exclusion criteria, study conduct, 
or study procedures will be documented as a deviation. Deviations will be documented and 
reported through the clinical monitoring of the trial. Deviations will be reported to the IRB/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 
• Concomitant and Rescue Medication Logs (take home for patient)  
• Investigator Brochure 
• Interactive Web-based Response System (IWRS) 
• Electronic Case Report Form (eCRF) instructions 
• Electronic Diary (eDiary): 1 will be given to each randomized patient 
• Instructions for  the  ePRO device and access to the portal 
• Laboratory Kits and Laboratory Manual 
• Home Pregnancy Test 
• ECG Machine and Instructions 
• Serious Adverse Event (SAE) forms 
• Pregnancy Surveillance Forms 
All sites will use an Electronic Data Capture (EDC) tool to submit study data to Sponsors CRO. 
Electronic Case Report Forms (eCRFs) will be prepared for all data collection fields including 
Serious Adverse Events (SAE) Reporting. SAE data (including responses to queries) will be 
submitted to the CRO using eCRFs. Electronic Patient Reported Outcomes (ePRO) will be used 
for all patient-rated scales and will be captured on an eDiary. 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/or sponsor. No additional source documents are required for scales and 
assessments completed by the patient in eDiary. 

 
 
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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) 
Body weight and height will be  recorded  at  the  scheduled  visits  as  outlined  in  Table 1. 
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. A central ECG service will be utilized for all ECGs and the investigator 
will determine if any abnormalities are clinically significant or not.  
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. 
6.2.4 
Laboratory Assessments 
6.2.4.1 
Safety Laboratory Testing 
Blood and urine samples will be obtained as outlined in Table 1 for clinical laboratory 
evaluations. A central laboratory vendor will be utilized for this study and a laboratory manual 
will be provided to each site. If possible, patients should be fasting for a minimum of 8 
hours prior to all blood draws. 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. 

 
 
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Hematology: Hemoglobin, hematocrit, red blood cell count, white blood cell count (WBC) 
with differential, and platelets 
Blood chemistry/electrolyte: Sodium, potassium, chloride, bicarbonate, calcium; glucose, 
BUN (urea), serum creatinine, uric acid, ALT, AST, alkaline phosphatase, LDH, total protein, 
albumin, total bilirubin, direct bilirubin, indirect bilirubin, CPK (with local lab fractionation, if 
central lab CK result is > 1.5 x ULN); 
Lipid panel: Cholesterol, LDL, HDL, triglycerides (Screening Only). 
Estimated glomerular filtration rate: eGFR using the estimated MDRD formula will be 
calculated and reported by the central lab at each visit that clinical laboratory tests are collected 
as outlined in Table 1. 
Urinalysis: pH, specific gravity, ketones, nitrites, urobilinogen, leukocyte esterase, protein, 
glucose and blood. If blood, protein or leukocytes are positive, reflex to microscopic 
examination. 
Urine Drug Screen: For drugs of abuse 
6.2.4.2 
Pregnancy Testing 
Pregnancy tests will be conducted (serum, urine, or home pregnancy test), if appropriate prior 
to randomization, and as outlined in Table 1. 
6.2.5 
 Sheehan Suicide Tracking Scale   
The Sheehan 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]. 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. The subject must immediately be discontinued from the study. The event should 
be recorded as either an AE or SAE as determined by the investigator and reported within 24 
hours to the Sponsor. 
 
6.3 
Efficacy Assessments 
6.3.1 
Pain 
Subjects are given an eDiary to record their migraine pain score, on a 4-point numeric rating 
[no pain, mild pain, moderate pain, severe pain] at the time points indicated in Table 1.  
 

 
 
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6.3.2 
Nausea, Phonophobia and Photophobia 
The migraine associated symptoms of photophobia, phonophobia and nausea are measured on a 
two point scale (present or absent), using the eDiary, at the time points listed in Table 1.  If a 
subject reports the presence of a symptom, the subject is then asked to rate the severity of the 
symptom on a four point scale (none, mild, moderate or serve). All assessment is done using 
the eDiary. 
The subjects are also asked to identify their most bothersome symptom on the eDiary (nausea, 
phonophobia or photophobia) at the onset of the migraine to be treated. The most bothersome 
symptom must be identified before the subject takes study medication.  
6.3.3 
Rescue Medication 
The subject’s use of rescue medication is recorded by the subject in a paper diary.  
6.3.4 
Functional Disability 
Impact of treatment on functional disability will be assessed using a single-question scale. 
Subjects rate the level of disability they perceive as a result of their migraine in performing 
normal actions. This is done in the eDiary, at the times indicated in Table 1, using a 4 point 
numeric rating scale: Normal Function, Mild Impairment, Severe Impairment, Required 
Bedrest.  
6.3.5 
Migraine Quality of Life Questionnaire 
Impact of treatment on subject-reported quality of life will be assessed using The Migraine 
Quality of Life Questionnaire (MQoLQ). The MQoLQ is a 15-item instrument that has been 
validated in migraine patients to measure the short-term impact of treatment (within 24-hours) 
on seven migraine-specific domains: work, social function, energy, vitality, feelings, concerns, 
and migraine symptoms.  The eDiary is used to evaluate the Migraine Quality of Life 
Questionnaire at 24 hours post-dose (see Table 1). 
6.3.6 
Migraine Preference of Medicine 
The Preference of Medication Scale (PoMs) is a brief scale that captures the subjects' 
perception of whether the medication they are taking has had a greater benefit compared with 
previous medications to treat their pain. The eDiary is used to evaluate the Preference of 
Medication Scale at 24 hours post-dose (see Table 1). 
 

 
 
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6.4 
Early Discontinuation from the Study 
Subjects MUST discontinue investigational product (and non-investigational product at the 
discretion of the investigator) for any of the following reasons: 
• Withdrawal of informed consent (subject’s decision to withdraw for any reason) 
• 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 
All subjects who discontinue should comply with protocol specified End of Treatment 
procedures as outlined in Table 1. The only exception to this requirement is when a subject 
withdraws consent for all study procedures or loses the ability to consent freely (i.e., is 
imprisoned or involuntarily incarcerated for the treatment of either a psychiatric or physical 
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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. 
The rimegepant tablet and the matching placebo appear identical visually, via touch, 
smell and taste.   
7.1.2 
Non-investigational Product 
Other medications used as support or escape 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: Not applicable for this study. 
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. If concerns regarding the quality or appearance of the study drug arise, do 
not dispense the study drug and contact the sponsor immediately. 
7.2 
Dose and Administration 
7.2.1 
Method of Assigning Patient Identification 
At the time of enrollment, immediately after written informed consent is obtained and 
before performing any study-related procedures, each subject will be assigned an unique 
sequential 4-digit subject number beginning with 0001, 0002, 0003, etc. for identification 

 
 
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throughout the study through an IWRS system. This subject number must not be reused 
for any other participant in the study. The physician/coordinator must contact the IWRS 
to enroll each subject into a centralized database at the time of signing consent. 
After completion of all screening evaluations all eligible subjects will be randomized in a 
1:1 ratio to the rimegepant or placebo treatment groups. The randomization will be 
stratified by the use of prophylactic migraine medications (yes or no). 
Randomization schedules will be generated and kept by 
 in a secure 
network folder with access limited to only unblinded team members. Each subject who is 
qualified for treatment will be randomized via the IWRS randomization option. Patients 
will maintain their subject number assigned at screening throughout the trial. The IWRS 
will provide the double-blind treatment assignments. 
The randomization will trigger a bottle number for the randomized treatment type. The 
drug will be dispensed at the time of randomization.  
7.2.2 
Selection and Timing of Dose and Administration 
Study medication (one 75mg tablet) will be in a bottle. There are no dose adjustments in 
this study and patients will receive one dose to treat  one  migraine  headache  of  
moderate  or  severe  intensity  within  the  45  days  of randomization (Baseline Visit). 
Patients will be administered the study medication at randomization (Baseline Visit) and 
will take the tablet from the bottle at the time of moderate or severe migraine headache 
onset after answering questions regarding their migraine symptoms on the eDiary.  The 
tablet should swallowed with water. 
7.2.3 
Dose Modifications 
There will be no dose adjustments in this study. 
7.3 
Blinding and Unblinding  
Blinding is critical to the integrity of this clinical study.  However, in the event of a 
medical emergency or pregnancy in an individual patient, in which knowledge of the 
investigational product is critical to the patient’s management, the blind for that patient 
may be broken by the treating physician.  
Before breaking the blind of an individual patient’s treatment, the investigator should 
have determined that the information is necessary, i.e., that it will alter the patient’s 
immediate management.   In many cases, particularly when the emergency is clearly not 
investigational product related, the problem may be properly managed by assuming that 
the patient is receiving active product without the need for unblinding.   
In cases of accidental unblinding, contact the Medical Monitor and ensure every attempt 
to preserve the blind is made.   
CCI

 
 
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7.4 
Treatment Compliance 
Responsible study personnel will dispense the study drug.  Accountability and 
compliance verification should be documented in the patient’s study records.   
Patients have to be counseled on the importance of taking the study drug as directed 
when a migraine occurs and reaches moderate or severe intensity.  If the patient does not 
have a migraine or take their study medication within 45 days of the Baseline Visit, they 
should return to the clinic for their End of Study Visit and return their study medication.  
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 related 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) 
A 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 
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  

 
 
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Definition of Terms 
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 severe form might have caused death. For example, drug induced hepatitis that 
resolved without evidence of hepatic failure would not be considered life threatening 
even though drug induced hepatitis can be fatal. 
Hospitalization: AEs requiring hospitalization should be considered SAEs. 
Hospitalization for elective surgery or routine clinical procedures that are not the result of 
AE (e.g., elective surgery for a pre-existing condition that has not worsened) need not be 
considered AEs or SAEs. If anything untoward is reported during the procedure, that 
occurrence must be reported as an AE, either 'serious' or 'non-serious' according to the 
usual criteria. 
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 

 
 
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AND 
3. No other immediately apparent possible causes of AT 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 on dosing 
adjustments 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 Baseline visit. Non-
serious AE information should also be collected from any observational period intended 
to establish a baseline status for a patient.  
Non-serious adverse events should be followed until conclusion or stabilization, or 
reported as SAEs if they become serious.   Follow-up is also required for non-serious 
AEs that cause interruption or discontinuation of study drug or those that are present at 
the end of study treatment.  
8.2.2 
Laboratory Test Abnormalities 
The following laboratory test abnormalities should be captured on the non-serious AE 
CRF page or SAE Report Form (paper or electronic) as appropriate: 
1. Any laboratory test result that is clinically significant or meets the definition of an 
SAE; 
2. Any laboratory abnormality that required the 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 
If approximately 90% of the 600 subjects randomized to each treatment arm have a 
migraine in the allotted time period, there will be approximately 550 treated subjects per 
group.  
Based on approximations from the Phase IIb study, 550 subjects provides more than 95% 
power to detect a difference between rimegepant and placebo on the subject’s self-
reported most bothersome symptom. Also, based on the Phase IIb study, 550 subjects 
provides more than 95% power to detect a difference in freedom from pain at 2 hours.  
Having at least 95% power on each co-primary endpoint provides at least 90% power to 
detect a difference on both endpoints jointly.  
9.3 
Populations for Analysis 
• Enrolled subjects: Patients who sign an informed consent form and are assigned a 
subject identification number.  
• Randomized subjects: Enrolled subjects who receive a randomization treatment 
assignment from the IWRS (rimegepant or placebo). 
• Treated subjects: Enrolled subjects who take study therapy (rimegepant or placebo). 
• Modified Intent to Treat (mITT) subjects: randomized subjects that take study 
therapy, have a migraine of moderate or severe baseline intensity, and provide at least 
one evaluable, post-baseline, efficacy data point.  
 

 
 
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9.4 
Statistical Methods 
9.4.1 
Primary Endpoint(s) 
BHV-3000 (rimegepant) is tested for superiority to placebo, at an alpha=0.05 level, on 
both pain freedom at 2 hours post-dose and freedom the most bothersome symptom at 2 
hours post-dose. Both endpoints are evaluated using Cochran-Mantel Haenszel tests. The 
test for pain is stratified by the use of prophylactic migraine medication (yes or no). The 
test for the most bothersome symptom is also stratified by the use of prophylactic 
migraine medication (yes or no). These tests are conducted using the mITT subjects, with 
missing data at two hours imputed to be failure (i.e., Non-Completers = Failure;  NC=F). 
Sensitivity analyses are described in the Statistical Analysis Plan (SAP).  
9.4.2 
Secondary Endpoint(s) 
If the primary endpoint tests are both significant, then the secondary endpoints are 
evaluated using a hierarchical gate-keeping procedure, with each test in the hierarchy 
conducted at p=0.05.  These secondary endpoints will be tested in the following order: 
1. Photophobia freedom at 2 hours 
2. Phonophobia Freedom at 2 hours  
3. Pain Relief at 2 hours 
4. Nausea Freedom at 2 hours 
5. Probability of requiring rescue medication within 24 hours 
6. Sustained pain freedom from 2 to 24 hours 
7. Sustained Pain Relief from 2 to 24 
8. Sustained Pain Freedom 2 to 48 hours 
9. Sustained Pain Relief from 2 to 48 hours 
10. Pain relapse from 2 to 48 hours 
11. Proportion of patients able to work or function normally at 2 hours. 
9.4.3 
Analysis of Safety 
The investigators determine the intensity of AEs and the relationship of AEs to study 
therapy. The investigators’ terms are coded and grouped by system organ class using the 

 
 
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latest version of the Medical Dictionary for Regulatory Activities (MedDRA) available. 
AEs are presented by system organ class and preferred term, ordered by the overall 
frequency of events.  If a subject had an adverse event with different intensities over 
time, then only the greatest intensity is reported. 
AEs are tabulated in all treated subjects. SAEs occurring in subjects enrolled but not 
treated are listed. Deaths are listed for enrolled subjects without regard to onset. 
The frequencies of the following safety events are summarized by treatment regimen, and 
overall, for treated subjects:  SAEs; all AEs, non-serious AEs, AEs by intensity; and AEs 
by relatedness.. 
Graphical and tabular displays of liver function test results are provided.  
9.4.4 
Demographic and Baseline Characteristics 
Tabulations of demographic and baseline characteristics are made for: subjects 
randomized but not treated; subjects randomized and treated; and overall. A separate set 
of tabulations are made for subjects enrolled but not randomized. 
9.5 
Interim Analysis 
There is a final analysis after the last subject has his/her last visit.  No interim analyses 
are anticipated. 
 

 
 
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10 ETHICS AND RESPONSIBILITIES  
10.1 Good Clinical Practice 
This study will be conducted in compliance with the protocol, Good Clinical Practice 
(GCP), Good Laboratory Practice (GLP) 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 found to be well tolerated in previous clinical studies.  
Safety will be closely monitored via the sites and procedures for unblinding in cases of 
emergency will be followed.  
10.3 Institutional Review Board/Independent Ethics Committee 
The Investigators 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 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.  

 
 
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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.   
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.  

 
 
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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.  
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 

 
 
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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 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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APPENDICES 
 
PPD

 
 
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APPENDIX II – 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. 

 
 
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In medical research on human subjects, considerations related to the well-being of the 
human subject should take precedence over the interests of science and society. 
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 monitoring information to the 
committee, especially any SAEs. The researcher should also submit to the committee, for 

 
 
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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 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. 

 
 
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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 
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. 

 
 
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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 REFERENCES 
 
1. 
IHS, International Classificaton of Headache Disorders, 3rd edition beta version. 
2013. 
2. 
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. 
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 
 
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CN170002, Effect of BMS-927711 on the Pharmacokinetics of a Combined Oral 
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