Clinical trial NCT03461757
Conditions: Migraine, With or Without Aura
Sponsor: Pfizer
Start date: 2018-02-27; Completion date: 2018-10-15
Enrollment: 1811 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study is to compare the efficacy of BHV-3000 (rimegepant ODT) versus placebo in subjects with Acute Migraines.

Detailed description:

Arms: arm 1: Participants were administered a single sublingual dose of 75 mg of rimegepant ODT on occurrence of migraine that reached moderate or severe intensity up to 45 days after randomization. arm 2: Participants were administered a single sublingual dose of matching placebo for rimegepant (75 mg) ODT on occurrence of migraine that reached moderate or severe intensity up to 45 days after randomization.
Interventions: intervention 1: Rimegepant intervention 2: Placebo
Intervention descriptions: intervention 1: 75 mg ODT QD intervention 2: Placebo ODT to match rimegepant dose QD

Protocol documents:
Prot_000.pdf: 
 
 
 
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DRUG: 
BHV-3000 (rimegepant) 
 
STUDY NUMBER(S): 
BHV3000-303 
 
PROTOCOL(S) TITLE: 
BHV3000-303: Phase 3: Double-Blind, 
Randomized, Placebo Controlled, Safety and 
Efficacy Trial of BHV-3000 (rimegepant) Orally 
Disintegrating Tablet (ODT) for the Acute 
Treatment of Migraine  
IND NUMBER: 
109886 
SPONSOR: 
Biohaven Pharmaceutical Holding Company 
Limited 
 
ORIGINAL PROTOCOL 
DATE: 
3 January 2018  
 
VERSION NUMBER: 
V 4.0  
 
VERSION DATE: 
23 July 2018 




 
 
 
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Name and Title 
Signature Approval 
Date 
 
PPD


 
 
 
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SUMMARY OF CHANGES 
 
Change 
Page(s)  
Affected 
Summary 
1. 2.2 Secondary  
31 
Ten new secondary objectives were added to the exisiting 
11 objectives. The new objectives are: 
• Sustained Freedom from MBS from 2 to 24 hours 
• Sustained Freedom from MBS from 2 to 48 hours 
• Sustained Freedom from Functional Disability, 2 to 24 
hours  
• Sustained Freedom from Functional Disability, 2 to 48 
hours  
• Freedom of from functional disability at 90 minutes 
• Freedom from functional disability at 60 minutes 
• MBS freedom at 90 minutes 
• Pain freedom at 90 minutes 
• Pain relief at 90 minutes 
• Pain relief at 60 minutes 
 
2. Exploratory 
32 
Two exploratory endpoints were removed, and were 
promoted to be new secondary endpoints. These endpoints 
were: 
• Pain relief at 90 minutes 
• Pain relief at 60 minutes 
3. 3.2 Secondary 
34 
Ten new secondary endpoints were added that correspond 
to the new objectives discussed in change number 1. 
4. 9.4.2 Secondary 
Endpoints 
66 
The order of testing of the secondary endpoints was 
changed to accommodate the new endpoints. 


 
 
 
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BHV-3000-303 
BHV3000-303: Phase 3: Double-Blind, Randomized, Placebo 
Controlled, Safety and Efficacy Trial of BHV-3000 (rimegepant) 
Orally Disintegrating Tablet (ODT) for the Acute Treatment of 
Migraine  
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:  
BHV3000-303: Phase 3: Double-Blind, Randomized, Placebo Controlled, 
Safety and Efficacy Trial of BHV-3000 (rimegepant) Orally Disintegrating 
Tablet (ODT) for the Acute Treatment of Migraine 
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 orally disintegrating tablet (ODT) 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 subjects with an acute migraine will 
also be obtained. 
Target 
Population: 
The study will recruit male and female subjects 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 1775 subjects will be screened to randomize approximately 
1430 subjects (approximately 715 per arm).  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 


 
 
 
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treatment of moderate or severe migraine. The study drug will be 
rimegepant presented in a 75 mg ODT or matching placebo.  
The study will randomize approximately 1430 subjects. 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 subject whose usual migraine attack results in headache pain of 
moderate or severe intensity and who is otherwise found acceptable for 
entry into this trial based on inclusion and exclusion criteria will first 
participate in the screening phase (3 – 28 day period). Subjects on 
prophylactic migraine medication are permitted to remain on therapy 
provided they have been on a stable dose for at least 3 months prior to 
study entry.  
After randomization, the subject will be dispensed a single dose of the 
double-blind study medication that will be taken at the time a migraine 
attack reaches moderate or severe pain intensity (described below) on the 
numeric rating scale (NRS) as indicated in the electronic diary (eDiary). 
The subject will be instructed to take their study medication, as an 
outpatient, when (if) they have a migraine headache which reaches 
moderate or severe pain intensity and only after they have identified their 
most bothersome migraine-associated symptom (phonophobia, 
photophobia or nausea) in the eDiary. The subject will complete an eDiary 
for forty-eight hours after taking study medication. The subject will 
telephone the study center immediately if a severe or serious adverse event 
occurs. 
 
Subjects 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. Subject should not dose with study 
medication until headache reaches moderate to 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 


 
 
 
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bedrest) will be recorded at the same time points as the headache severity 
ratings. Subjects will also complete the migraine-specific quality-of-life 
questionnaire and preference of medication (PoM) scale 24 hours after 
dosing. Subjects who experience reduction of  headache pain to a mild 
intensity or pain free intensity level will be considered to have achieved 
pain relief. The subject who does not experience relief of their migraine 
headache at the end of 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. If at the end of 48-hours after dosing with study 
medication (but before the End of Treatment Visit) subjects are in need of 
migraine relief, they may take their prescribed standard of care 
medications, including triptans if not contraindicated, provided all of the 
assessments have been completed on the eDiary. Exclusionary rescue 
medication such as opioids, ergotamines, butalbital compounds, and 
muscle relaxants  (except baclofen as a rescue medication, see above) are 
not allowed 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 subject will be 
permitted to take the same rescue therapy as outlined above. In all 
circumstances, the subject will always continue to complete his or her 
eDiary for up to forty-eight hours after consuming the study medication. 
During the 45 days the subject is participating in the study, if the subject 
has a nonqualifying migraine (mild migraine) or a migraine that they do 
not treat with study medication, the subject is permitted to use only the 
following medications: aspirin, ibuprofen, naprosyn (or any other type of 
non- steroidal anti-inflammatory (NSAID)), antiemetics (e.g., 
metoclopramide or promethazine), or baclofen. 
Subjects will return to the study site within 7 days (+2) 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 subject has NOT experienced a migraine  
headache of sufficient severity within 45 days after randomization, they 


 
 
 
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still are required to complete all EOT visit procedures.  All subjects must 
return 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) ..................................................................................6 
STUDY SCHEMATIC ....................................................................................................10 
TABLE OF CONTENTS ................................................................................................11 
LIST OF ABBREVIATIONS .........................................................................................16 
1 
INTRODUCTION AND RATIONALE .................................................................19 
1.1 
THERAPEUTIC AREA BACKGROUND .......................................................19 
1.2.2.8 
DOSE-RANGING TRIAL OF RIMEGEPANT FOR ACUTE 
MIGRAINE (CN170003) .........................................................................25 
1.2.3.4 
PHASE 1 STUDIES .................................................................................26 
1.2.3.5 
ONGOING PHASE 2/3 STUDIES IN ACUTE MIGRAINE ..............26 
1.2.4 
CLINICAL ADVERSE EVENT PROFILE ................................................27 
1.3 
STUDY RATIONALE .........................................................................................27 
1.3.1 
STUDY DESIGN RATIONALE ..................................................................29 
1.3.2 
DOSE SELECTION RATIONALE .............................................................29 
1.3.3 
OTHER RATIONALE RELATED TO THE 
COMPOUND/STUDY ...................................................................................30 
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1.4 
RESEARCH HYPOTHESIS ..............................................................................30 
2 
STUDY OBJECTIVES ............................................................................................30 
2.1 
PRIMARY ............................................................................................................30 
2.2 
SECONDARY ......................................................................................................31 
2.3 
EXPLORATORY ................................................................................................32 
3 
STUDY ENDPOINTS ..............................................................................................34 
3.1 
PRIMARY ............................................................................................................34 
3.2 
SECONDARY ......................................................................................................34 
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).............................................................43 
4.3.2 
ACUTE (RANDOMIZATION) PHASE (45 DAYS) ..................................43 
4.3.2.1 
EDIARY DATA COLLECTION ...........................................................43 
4.3.3 
EXTENSION PHASE ....................................................................................44 
4.3.4 
END OF TREATMENT (7 DAYS AFTER TREATMENT) .....................45 
4.4 
POST STUDY ACCESS TO THERAPY ..........................................................45 
5 
POPULATION ..........................................................................................................45 
5.1 
NUMBER OF SUBJECTS ..................................................................................45 
5.2 
INCLUSION CRITERIA ....................................................................................45 
5.3 
EXCLUSION CRITERIA ...................................................................................46 
5.4 
PROHIBITED CONCOMITANT MEDICATION ..........................................49 
5.4.1 
RESCUE MEDICATIONS ...........................................................................50 
5.5 
WOMEN OF CHILDBEARING POTENTIAL ...............................................51 
5.6 
OTHER RESTRICTIONS AND PRECAUTIONS (IF APPLICABLE) ........51 
5.7 
DEVIATION FROM INCLUSION/EXCLUSION CRITERIA ......................51 
6 
STUDY CONDUCT AND DESCRIPTION OF STUDY PROCEDURES .........52 
6.1 
STUDY MATERIALS .........................................................................................52 
6.2 
SAFETY ASSESSMENTS ..................................................................................53 
6.2.1 
VITAL SIGNS AND PHYSICAL MEASUREMENTS (HEIGHT 
AND WEIGHT) .............................................................................................53 
6.2.2 
ELECTROCARDIOGRAM (ECG) .............................................................53 
6.2.3 
PHYSICAL EXAM ........................................................................................53 
6.2.4 
LABORATORY ASSESSMENTS ...............................................................53 
6.2.4.1 
SAFETY LABORATORY TESTING ...................................................53 
6.2.4.2 
PREGNANCY TESTING .......................................................................54 
6.2.5 
SHEEHAN SUICIDE TRACKING SCALE ...............................................54 


 
 
 
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6.3 
EFFICACY ASSESSMENTS .............................................................................54 
6.3.1 
PAIN ................................................................................................................54 
6.3.2 
NAUSEA, PHONOPHOBIA AND PHOTOPHOBIA ................................55 
6.3.3 
RESCUE MEDICATION .............................................................................55 
6.3.4 
FUNCTIONAL DISABILITY ......................................................................55 
6.3.5 
MIGRAINE QUALITY OF LIFE QUESTIONNAIRE .............................55 
6.3.6 
MIGRAINE PREFERENCE OF MEDICINE ............................................55 
6.4 
EARLY DISCONTINUATION FROM THE STUDY .....................................56 
7 
STUDY DRUG MANAGEMENT ...........................................................................57 
7.1 
DESCRIPTION OF STUDY DRUG ..................................................................57 
7.1.1 
INVESTIGATIONAL PRODUCT...............................................................57 
7.1.2 
NON-INVESTIGATIONAL PRODUCT ....................................................57 
7.1.3 
PACKAGING, SHIPMENT AND STORAGE ...........................................57 
7.2 
DOSE AND ADMINISTRATION .....................................................................57 
7.2.1 
METHOD OF ASSIGNING SUBJECT IDENTIFICATION ...................57 
7.2.2 
SELECTION AND TIMING OF DOSE AND 
ADMINISTRATION .....................................................................................58 
7.2.3 
DOSE MODIFICATIONS ............................................................................58 
7.3 
BLINDING AND UNBLINDING .......................................................................58 
7.4 
TREATMENT COMPLIANCE .........................................................................59 
7.5 
DESTRUCTION AND RETURN OF STUDY DRUG .....................................59 
8 
ADVERSE EVENTS ................................................................................................59 
8.1 
SERIOUS ADVERSE EVENT ...........................................................................60 
8.1.1 
DEFINITION OF SERIOUS ADVERSE EVENT (SAE) ..........................60 
8.1.2 
COLLECTION AND REPORTING SERIOUS ADVERSE 
EVENTS..........................................................................................................61 
8.1.3 
OVERDOSE ...................................................................................................63 
8.1.4 
PREGNANCY ................................................................................................63 
8.1.5 
POTENTIAL DRUG INDUCED LIVER INJURY (DILI) .......................63 
8.2 
NON-SERIOUS ADVERSE EVENTS ...............................................................64 
8.2.1 
COLLECTION AND REPORTING OF NON-SERIOUS 
ADVERSE EVENTS .....................................................................................64 
8.2.2 
LABORATORY TEST ABNORMALITIES ..............................................64 
9 
STATISTICS .............................................................................................................65 
9.1 
GENERAL PROCEDURES ...............................................................................65 
9.2 
SAMPLE SIZE .....................................................................................................65 
9.3 
POPULATIONS FOR ANALYSIS ....................................................................65 
9.4 
STATISTICAL METHODS ...............................................................................66 
9.4.1 
PRIMARY ENDPOINT(S) ...........................................................................66 


 
 
 
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9.4.2 
SECONDARY ENDPOINT(S) .....................................................................66 
9.4.3 
ANALYSIS OF SAFETY ..............................................................................66 
9.4.4 
DEMOGRAPHIC AND BASELINE CHARACTERISTICS ...................66 
9.5 
INTERIM ANALYSIS ........................................................................................67 
10 ETHICS AND RESPONSIBILITIES .....................................................................68 
10.1 
GOOD CLINICAL PRACTICE ........................................................................68 
10.2 
DATA AND SAFETY MONITORING COMMITTEE ..................................68 
10.3 
INSTITUTIONAL REVIEW BOARD/INDEPENDENT ETHICS 
COMMITTEE ......................................................................................................68 
10.4 
INFORMED CONSENT .....................................................................................69 
10.5 
CASE REPORT FORMS ....................................................................................70 
10.6 
RECORDS MANAGEMENT AND RETENTION ..........................................70 
10.7 
SOURCE DOCUMENTATION .........................................................................71 
10.8 
STUDY FILES AND RECORD RETENTION ................................................71 
11 AMENDMENTS .......................................................................................................71 
12 STUDY REPORT AND PUBLICATIONS ............................................................72 
13 STUDY DISCONTINUATION ...............................................................................72 
14 CONFIDENTIALITY ..............................................................................................72 
15 APPENDICES ...........................................................................................................73 
15.2 
APPENDIX II – DECLARATION OF HELSINKI .........................................74 
15.3 
APPENDIX III – STRONG CYP3A4 INHIBITORS AND 
INDUCERS (NOT ALL INCLUSIVE) ..............................................................79 
16 REFERENCES .........................................................................................................80 
 
 
 
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LIST OF TABLES 
Table 1:  
Schedule of Assessments ..........................................................................38 
 
 
 


 
 
 
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LIST OF ABBREVIATIONS 
 
ACS 
ADHD 
AE 
 
Acute Coronary Syndrome 
Attention Deficit Hyperactivity Disorder 
Adverse Event  
ALT 
Alanine Aminotransferase 
AST 
Aspartate Aminotransferase 
AUC 
Area Under the Curve 
BID 
BHV 
Twice Daily 
Biohaven Pharmaceuticals  
BP 
Blood Pressure 
BUN 
Blood Urea Nitrogen 
Cmax 
Cmin 
CGRP 
CNS 
Maximum Plasma Concentration 
Minimum Concentration 
Calcitonin gene-related peptide 
Central Nervous System 
CONMED 
Concomitant Medication 
CRO 
CV 
DILI 
Clinical Research Organizations 
Coefficient of Variation 
Drug induced liver injury 
DSMC 
DSM V 
Data and Safety Monitoring Committee 
Diagnostic and Statistical manual of mental Disorders Fifth edition 
EC 
ECG 
eCRF 
EDC 
eDiary 
EE 
Ethics Committee 
Electrocardiogram 
Electronic case report forms 
Electronic Data Capture 
Electronic Diary 
Ethinyl Estradiol 
PPD


 
 
 
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eGFR 
EOT 
ePRO 
FDA 
Glomerular Filtration Rate 
End of Treatment  
Electronic Patient Reported Outcome 
Food and Drug Administration 
FSH 
Follicle Stimulating Hormone 
GCP 
GLP 
HIV 
Good Clinical Practice 
Good Laboratory Practice 
Human Immunodeficiency Virus 
HR 
HRT 
Heart Rate 
Hormone Replacement Therapy 
IB 
ICF 
Investigator Brochure 
Informed Consent Form 
ICH 
International Conference on Harmonization 
IHS 
IEC 
IP 
International Headache Society 
Independent Ethics Committee 
Investigational Product 
IRB 
Institutional Review Board 
Iv 
IWRS 
LDH 
LDL 
LOCF 
Intravenous 
Interactive Web Response System 
Lactate Dehydrogenase 
Low-density lipoprotein 
Last Observation Carried Forward 
kg 
Kilogram 
kBq 
MBS 
MBq 
MDRD 
MedRA 
mITT 
mg 
Kilobecquerel 
Most bothersome Symptom 
Megabecquerel 
Modification of Diet in Renal Disease 
Medical Dictionary for Regulatory Activities  
Modified Intent to Treat  
Milligram 


 
 
 
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MI 
Min 
MQoLQ 
Myocardial Infarction  
Minute 
Migraine-Specific Quality-of-Life Questionnaire  
msecs 
MTD 
NSAIDs 
NRS 
OC 
Milliseconds 
Maximum tolerated dose 
Non-Steroidal Anti-Inflammatories 
Numeric Rating Scale  
Oral Contraceptive 
ODT 
PCI 
Orally disintegrating tablet 
Percutaneous Coronary Intervention 
PCP 
PK 
PoM 
PVG 
Phencyclidine 
Pharmacokinetic 
Preference of Medication  
Pharmacovigilance 
QD 
QTc 
Once Daily 
Interval between Q-wave and T-wave in the cardiac cycle 
SAE 
TBL 
TIA 
Serious Adverse Event 
Total Bilirubin  
Transient Ischemic Attack 
ULN 
USPI 
WBC 
Upper Limit of Normal 
US Prescribing Information  
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 
Migraine is a common and debilitating neurological disorder that affects approximately 
15% of the adult population. It is characterized by moderate-to-severe episodic unilateral 
pulsating headaches that last for 4 to 72 hours. Typical characteristics of the headache are 
unilateral location, pulsating quality, moderate or severe intensity, aggravation by routine 
physical activity, and association with nausea and/or photophobia and phonophobia.  
BHV-3000 (rimegepant, /rih-MEJ-eh-pant/) is a calcitonin gene-related peptide (CGRP) 
receptor antagonist in development for the acute treatment of migraine. The CGRP 
receptor is located within pain-signaling pathways, intracranial arteries and mast cells and 
its activation is thought to play a causal role in migraine pathophysiology. For example, 
research and clinical studies have shown: serum levels of CGRP are elevated during 
migraine attacks, infusion of intravenous CGRP produces persistent pain in migraine 
sufferers and non-migraine sufferers, and treatment with anti-migraine drugs normalize 
CGRP levels. Additionally, multiple clinical studies show that small molecule CGRP 
receptor antagonists, which inhibit the binding of endogenous CGRP to CGRP receptors, 
are effective in aborting migraine attacks. Treatment with a CGRP receptor antagonist is 
believed to relieve migraine through the possible mechanisms of 1) blocking neurogenic 
inflammation, 2) decreasing artery dilation, and 3) inhibiting pain transmission. This new 
approach to the treatment of migraine avoids the cardiovascular effects produced by 
active vasoconstriction associated with the current standard triptan therapy (non-selective 
5-HT1B/1D agonists (e.g., sumatriptan [Imitrex™]). 
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1.2.2.8 
Dose-ranging trial of rimegepant for acute migraine (CN170003) 
Study CN170003 [2] 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 
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 [7].  This dose was selected as the optimal dose to support Phase 3 clinical 
trials, given that larger doses showed a similar efficacy profile and there was negligible 
benefit identified with larger doses, consistent with previously published migraine studies 
characterizing the dose-response profiles of acute treatments for migraine [8].   
Rimegepant at 75 mg showed statistically significant efficacy across all four traditional 
endpoints at 2 hr (pain, nausea, photophobia and phonophobia) which was durable and 
persisted through 24 hr.  At 2 hr following a single oral dose of 75 mg, subjects 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).   
In conclusion, Study CN170003[2] 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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1.2.3.4 
Phase 1 Studies 
There is currently a series of Clinical Pharmacology studies being conducted with 
rimegepant. Relevant information will be provided in the Investigator Brochure or 
protocol when available. 
1.2.3.5 
Ongoing Phase 2/3 Studies in Acute Migraine 
Currently there are three ongoing Phase 2/3 trials being conducted with rimegepant using 
the 75 mg dose for the acute treatment of migraine. The BHV3000-301 study and 
BHV3000-302 study are single dose Phase 3 studies in the acute treatment of migraine.  
CCI


 
 
 
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Both studies are randomized, double-blind, placebo-controlled studies.  Each study 
randomized approximately 1200 subjects and both are expected to complete in early 
2018.  Additionally, the BHV3000-201 study is a Phase 2/3, 52-week, open-label, safety 
study that is designed to enroll approximately 2000 subjects.  Enrollment is ongoing, and 
the study is expected to continue through the end of 2018/early 2019. 
1.2.4 
Clinical Adverse Event Profile 
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 current version of 
Investigators Brochure for a summary of the clinical safety profile.  
The primary identified AE of interest is potential change in liver function tests. 
Investigators must carefully monitor routine liver function tests (ALT, AST, total 
bilirubin, and ALP) and potentially liver related symptoms and signs. Clinicians should  
also monitor changes in hematology and other laboratory measures. Please refer to the 
current Investigators Brochure for further information regarding the clinical safety profile 
of rimegepant.  
1.3 
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 


 
 
 
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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 risk factors.  The US Prescribing Information (USPI) 
for triptans includes warnings and precautions for migraine subjects with risk factors for 
cardiovascular disease and states that high risk subjects, including those with increased 
age, diabetes, hypertension, smoking, obesity or a strong family history of coronary 
artery disease, should be evaluated prior to receiving the first dose of a triptan. Triptans 
are contraindicated in subjects with a history of ischemic heart disease, coronary artery 
vasospasm, history of stroke, peripheral vascular disease or uncontrolled hypertension. 
Even in subjects 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 [2] 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 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. 


 
 
 
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1.3.1 
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 ODT (administered 
sublingually) or a matching placebo. The subjects will be instructed to take their study 
medication, as an outpatient, when (if) they have a migraine headache which reaches 
moderate or severe intensity.  
The study will randomize approximately 1430 subjects. 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 subjects with a broad range of comorbidities, 
including cardiovascular conditions, representative of the potential treatment population. 
1.3.2 
Dose Selection Rationale 
Study CN170003 was a double-blind, randomized, placebo-controlled, dose-ranging trial 
of rimegepant for the acute treatment of migraine [7].  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 


 
 
 
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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, 
subjects 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, subjects also showed significant 
freedom from nausea (67.4%, p = 0.0074) freedom from phonophobia (52.3%, p = 
0.0001) and freedom from photophobia (41.9%, p = 0.0023) vs. placebo (51.2%, 28.1% 
and 24.1%, respectively).  The lasting nature of these beneficial anti-migraine effects 
were evidenced by a comparatively similar efficacy profile in the 2-24 hr measures, 
where rimegepant at 75 mg produced significant 2-24 hr sustained pain freedom (27.9%, 
p < 0.0001) and 2-24 hr sustained pain relief (69.8%, p < 0.0001) vs. placebo (7.4% and 
42.4%, respectively).   
1.3.3 
Other Rationale related to the compound/study 
Prior to initiation of this study, a Phase 1 crossover study will be conducted in healthy 
volunteers to assess the pharmacokinetic comparability of a single dose of the rimegepant 
ODT with the previously studied rimegepant tablet. This information will be incorporated 
in a future version of the Investigator Brochure. 
1.4 
Research Hypothesis 
Rimegepant will have efficacy superior to placebo in the treatment of acute migraine with 
a favorable safety profile suitable for use by a broad subject population. 
2 STUDY OBJECTIVES 
2.1 
Primary 
To evaluate the efficacy of rimegepant compared with placebo in the acute treatment of 
migraine as measured by the co-primary endpoints of pain freedom and freedom from 
the most bothersome symptom (MBS), associated with migraine, at two hours post 
dose.   
 
 


 
 
 
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2.2 
Secondary 
1) To evaluate rimegepant compared to placebo on pain relief at 2 hours post-dose 
 
2) To evaluate the effect of rimegepant relative to placebo on the ability to function 
normally at 2 hours post-dose as reported on the Functional Disability scale. 
 
3) To evaluate rimegepant compared to placebo on sustained pain relief from 2 to 
24 hours post-dose 
 
4) To evaluate rimegepant compared to placebo on sustained freedom from the 
most bothersome symptom, associated with migraine, from 2 to 24 hours post-
dose. 
 
5) To evaluate rimegepant compared to placebo on the probability of requiring 
rescue medication within 24 hours of initial treatment 
 
6) To evaluate rimegepant compared to placebo on the sustained ability to function 
at a normal level, as measured by the functional disability scale, from 2 to 24 
hours post-dose. 
 
7) To evaluate rimegepant compared to placebo on sustained pain relief from 2 to 
48 hours post-dose 
 
8) To evaluate rimegepant compared to placebo on freedom from the most 
bothersome symptom, associated with migraine, from 2 to 48 hours post-dose. 
 
9) To evaluate rimegepant compared to placebo on the sustained ability to function 
at a normal level, as measured by the functional disability scale, from 2 to 48 
hours post-dose. 
 
10) To evaluate rimegepant compared to placebo on freedom from photophobia at 2 
hours post-dose 
 
11) To evaluate the effect of rimegepant relative to placebo on the ability to function 
at a “normal” level at 90 minutes post-dose as reported on the Functional 
Disability scale 
 
12) To evaluate rimegepant compared to placebo on pain relief at 90 minutes post-
dose 


 
 
 
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13) To evaluate rimegepant compared to placebo on sustained pain freedom from 2 
to 24 hours post-dose 
 
14) To evaluate rimegepant compared to placebo on freedom from the most 
bothersome symptom, associated with migraine, at 90 minutes post-dose. 
 
15) To evaluate rimegepant compared to placebo on pain freedom at 90 minutes 
post-dose 
 
16) To evaluate rimegepant compared to placebo on freedom from phonophobia at  
2 hours post-dose 
 
17) To evaluate rimegepant compared to placebo on sustained pain freedom from 2 
to 48 hours post-dose 
 
18) To evaluate rimegepant compared to placebo on pain relief at 60 minutes post-
dose 
 
19) To evaluate the effect of rimegepant relative to placebo on the ability to function 
at a “normal” level at 60 minutes post-dose, as reported on the Functional 
Disability scale. 
 
20) To evaluate rimegepant compared to placebo on freedom from nausea at 2 hours 
post-dose 
 
21) To evaluate rimegepant compared to placebo for the incidence of pain relapse 
from 2 to 48 hours post-dose 
2.3 
Exploratory  
• To evaluate the effect of rimegepant relative to placebo on the subjects ability to work 
or function at 24 hrs post dose according to the Functional Disability scale 
• To evaluate rimegepant compared to placebo on pain relief at 30 minutes post-dose 
• To evaluate rimegepant compared to placebo on pain relief at 15 minutes post-dose 
• To evaluate the effect of rimegepant relative to placebo on the Migraine Preference 
of Medication (PoM) 


 
 
 
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• To evaluate rimegepant relative to placebo for pain relief on the 4 point scale at all 
scheduled time points post dose 
• To evaluate the effect of rimegepant relative to placebo on the Migraine Quality of 
Life (MQoLQ) 
• To evaluate the tolerability and safety of rimegepant 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 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 
 
1) Pain Relief at 2 hours post-dose, will be assessed using the number of subjects 
that report a pain level of moderate or severe at baseline and then report a pain 
level of none or mild at two hours post-dose. 
 
2) The proportion of subjects able to function normally, at 2 hours post-dose, will 
be assessed using the number of subjects that self-report as “normal” on the 
Functional Disability scale. 
 
3) 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. 
 
4) Sustained freedom from the most bothersome symptom, from 2 to 24 hours, 
will be assessed using the number of subjects that do not experience their most 
bothersome symptom through the time period of interest.  
 
5) 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 (rimegepant or placebo). 
 
6) Sustained ability to function at a normal level, from 2 to 24 hours, will be 
assessed using the number of subjects  that self-report as “normal” on the 
Functional Disability scale through the time period of interest.  
 


 
 
 
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7) 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. 
 
8) Sustained freedom from the most bothersome symptom, from 2 to 48 hours, 
will be assessed using the number of subjects that do not experience their most 
bothersome symptom through the time period of interest.  
 
9) Sustained ability to function at a normal level, from 2 to 48 hours, will be 
assessed using the number of subjects  that self-report as “normal” on the 
functional disability scale through the time period of interest.  
 
10) 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. 
 
11) The proportion of subjects able to function normally, at 90 minutes post-dose, 
will be assessed using the number of subjects that self-report as “normal” on the 
functional disability scale. 
 
12) Pain relief at 90 minutes post-dose, will be assessed using the number of 
subjects that report a pain level of moderate or severe  at baseline and then report 
a pain level of none or mild at 90 minutes post-dose. 
 
13) 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.  
 
14) Freedom from the most bothersome symptom (MBS) will be assessed using 
the number of evaluable subjects that report the absence of their MBS at 90 
minutes post-dose.   
 
15) Pain freedom will be assessed using the number of evaluable subjects that report 
no pain at 90 minutes post-dose.  
 
16) 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. 


 
 
 
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17) 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. 
 
18) Pain Relief at 60 minutes post-dose, will be assessed using the number of 
subjects that report a pain level of moderate or severe at baseline and then report a 
pain level of none or mild at 60 minutes post-dose. 
 
19) The proportion of subjects able to function normally, at 60 minutes post-dose, 
will be assessed using the number of subjects that self-report as “normal” on the 
functional disability scale. 
 
20) 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. 
 
21) 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). 
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-STS) 
• 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. Subjects will be dispensed one dose of study medication consisting of a 
rimegepant 75 mg ODT (administered sublingually) 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 subject 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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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. 
5 Screening Visit: All screening visit laboratory test results must be received prior to Baseline (randomization) 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. WOCBP subjects must complete the urine pregnancy test at home prior to taking study medication. 
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. SAEs that occur during the treatment period should be reported to site in real time.  Non-
serious AEs that occur during the treatment period should be reported to the site at the EOT.  
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 Subjects will be randomized in the IWRS system at the Baseline Visit (Randomization Day 01). 
10 Subjects should be instructed that the dose should be taken once the migraine attack reaches moderate or severe pain and after the subject has completed all required 
migraine assessments in the eDiary.  The eDiary will prompt the subject to take study medication.   
11 Site staff to review and confirm entries with subjects and confirm all data points are transferred to the system and reset eDiary for future subject use, PRIOR to the 
subject leaving the clinic. 
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. Subjects 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. Subjects will also be asked about their typical most bothersome symptom when having a migraine. 
15Subjects should return to the site for their EOT visit within 7 (+2) days from their migraine occurring.  


 
 
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4.3.1 
Screening Phase (3-28 days) 
It is estimated that approximately 1775 subjects will be screened to allow approximately 1430 
subjects to be randomized at the Baseline visit. All subjects who are screened into the study 
will be entered into the IWRS system. After obtaining informed consent, subjects will undergo 
all screening procedures as detailed in Table 1. After all screening procedures are complete, 
subjects may return 3-28 days from signing informed consent to be randomized at the Baseline 
visit if they meet all eligibility criteria.  
Subjects in this study may be screened only once. Rescreening is not permitted. 
4.3.2 
Acute (Randomization) Phase (45 days) 
If the subject meets all eligibility criteria they will be randomized at the Baseline Visit via the 
IWRS. The subjects will be provided with an eDiary. The study personnel will instruct the 
subject on the proper use of the eDiary and ensure proper understanding and use of the tool, 
prior to the subject leaving the office. 
After randomization via the IWRS, the subject 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 subject 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 subject will complete an eDiary for forty-eight hours after taking 
study medication to record efficacy and other quality of life measures.  
Subjects in this study may be randomized only once. Under no circumstances may a subject be 
re-randomized.  
 
4.3.2.1 
eDiary Data Collection  
 
Subjects will record efficacy and other quality of life measures 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 subjects 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. Subjects will also identify their currently most bothersome symptom before 


 
 
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taking study medication. Subjects will record the date and time study therapy was taken in their 
eDiary. Subjects will also complete the migraine-specific quality-of-life questionnaire 
(MQoLQ) and preference of medication (PoM) 24 hours after dosing. Subjects 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 subject 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) subject may take their prescribed standard of care medications for treatment of 
migraine, including triptans if not contraindicated, provided all of the assessments have been 
completed on the eDiary. Exclusionary rescue medication such as, opioids, ergotamines, 
butalbital compounds, and muscle relaxants (except baclofen as a rescue medication, see 
above) are not allowed on this study. Similarly, if the migraine is relieved by study medication 
at 2 hours after dosing but then recurs to a moderate or severe intensity level between two and 
forty-eight hours, the subject will be permitted to take the same rescue therapy as outlined 
above.   
 
Subjects should be encouraged to treat the first qualifying (moderate to severe) migraine that 
occurs during the treatment phase. If subjects are unable to treat their first qualifying migraine 
due to scheduling, etc. the same medication restrictions would still apply (i.e. ) aspirin, 
ibuprofen, acetaminophen up to 1000mg/day (this includes Excedrin Migraine) naproxen (or 
any other type of nonsteroidal anti-inflammatory (NSAID)), antiemetics (e.g., metoclopramide, 
promethazine, or baclofen).  
 
Similarly, for treatment of non-qualifying migraines (i.e. mild migraines, or other headaches) 
that occur during the randomization period before a qualifying migraine is reported, subject 
will only be permitted to use the medications listed above. Triptans and acetaminophen (over 
1000mg/day) are prohibited after randomization except as rescue medication as described in 
Section 5.4.1.  In all circumstances, the subject 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 


 
 
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4.3.4 
End of Treatment (7 days after Treatment) 
Subjects 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 subject has  NOT  
experienced a migraine headache of sufficient severity within 45 days after randomization, they 
still are required to complete all EOT visit procedures.  All subjects must return unused study 
medication and eDiary to the study center.   
4.4 
Post Study Access to Therapy  
At the end of the study the sponsor will not continue to supply study drug to 
subjects/investigators. The investigator should ensure that the subject receives the appropriate 
standard of care to treat the condition under study.  
5 POPULATION 
Individuals entered in this trial will be subjects who suffer from migraines. The treatment 
setting for these subjects may include clinics, institutions or private office practices. Subjects 
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 approximately 1775 subjects will need to be screened in order to 
randomize approximately 1430 subjects. 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 70 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 subject in accordance with 
requirements of the study center’s institutional review board (IRB) or ethics 
committee, prior to the initiation of any protocol-required procedures. 
2. Target Population 
Subjects 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 


 
 
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c) Not more than 8 attacks of moderate or severe intensity per month within last 3 
months 
d) Subjects 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) Subjects on prophylactic migraine medication are permitted to remain on therapy 
if they have been on a stable dose for at least 3 months prior to screening visit, 
and the dose is not expected to change during the course of the study 
h) Subjects with contraindications for use of triptans may be included provided they 
meet all other study entry criteria 
3. Age and Reproductive Status 
a) Male and Female subjects ≥ 18 years and older 
b) Women of childbearing potential (WOCBP) with male partners and men with 
women partners of childbearing potential 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 the screening visit 
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 urine pregnancy test 
e) Women must not be breastfeeding 
5.3 
Exclusion Criteria 
1. Disease Target Exclusion 
a) Subjects has a history of basilar migraine or hemiplegic migraine 
2. Medical History and Concurrent Diseases 
a) Subjects history of  HIV disease 
b) Subject history with current evidence of uncontrolled, unstable or recently 


 
 
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diagnosed cardiovascular disease, such as ischemic heart disease, coronary artery 
vasospasm, and cerebral ischemia. subjects with Myocardial Infarction (MI), 
Acute Coronary Syndrome (ACS), Percutaneous Coronary Intervention (PCI), 
cardiac surgery, stroke or transient ischemic attack (TIA) during the 6 months 
prior to screening 
c) Uncontrolled hypertension (high blood pressure), or uncontrolled diabetes 
(however subjects can be included who have stable hypertension and/or diabetes 
for at least 3 months prior to being enrolled) 
d) Subject 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) Subject has a history of gastric, or small intestinal surgery (including Gastric 
Bypass, Gastric Banding, Gastric Sleeve, Gastric Balloon, etc.), or has a disease 
that causes malabsorption 
f) The subject 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 subjects 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) Subjects should be excluded if they have a positive drug screen for drugs of abuse 
that in the investigator’s judgment is medically significant, in that it would impact 
the safety of the subject or the interpretation of the study results. In addition: 
i) Detectable levels of cocaine, amphetamine, and phencyclidine (PCP) in the 
drug screen are exclusionary. Subjects who are positive for amphetamines, 
and who are on a prescribed amphetamine medication for an approved 
indication (e.g. ADHD) will be allowed into the study at the Investigator’s 
discretion.  This determination by the Investigator must be well documented 
in the subject’s source medical records.  The stimulant dose must be stable 
from 3 months prior to baseline until the end of treatment visit occurs.    
ii) Detectable levels of marijuana in the drug screen are not exclusionary, if in  
the investigator’s documented opinion the subject does not meet DSM-V  
criteria [15] for substance use disorder, and the positive test does not signal a 
clinical condition that would impact the safety of the subject or interpretation 
of the study results. 
i) Hematologic or solid malignancy diagnosis within 5 years prior to screening. 
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eligible for the study if they are cancer-free prior to the screening visit in this 
study.   
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), at Screening 
c) Left Bundle Branch block 
d) Right Bundle Branch Block with a QRS duration ≥ 150 msec. 
e) Intraventricular Conduction Defect with a QRS duration ≥ 150 msec. 
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) Participation in clinical trial with non-biological investigational agents or 
investigational interventional treatments within the 30 days prior to Baseline Visit 
d) Subjects who have previously participated in any BHV-3000/ BMS-927711/ 
rimegepant study within the last 2 years 
e) Participation in clinical trial with biological investigational agents within the 90 
days prior to Baseline visit 
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prior to Screening and during the study 
g) Participation in any other investigational clinical trial while participating in this 
clinical trial 
7. Please see 5.4 for Prohibited medications and 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. Barbiturate-containing products (e.g. Fioricet, Fiorinal, butalbital, phenobarbital) 
should not be taken 14 days prior to randomization and throughout the study.  
3. Modafinil (PROVIGIL®) should not be taken 14 days prior to randomization and 
throughout the study. 
4. Butterbur root or extracts should not be taken 14 days prior to randomization and 
throughout the study. 
5. History of use of ergotamine medications on greater than/equal 10 days per month  on 
a regular basis for greater than/equal 3 months. 
6. History of non-narcotic analgesic intake on greater than/equal 15 days per month for 
greater than/equal 3 month (e.g. acetaminophen, NSAIDs, gabapentin etc.) for other 
pain indications. (Please refer to Section 5.4.1 for rescue medication). 
7. Use of narcotic medication, such as opioids (e.g. morphine, codeine, oxycodone and 
hydrocodone) for at least 2 days prior to randomization. 
8. Use of all acetaminophen or acetaminophen containing products must be discontinued 
at least 2 days prior to randomization (acetaminophen < 1000mg/day is allowed as 
rescue medication, see Section 5.4.1). During the screening phase (3-28 days) use of 
acetaminophen or acetaminophen containing products at daily dosing levels of greater 
than 1000mg/day is prohibited.   
9. Use of marijuana is prohibited during the study. 
10. Muscle relaxants (baclofen is allowed as rescue medication, see Section 5.4.1). 
11. Concomitant use of strong CYP3A4 inhibitors with rimegepant is prohibited during 
the study. If use of a strong CYP3A4 inhibitor is required, such as use of HIV Protease 
Inhibitors, Hepatitis C protease inhibitors, certain azole antifungals, or clarithromycin, 
dosing with rimegepant should be stopped and should not start again until 14 days 
after the last dose of the strong CYP3A4 inhibitor. Please see Appendix 3 
12. Concomitant use of strong CYP3A4 inducers with rimegepant is prohibited during the 
study. If use of a strong CYP3A4 inducer is required, such as use of carbamazepine, 
phenytoin, or rifampin, dosing with rimegepant should be stopped and should not start 
again until 14 days after the last dose of the strong CYP3A4 inducer. Please see 
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Appendix 3. 
Subjects on prophylactic migraine medication are permitted to remain on therapy provided they 
have been on a stable dose for at least 3 months prior to study entry.  
Low dose aspirin (e.g. 81 mg or less) for documented cardiovascular prophylaxis is allowed. 
5.4.1 
Rescue Medications 
After dosing with study medication, all other headache medication is prohibited during the 2 
hours post dose. However, a subject who does not experience relief of their migraine headache 
at the end of 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) subject may take their prescribed standard of 
care medications for treatment of migraine (including triptans if not contraindicated, provided 
all of the assessments have been completed on the eDiary. 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 subject will be permitted to take the same rescue 
therapy as outlined above. In all circumstances, the subject will always continue to complete 
his or her eDiary entries through the 48-hour assessment after consuming the study medication. 
Use of concomitant medication after randomization, including rescue medication, will be 
recorded by the subject on a paper diary and reported to the site. The site will record 
medications that were taken within 14 days of dosing with study medication (or until the End of 
Treatment Visit).  
During the 45 days the subject is participating in the study, if the subject has a nonqualifying 
migraine (mild migraine) or a migraine that they do not treat with study medication, the subject 
is permitted to use only the following medications: aspirin, ibuprofen, naprosyn (or any other 
type of non- steroidal anti-inflammatory (NSAID)), antiemetics (e.g., metoclopramide or 
promethazine), or baclofen. 
After completing all assessments (through 48 hours and before End of Treatment Visit) in their 
eDiary, if subjects experience a migraine they are allowed to take their prescribed standard of 
care medication (including triptans if not contraindicated and acetaminophen up to 
1000mg/day, this includes Excedrin Migraine). 


 
 
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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) with male partners and men with women partners 
of childbearing potential must be using two acceptable methods of contraception to avoid 
pregnancy throughout the study and for up to 56 days after the last dose of investigational 
product in such a manner that risk of pregnancy is minimized. It is required that all WOCBP 
use two methods of contraception for the duration of the study (i.e. beginning before treatment 
with the 1 dose of study medication to 56 days after dosing). The two methods should include 
one barrier method (i.e. 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. Subjects 
should not take Investigational Study Drug if they are pregnant and subject 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. Clinically significant 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 subject)  
• Investigator Brochure 
• Interactive Web-based Response System (IWRS) 
• Electronic Case Report Form (eCRF) instructions 
• Electronic Diary (eDiary): 1 will be given to each randomized subject 
• 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 subject in the eDiary will be transferred from the site/ subject 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 subject 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 the 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 
Subjects will undergo a routine physical examination during the Screening Phase and at the 
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, subjects should be fasting for a minimum of 8 
hours prior to all blood draws. However, if a subject is not fasting at a given visit, the blood 
draw should still be performed, and the non-fasting status should be documented.


 
 
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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, CK.  End of Treatment Visit – 
elevations in CK (>1.5xULN) may have further CK fractionation tests performed through the 
central lab.   
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, subjects 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 are done using 
the eDiary. 
The subjects are also asked to identify their most bothersome symptom on the eDiary (nausea, 
phonophobia or photophobia) at the onset of the migraine to be treated. The most bothersome 
symptom must be identified before the subject takes study 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 subjects to measure the short-term impact of treatment (within 24-hours) 
on 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 or sponsor, 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 
illness).


 
 
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7 STUDY DRUG MANAGEMENT 
7.1 
Description of Study Drug 
7.1.1 
Investigational Product  
An investigational product, also known as investigational medicinal product in some 
regions, is defined as follows: 
A pharmaceutical form of an active substance or placebo being tested or used as a 
reference in a clinical study, including products already with a marketing authorization 
but used or assembled (formulated or packaged) in a way different from the authorized 
form, or used for an unauthorized indication, or when used to gain further information 
about the authorized form. 
The investigational product should be stored in a secure area according to local 
regulations. It is the responsibility of the investigator to ensure that investigational  
product is only dispensed to study subjects. The investigational product must be 
dispensed only from official study sites by authorized personnel according to local 
regulations. 
The rimegepant ODT 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 Subject 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. This subject number must not be reused for any 
other subject 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). It is 
important for you to correctly enter subjects who are using prophylactic migraine 
medication in the IWRS system. Once a patient is stratified in the IWRS, this 
cannot be changed and will be considered a deviation. 
Randomization schedules will be generated and kept by the IWRS vendor in a secure 
network folder with access limited to only unblinded team members. Each subject who is 
qualified for treatment will be randomized via the IWRS randomization option. Subjects 
will maintain their subject number assigned at screening throughout the trial. The IWRS 
will provide the double-blind treatment assignments. 
The randomization will trigger a 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 75 mg orally disintegrating tablet or matching placebo) will be 
packaged in a blister card. There are no dose adjustments in this study and subjects will 
receive one dose to treat one migraine headache of moderate or severe intensity within 45  
days  of randomization (Baseline Visit). Subjects will be dispensed the study medication 
at randomization (Baseline Visit) and will take the ODT from the kit at the time of 
moderate or severe migraine headache onset ONLY after answering questions regarding 
their migraine symptoms in the eDiary device.  The tablet should be placed under the 
tongue until fully dissolved then swallowed.  Subjects should be instructed to use dry 
hands when handling the study medication.   
7.2.3 
Dose Modifications 
There will be no dose adjustments in this study. 
7.3 
Blinding and Unblinding  
Blinding is critical to the integrity of this clinical study.  However, in the event of a 
medical emergency or pregnancy in an individual subject, in which knowledge of the 
investigational product is critical to the subject’s management, the blind for that subject 
may be broken by the treating physician.  
Before breaking the blind of an individual subject’s treatment, the investigator should 
have determined that the information is necessary, (i.e., that it will alter the subject’s 
immediate management).   In many cases, particularly when the emergency is clearly not 


 
 
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investigational product related, the problem may be properly managed by assuming that 
the subject is receiving active product without the need for unblinding.   
In cases of accidental unblinding, contact the Medical Monitor and ensure every attempt 
to preserve the blind is made.   
7.4 
Treatment Compliance 
Responsible study personnel will dispense the study drug.  Accountability and 
compliance verification should be documented in the subject’s study records.   
Subjects 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 subject 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.  
8 ADVERSE EVENTS 
An Adverse Event (AE) is defined as any new untoward medical occurrence or 
worsening of a pre-existing medical condition in a subject or clinical investigation subject 
administered an investigational (medicinal) product and that does not necessarily have a 
causal relationship with this treatment.  An AE can therefore be any unfavorable and 
unintended sign (including an abnormal laboratory finding for example) symptom, or 
disease temporally associated with the use of the 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 subject.  In order to prevent reporting bias, 
subjects should not be questioned regarding the specific occurrence of one or more AEs.  
Subjects should be instructed to notify the Investigator when a Serious Adverse Event 
occurs.  


 
 
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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  
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 


 
 
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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 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.   
All SAEs should be followed to resolution or stabilization. 
An SAE report should be completed for any event where doubt exists regarding its status 
of seriousness.   
If the investigator believes that an SAE is not related to the study drug, but is potentially 
related to the conditions of the study (such as a withdrawal of previous therapy or a 


 
 
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complication related to study procedure), the relationship should be specified in the 
narrative section of the SAE Report Form.  
SAEs, whether related or not related to study drug, overdose (see section 8.1.3), potential 
drug induced liver injury (see section 8.1.5) and pregnancies (see section 8.1.4) must be 
reported within 24 hours of the Investigator becoming aware of the event. For this study 
we will be capturing SAEs through electronic data capture (EDC) and on the SAE form. 
The Investigator is responsible for reporting all SAEs and all Other Important Medical 
Events to 
 within 24 hours of learning of the event. 
 will then immediately notify 
the Biohaven Medical Monitor of the event. The Investigator is responsible for 
submitting all applicable events to the Independent Review Board (IRB) as per the IRB’s 
reporting requirements.  Additionally, the Investigator, or designated staff, is responsible 
for entering the SAE information in the Electronic Data Capture (EDC) system (i.e.: 
event term, start stop dates, causality, severity). 
Any serious adverse event must be reported immediately or no later than 24 hours after 
awareness of the event to 
 Pharmacovigilance (PVG).  A written description of any 
serious adverse event, using the 
 SAE report form, must be sent to 
 PVG by 
facsimile (fax) within 24 hours after awareness of the event:  
• North America - 1-888
 
If a form is unable to be submitted within 24 hours, the SAE may be reported by 
telephone via the Safety Hotline Number: 
• North America – 1-800
 
If only limited information is initially available, follow-up reports are required. If an 
ongoing SAE changes in its intensity or relationship to study drug or if new information 
becomes available, a follow-up SAE report should be sent within 24 hours of the 
Investigator becoming aware of the updated information using the same procedure used 
for the transmission of the initial SAE and the same event term should be used. 
The minimum information required for an initial SAE report is: 
Sender of report (Site number, Investigator name) 
Subject identification (subject number) 
Protocol number 
SAE term (if an SAE is being reported) 
CCI
CCI
CCI
CCI
CCI
CCI
CCI


 
 
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8.1.3 
Overdose 
An overdose is defined as the accidental or intentional administration of any dose of the 
product that is considered excessive and medically important as determined by the 
investigator.  All occurrences of  overdose (suspected or confirmed and irrespective of 
whether or not it involved rimegepant or placebo) must be communicated to Biohaven or 
a specified designee within 24 hours and be fully documented as an SAE. Details of any 
signs or symptoms and their management should be recorded including details of any 
antidote(s) administered. 
8.1.4 
Pregnancy 
If following the baseline visit, it is subsequently discovered that a study subject, or the 
female partner of a male study subject, is pregnant or may have been pregnant at the time 
of the investigational product exposure, including during at least 6 half-lives after the 
product administration, the investigational product will be permanently discontinued in 
an appropriate manner (i.e., dose tapering if necessary for subject's safety).  Protocol-
required procedures for the study discontinued and the follow-up must be performed on 
the subject unless contraindicated by the pregnancy (i.e., x-ray studies).  Other 
appropriate pregnancy follow-up procedures should be considered if indicated.   
Sites should instruct subjects to contact the Investigator immediately if they become 
pregnant during the course of the study. The Investigator must immediately notify the 
Biohaven Medical Monitor (or designee) of the event and complete and forward the 
Pregnancy Report Form to 
 immediately via telephone within 24 hours and in 
accordance with SAE reporting procedures as described in Section 8.1.2.  
Follow-up information regarding the course of the pregnancy, including perinatal and 
neonatal outcome and, where applicable offspring information must be reported on a 
Pregnancy Report Form. 
Any pregnancy that occurs in a female partner of a male study subject should be reported 
to the sponsor.  Information on this pregnancy will be collected on the Pregnancy Report 
Form, as appropriate.    
8.1.5 
Potential Drug Induced Liver Injury (DILI) 
Wherever possible, timely confirmation of the initial liver-related laboratory 
abnormalities should occur prior to the reporting of a potential DILI event.  All 
occurrences of potential DILIs, meeting the defined criteria, must be reported as SAEs as 
per Section 8.1.2.  
Potential drug induced liver injury is defined as:  
1. Aminotransferases (AT) (ALT or AST) elevation > 3 times the upper limit of normal 
(ULN) 
 
CCI


 
 
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AND 
2. Total bilirubin (TBL) > 2 times ULN, without initial findings of cholestasis (elevated 
serum alkaline phosphatase) 
 
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 subject 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 subject.  
Non-serious adverse events should be followed until conclusion or stabilization, or 
reported as SAEs if they become serious.   Follow-up is also required for non-serious 
AEs that cause interruption or discontinuation of study drug or those that are present at 
the end of study treatment.  
8.2.2 
Laboratory Test Abnormalities 
The following laboratory test abnormalities should be captured on the non-serious AE 
CRF page or SAE Report Form (paper or electronic) as appropriate: 
1. Any laboratory test result that is clinically significant or meets the definition of an 
SAE; 
2. Any laboratory abnormality that required the subject to have the study drug 
discontinued or interrupted; 
3. Any laboratory abnormality that required the subject to receive specific corrective 
therapy. 
 


 
 
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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 roughly 85% of the 715 subjects randomized to each treatment arm have a migraine in 
the allotted time period, there will be approximately 600 treated subjects per group.  
Based on data from studies BHV3000-301 and BHV3000-302, , 600 treated subjects 
provides 95% power to detect a difference between rimegepant and placebo on the 
subject’s self-reported most bothersome symptom. Also, 600 subjects provides  95% 
power to detect a difference in freedom from pain at 2 hours. Having at 95% power on 
each co-primary endpoint provides roughly 90% power to detect a difference on both 
endpoints jointly.  
9.3 
Populations for Analysis 
• Enrolled subjects: Subjects 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  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 
methodology to estimate the common risk difference, and are 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 order shown in the 
Study Objectives section of this protocol.   
 
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 
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.  
Further safety analyses will be described in the statistical analysis plan.   
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. 


 
 
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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 subject 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 subjects 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 and Safety Monitoring Committee (DSMC). 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 subjects, or, in those situations where consent cannot be 
given by subjects, their legally acceptable representatives, are clearly and fully informed 
about the purpose, potential risks, and other critical issues regarding clinical studies in 
which they volunteer to participate.  
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 subject’s legal guardian or legally acceptable 
representative, and the subject subsequently becomes capable of making and 
communicating their informed consent during the study, then the consent must 
additionally be obtained from the subject.  
The informed consent form must also include a statement that Biohaven and its 
representatives and regulatory authorities may have direct access to subject records.  
The rights, safety, and well-being of study subjects 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 subject. Data reported on the CRF that are derived from source documents must be 
consistent with the source documents or the discrepancies must be explained. 
Electronic CRFs will be prepared for all data collections fields when EDC is being used.    
The confidentiality of records that could identify subjects must be protected, respecting 
the privacy and confidentiality rules in accordance with the applicable regulatory 
requirement(s).  
The Investigator must retain a copy of the CRFs including records of changes and 
corrections.   If EDC is being used, signatures will be obtained electronically and a copy 
of the electronic CRFs will be provided (or the data from the CRFs) for future reference.  
10.6 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 subject 
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 subject 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.  
 
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. 
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. 
14 CONFIDENTIALITY 
All information generated in this study is considered highly confidential and must not be 
disclosed to any person or entity not directly involved with the study unless prior written 
consent is gained from Biohaven. However, authorized regulatory officials, IRB/IEC 
personnel, Biohaven and its authorized representatives are allowed full access to the 
records. 
Identification of subjects and eCRFs shall be by initials, subject numbers only. Only if 
required by law, the subject's full name may be made known to an authorized regulatory 
agency or other authorized official. 
 
 


 
 
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15 APPENDICES 
PPD


 
 
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15.2 APPENDIX 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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15.3 APPENDIX III – Strong CYP3A4 Inhibitors and Inducers (Not all 
inclusive) 
The following medications and medication combinations are some of the strong 
inhibitors of CYP3A4. This list should not be considered all-inclusive. As described in 
the study protocol, concomitant use of strong CYP3A inhibitors is prohibited. Individual 
drug labels should be reviewed for specific information on propensity to inhibit CYP3A4 
for a specific compound.  
Strong CYP3A inhibitors 
Boceprevir, cobicistat, conivaptan, danoprevir and ritonavir, elvitegravir and ritonavir, 
indinavir and ritonavir, itraconazole, ketoconazole, lopinavir and ritonavir, paritaprevir 
and ritonavir and (ombitasvir and/or dasabuvir), posaconazole, ritonavir, saquinavir 
and ritonavir, telaprevir, tipranavir and ritonavir, troleandomycin, voriconazole, 
clarithromycin, nefazodone, nelfinavir 
 
The following medications and supplements are some of the strong inducers of CYP3A4. 
The list should not be considered all-inclusive. As described in the study protocol, 
concomitant use of strong CYP3A inducers is prohibited. Individual product labels 
should be reviewed for specific information on propensity to induce CYP3A4 for a 
specific compound. 
 
Strong CYP3A inducers 
Carbamazepine, phenytoin, rifampin, St. John’s Wort 
 
Resources:  
https://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/DrugI
nteractionsLabeling/ucm093664.htm#table3-2 
 
https://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/DrugI
nteractionsLabeling/ucm093664.htm#table3-3 
 
Hachad H, Ragueneau-Majlessi I, Levy RH. A useful tool for drug interaction evaluation: 
the University of Washington Metabolism and Transport Drug Interaction Database. Hum 
Genomics. 2010 Oct;5(1):61-72 
 
University of Washington Metabolism and Transport Drug Interaction Database accessible 
at https://www.druginteractioninfo.org/ 
 


 
 
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16 REFERENCES 
 
1. 
Headache Classification Committee of the International Headache Society (IHS). 
The International Classificaton of Headache Disorders, 3rd edition beta version. 
Cephalagia. 2013 Jul; 33(9): 629-808. 
2. 
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 
3. 
CN170002, Effect of BMS-927711 on the Pharmacokinetics of a Combined Oral 
Contraceptive Containing Ethinyl Estradiol and Norgestimate in Healthy Female 
Subjects. 2012, Bristol-Myers Squibb Company. 
4. 
CN170004, Phase 1 open-label, randomized single sequence study with two dose 
groups to compare the pharmacokinetics of BMS-927711 in migraine subjects 
during an acute migraine attack and during nonmigraine period. 2012, Bristol-
Myers Squibb Company. 
5. 
CN170006, Phase 1 Mass Balance Recovery Study - Rimegepant oral dosing and 
infusion. Bristol-Myers Squibb Company 
6. 
CN170007, DDI with Midazolam (CYP3A4 substrate) to study the changes of 
midazoloam pharmacokinetics with or without BMS-92771. Bristol-Myers Squibb 
Company. 
7. 
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. 
8. 
Hougaard, A. and P. Tfelt-Hansen, Review of dose-response curves for acute 
antimigraine drugs: triptans, 5-HT1F agonists and CGRP antagonists. Expert 
Opin Drug Metab Toxicol, 2015. 11(9): p. 1409-18. 
9. 
Vos, T., et al., Years lived with disability (YLDs) for 1160 sequelae of 289 
diseases and injuries 1990-2010: a systematic analysis for the Global Burden of 
Disease Study 2010. Lancet, 2012. 380(9859): p. 2163-96. 
10. 
Burch, R.C., et al., The prevalence and burden of migraine and severe headache 
in the United States: updated statistics from government health surveillance 
studies. Headache, 2015. 55(1): p. 21-34. 
11. 
Lipton, R.B., et al., Migraine in the United States: epidemiology and patterns of 
health care use. Neurology, 2002. 58(6): p. 885-94. 
12. 
Lipton, R.B., W.F. Stewart, and P.J. Goadsby, Headache-related disability in the 
management of migraine. Neurology, 2001. 56(6 Suppl 1): p. S1-3. 
13. 
Brandes, J.L., Global trends in migraine care: results from the MAZE survey. 
CNS Drugs, 2002. 16 Suppl 1: p. 13-8. 
14. 
Buse, D.C., M.F. Rupnow, and R.B. Lipton, Assessing and managing all aspects 
of migraine: migraine attacks, migraine-related functional impairment, common 
comorbidities, and quality of life. Mayo Clin Proc, 2009. 84(5): p. 422-35. 
15. 
APA, Diagnostic and Statistical Manual of Mental Disorders, 5th Edition: DSM-
5 5th Edition. 5th ed, ed. A.P. Association. 2013: American Psychiatric 
Publishing. 


 
 
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16. 
Sheehan, D.V., et al., Comparative Validation of the S-STS, the ISST-Plus, and 
the C-SSRS for Assessing the Suicidal Thinking and Behavior FDA 2012 
Suicidality Categories. Innov Clin Neurosci, 2014. 11(9-10): p. 32-46. 
17. 
Sheehan, D.V., J.M. Giddens, and I.S. Sheehan, Status Update on the Sheehan-
Suicidality Tracking Scale (S-STS) 2014. Innov Clin Neurosci, 2014. 11(9-10): p. 
93-140. 
 

SAP_001.pdf: 
Confidentiality
This document is confidential and proprietary property of Biohaven Pharmaceuticals and to be used only as 
authorized by Biohaven Pharmaceuticals.  No part is to be reproduced, disclosed to others, or quoted without prior 
written authorization from Biohaven Pharmaceuticals.
Biohaven Pharmaceuticals
Protocol BHV3000-303
A Phase III, Double-Blind, Randomized, Placebo-Controlled, Safety and 
Efficacy Trial of BHV-3000 (rimegepant) Orally Disintegrating Tablet (ODT)
for the Acute Treatment of Migraine
Statistical Analysis Plan
Final Version 2.0
Date: 15 November 2018




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Table of Contents
TABLE OF CONTENTS ..................................................................................................3
TABLE OF TABLES.........................................................................................................4
TABLE OF FIGURES.......................................................................................................4
1
INTRODUCTION AND OBJECTIVES OF ANALYSIS ......................................8
1.1
INTRODUCTION..................................................................................................8
1.2
STUDY OBJECTIVES..........................................................................................8
1.2.1
PRIMARY OBJECTIVES..............................................................................8
1.2.2
SECONDARY OBJECTIVES........................................................................8
1.2.3
EXPLORATORY OBJECTIVES..................................................................9
2
STUDY DESIGN ......................................................................................................10
2.1
SYNOPSIS OF STUDY DESIGN.......................................................................10
2.2
RANDOMIZATION METHODOLOGY..........................................................11
2.3
STUDY ESTIMANDS .........................................................................................11
2.3.1
PRIMARY ESTIMANDS .............................................................................12
2.3.2
SECONDARY ESTIMANDS .......................................................................12
2.3.3
EXPLORATORY ESTIMANDS..................................................................15
3
SUBJECT POPULATIONS ....................................................................................16
3.1
POPULATION DEFINITIONS .........................................................................16
3.2
PROTOCOL DEVIATIONS ..............................................................................16
4
STATISTICAL METHODS....................................................................................17
4.1
SAMPLE SIZE JUSTIFICATION ....................................................................17
4.2
GENERAL STATISTICAL METHODS AND DATA HANDLING .............18
4.2.1
GENERAL METHODS ................................................................................18
4.2.2
COMPUTING ENVIRONMENT ................................................................19
4.2.3
METHODS OF POOLING DATA ..............................................................19
4.2.4
ADJUSTMENTS FOR COVARIATES AND STRATIFICATION.........19
4.2.5
MULTIPLE COMPARISONS .....................................................................19
4.2.6
SUBPOPULATIONS.....................................................................................20
4.2.7
MISSING AND PARTIAL DATES .............................................................22
4.2.8
VISIT WINDOWS.........................................................................................22
4.3
PLANNED ANALYSES......................................................................................23
4.4
SUBJECT DISPOSITION ..................................................................................23
4.5
DEMOGRAPHIC AND BASELINE CHARACTERISTICS .........................25
4.6
MISSING EFFICACY DATA DESCRIPTION ...............................................25
4.7
EFFICACY EVALUATION...............................................................................26
4.7.1
RESCUE MEDICATION .............................................................................26
4.7.2
MBS RECORDED AFTER IP IS TAKEN .................................................27
4.7.3
PRIMARY EFFICACY ENDPOINTS ........................................................27
4.7.4
SECONDARY EFFICACY ENDPOINTS ..................................................30
4.7.5
EXPLORATORY EFFICACY ENDPOINTS ............................................34
4.8
PHARMACOKINETIC EVALUATION..........................................................37
4.9
SAFETY EVALUATION....................................................................................37
4.9.1
EXTENT OF EXPOSURE............................................................................37
4.9.2
ADVERSE EVENTS .....................................................................................38


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4.9.3
LABORATORY DATA.................................................................................39
4.9.4
VITAL SIGNS AND PHYSICAL MEASUREMENTS .............................41
4.9.5
ELECTROCARDIOGRAM.........................................................................41
4.9.6
NON-STUDY MEDICATIONS....................................................................41
4.9.7
SHEEHAN-SUICIDALITY TRACKING SCALE (S-STS) ......................42
APPENDIX 1:
TABLES, LISTINGS, AND FIGURES ...........................................43
APPENDIX 2:
SCHEDULE OF ASSESSMENTS ...................................................52
APPENDIX 3:
SUPPORTIVE ANALYSES .............................................................56
1
DURABILITY ENDPOINTS ..................................................................................56
1.1
SUSTAINED PAIN FREEDOM ........................................................................56
1.2
SUSTAINED PAIN RELIEF..............................................................................57
1.3
SUSTAINED FREEDOM FROM MOST BOTHERSOME SYMPTOM .....58
1.4
SUSTAINED FREEDOM FROM FUNCTIONAL DISABILITY..................58
1.5
SUSTAINED FREEDOM FROM NAUSEA.....................................................59
1.6
SUSTAINED FREEDOM FROM PHOTOPHOBIA.......................................59
1.7
SUSTAINED FREEDOM FROM PHONOPHOBIA.......................................60
2
TIME TO EVENT ANALYSES..............................................................................61
2.1
TIME TO RESCUE MEDICATION.................................................................61
2.2
TIME TO FIRST REPORT OF ABSENCE OF VARIOUS SYMPTOMS...61
2.2.1
KAPLAN-MEIER PLOTS AND TABLES: ACTUAL TIME FOR 
EVENT OF INTEREST................................................................................62
2.2.2
KAPLAN-MEIER PLOTS AND TABLES: NOMINAL TIME FOR 
EVENT OF INTEREST................................................................................62
3
PAIN AND MBS AT 3 HOURS POST DOSE.......................................................62
3.1
PAIN FREEDOM AT 3 HOURS POST DOSE ................................................62
3.2
FREEDOM FROM MBS AT 3 HOURS POST DOSE....................................63
4
OTHER ENDPOINTS AT 3 HOURS POST DOSE .............................................63
4.1
FREEDOM FROM PHOTOPHOBIA, PHONOPHOBIA, OR NAUSEA AT 
3 HOURS ..............................................................................................................63
4.2
PAIN RELIEF AT 3 HOURS POST DOSE......................................................64
4.3
FUNCTIONAL DISABILITY SCALE AT 3 HOURS POST DOSE..............64
APPENDIX 4:
TABLES AND FIGURES FOR SUPPORTIVE ANALYSES.......65
Table of Tables
Table 1:
Estimands for the Co-Primary Objectives ............................................12
Table 2:
Estimands for the Secondary Objectives...............................................13
Table 3:
Estimands for the Exploratory Efficacy Objectives .............................15
Table 4:
Layout Specifications...............................................................................18
Table 5:
Questions Used to Determine Triptan Non-response ...........................21
Table 6:
Evaluation Intervals for Efficacy Analysis............................................23
Table of Figures
Figure 1:
Study Schematic.......................................................................................11
Figure 2:        Consort Diagram......................................................................................24


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ABBREVIATIONS
Abbreviation
Definition
AE
Adverse event
ALP
Alkaline phosphatase 
ALT
Alanine aminotransferase 
ASE
Asymptotic standard error
AST
Aspartate aminotransferase 
AT
Aminotransferases
ATC
Anatomic therapeutic class
BOCF
Baseline observation carried forward
BUN
Blood urine nitrogen 
CI
Confidence interval
CPK
Creatinine phosphokinase
CMH
Cochran-Mantel-Haenszel
CRF
Case report form
CSR
Clinical study report
CV
Cardiovascular 
DILI
Drug-induced liver injury
ECG
Electrocardiogram
EDC
Electronic data capture
eDiary
Electronic diary 
eDISH
Evaluation of Drug-Induced Serious Hepatotoxicity
eGFR
Estimated glomerular filtration rate
FCS
Fully conditional method
FDS
Functional Disability Scale 
HDL
High-density lipoprotein 
ICH
International Conference on Harmonization
IP
Investigational product
IRB/EC
Institutional Review Board/Ethics Committee
IWRS
Interactive web response system
LDH
Lactate dehydrogenase 
LDL
Low-density lipoprotein 
LOCF
Last observation carried forward
MBS
Most bothersome symptom


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Abbreviation
Definition
MDRD 
Modification of diet in renal disease
MedDRA
Medical Dictionary for Regulatory Activities
MI
Multiple imputation
mITT
Modified Intent-to-Treat
MQoLQ
Migraine Specific Quality of Life Questionnaire
NC=F
Non-Completer Equals Failure
NC1=F
Non-Completer with more than 1 missing data point equals Failure
NC=M
Non-Completer Equals Missing
NRS
Numeric rating scale
ODT
Orally Disintegrating Tablet
PID
Patient identifier
POM
Preference of medication
PP
Per protocol set
PT
Preferred term
PVD
Peripheral vascular disease
QD
Quaque Die (one daily)
RM=F
Rescue Medication = Failure
S-STS
Sheehan-Suicidality Tracking Scale
SAE
Serious adverse event
SAP
Statistical analysis plan
SD
Standard deviation
SDS
Sheehan Disability Scale
SOC
System Organ Class
TBL
Total bilirubin
TIA
Transient ischemic attack
ULN
Upper limit of normal
WHO-DD
World Health Organization-Drug Dictionary


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REVISION HISTORY
Version
Description of Change
1.0
Original Issue
2.0

Added “Revision History” table after “Abbreviations” table.

Section 4.7.1: Revised text for clarity and defined rescue medications.

Section 4.7.3.1: Added a fifth sensitivity analysis to exclude Site 002.

Section 4.7.3.2: Added a sixth sensitivity analysis to exclude Site 002.

Section 4.7.4: Specified that secondary endpoints are also assessed excluding 
Site 002.

Section 4.9.3: Specified that shift categories are independent of US and SI units, 
and that SI and US units are the same for ALT and AST shift categories.

Section 4.9.6:
o
Changed section title to “Non-Study Medications”.
o
Defined prior medications, changed definition of concomitant medications, 
and modified summaries of prophylactic migraine and rescue medications.

Appendix 1:
o
Modified titles of Tables 14.1.4.1 – 5  and Listing 16.2.2.3.
o
Renumbered 4 efficacy tables (14.2.2.7, 14.2.2.14, 14.2.2.15, 14.2.2.16)
o
Added 23 tables for primary and secondary efficacy endpoints to exclude 
Site 002, as per changes to Sections 4.7.3.1, 4.7.3.2, and 4.7.4.
o
Removed 4 laboratory test shift tables and renumbered 4 remaining shift 
tables, as per changes to Section 4.9.3.
o
Added 2 tables of non-study medications, and modified the titles of the 
other 3 tables of non-study medications, as per changes to Section 4.9.6.

Appendix 3
o
Section 2.2: Specified that the analysis population for functional disability 
was the subset of mITT subjects that reported abnormal functioning at the 
onset of their study migraine.


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1
INTRODUCTION AND OBJECTIVES OF ANALYSIS
1.1
Introduction
This document presents the statistical analysis plan (SAP) for Biohaven Pharmaceuticals, 
Protocol BHV3000-303: A Phase III, Double-Blind, Randomized, Placebo-Controlled, Safety 
and Efficacy Trial of BHV-3000 (rimegepant) Orally Disintegrating Tablet (ODT) for the Acute 
Treatment of Migraine.
This SAP is based on the BHV3000-303, V4.0, protocol dated 23-July-2018. It contains the 
analysis details and methodology to answer the study objectives, including planned summary 
tables, by-subject listings, and figures, which will provide the basis for the results section of the 
clinical study report (CSR). Operational aspects related to collection and timing of planned 
clinical assessments are not repeated in this SAP unless relevant to the planned analyses.
1.2
Study Objectives
1.2.1
Primary Objectives
To evaluate the efficacy of rimegepant compared with placebo in the acute treatment of 
migraine as measured by the co-primary endpoints of:

Pain freedom at two hours post-dose.

Freedom from the most bothersome symptom (MBS), associated with migraine, at two 
hours post-dose.
1.2.2
Secondary Objectives
1. To evaluate rimegepant compared to placebo on pain relief at 2 hours post-dose.
2. To evaluate the effect of rimegepant relative to placebo on the ability to function 
normally at 2 hours post-dose as reported  on the Functional Disability scale (FDS).
3. To evaluate rimegepant compared to placebo on sustained pain relief from 2 to 24 hours 
post-dose.
4. To evaluate rimegepant compared to placebo on sustained freedom from MBS, 
associated with migraine, from 2 to 24 hours post-dose.
5. To evaluate rimegepant compared to placebo on the probability of requiring rescue 
medication within 24 hours of initial treatment.
6. To evaluate rimegepant compared to placebo on sustained ability to function at a normal 
level, as measured by the FDS, from 2 to 24 hours post-dose.


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7. To evaluate rimegepant compared to placebo on sustained pain relief from 2 to 48 hours 
post-dose.
8. To evaluate rimegepant compared to placebo on freedom from the MBS, associated with 
migraine, from 2 to 48 hours post-dose.
9. To evaluate rimegepant compared to placebo on the sustained ability to function at a 
normal level, as measured by the FDS, from 2 to 48 hours post-dose.
10. To evaluate rimegepant compared to placebo on freedom from photophobia at 2 hours 
post-dose.
11. To evaluate the effect of rimegepant relative to placebo on the ability to function at a 
“normal” level at 90 minutes post-dose as reported on the FDS.
12. To evaluate rimegepant compared to placebo on pain relief at 90 minutes post-dose.
13. To evaluate rimegepant compared to placebo on sustained pain freedom from 2 to 24 
hours post-dose.
14. To evaluate rimegepant compared to placebo on freedom from the MBS, associated with 
migraine, at 90 minutes post-dose.
15. To evaluate rimegepant compared to placebo on pain freedom at 90 minutes post-dose.
16. To evaluate rimegepant compared to placebo on freedom from phonophobia at 2 hours 
post-dose.
17. To evaluate rimegepant compared to placebo on sustained pain freedom from 2 to 48 
hours post-dose.
18. To evaluate rimegepant compared to placebo on pain relief at 60 minutes post-dose.
19. To evaluate the effect of rimegepant relative to placebo on the ability to function at a 
“normal” level at 60 minutes post-dose, as reported on the FDS.
20. To evaluate rimegepant compared to placebo on freedom from nausea at 2 hours post-
dose.
21. To evaluate rimegepant compared to placebo for the incidence of pain relapse from 2 to 
48 hours post-dose.
1.2.3
Exploratory Objectives
1. To evaluate the effect of rimegepant relative to placebo on the subjects’ ability to work 
or function at 24 hours post-dose according to the FDS.


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2. To evaluate the effect of rimegepant compared to placebo on pain relief at 30 minutes
post-dose.
3. To evaluate the effect of rimegepant compared to placebo on pain relief at 15 minutes 
post-dose.
4. To evaluate the effect of rimegepant relative to placebo on the Migraine Preference of 
Medication (PoM).
5. To evaluate rimegepant relative to placebo for pain relief on the 4-point scale at all 
scheduled time points post-dose.
6. To evaluate the effect of rimegepant relative to placebo on the Migraine Quality of Life 
Questionnaire (MQoLQ).
7. To evaluate the tolerability and safety of rimegepant 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.  
8. To evaluate the effect of rimegepant (75 mg ODT) relative to placebo on the Sheehan 
Suicidality Tracking Scale (S-STS).
2
STUDY DESIGN
2.1
Synopsis of Study Design
BHV3000-303 is a Phase III, multicenter, randomized, double-blind, 2-arm placebo-controlled 
parallel-group study designed to assess safety and efficacy in the treatment of moderate to 
severe migraine.
After providing informed consent, subjects will first participate in the screening phase (3-28 day 
period) to determine eligibility for the study.  
After randomization, the subject will be dispensed a single dose of the double-blind study 
medication consisting of a rimegepant 75 mg ODT (administered sublingually) or matching 
placebo 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 
electronic diary (eDiary).  The subject will complete an eDiary for up to 48 hours after taking 
the study medication.  Subjects will record efficacy data in their eDiary and will telephone the 
study center immediately if a severe or serious adverse event occurs.  
Subjects 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.  If a subject has 
NOT experienced a migraine headache of sufficient severity within the 45 days after 
randomization, they still are required to complete all EOT visit procedures and return unused 
study medication and eDiary to the study center.


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2.2
Randomization Methodology
Subjects in this study may be randomized only once.  Under no circumstances may a subject be 
re-randomized.
The study will randomize approximately 1,430 subjects. The subjects will be randomized in a 
1:1 ratio to receive rimegepant in a 75 mg ODT or matching placebo (see Figure 1). The 
randomization will be stratified by the use of prophylactic migraine medications (yes or no).
Figure 1:
Study Schematic
2.3
Study Estimands 
The tables that follow lay out the estimands corresponding to the study objectives.  In these 
tables, the following abbreviations are used to describe the handling of intercurrent events for 
efficacy estimands:
NC=F: Non-Completers = Failure.  
A subject with any missing data for an endpoint is classified as a treatment failure.
NC1=F: Non-Completers with more than 1 missing data point = Failure.
Subjects with more than 1 missing data point, other than at the 2, 24 or 48 hour data points, are 
classified as treatment failures. This applies to endpoints that are based on data from multiple 
time points. For example, for the durability endpoint of sustained pain freedom from 2 to 24
hours, the subjects should provide data at 2, 3, 4, 6, 8, and 24 hours. For NC1=F imputation, the 
data at 2 and 24 hour time points must be present or the subject is classified as a failure.
However, any single data point may be missing at 3, 4, 6 or 8 hours without penalty. For 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 


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sustained pain freedom from 2 to 48 hours, the data at 2, 24, and 48 hours are required to be 
present. 
RM=F: Rescue Medication = Failure. 
Subjects that take rescue medication before, or at, the time of the event of interest are classified 
as failures. If the time of rescue medication is missing, all events on or after the date of rescue 
medication are classified as failures.
2.3.1
Primary Estimands
The estimands corresponding to the co-primary objectives for this study are shown in Table 1.
The population summary for all primary estimands is the difference in the percentage of 
subjects with a positive result (‘risk difference’) between the BHV-3000 and the Placebo 
treatment groups. This summary is computed using the modified Intent-to-Treat (mITT) 
population as defined in section 3.1.
Table 1:
Estimands for the Co-Primary Objectives
Objective
Pain Freedom at 2 hours post-dose
Population
mITT
Variable
Percent of subjects reporting no pain at 2 hours post-dose
Intercurrent Events
NC=F; RM=F. 
Objective
Freedom from Most Bothersome Symptom (MBS)
Population
mITT
Variable
Percent of subjects reporting absence of their MBS at 2 hours post dose
Intercurrent Events
NC=F;  RM=F; Failure to report MBS = F;  Study medication taken before 
reporting MBS=F.
2.3.2
Secondary Estimands
The estimands corresponding to the secondary objectives are shown in Table 2.
The population summary for all secondary estimands is the difference in the percentage of 
subjects with a positive result (‘risk difference’) between the BHV-3000 and the Placebo 
treatment groups.


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Table 2:
Estimands for the Secondary Objectives
Objective
Pain Relief (at 60 minutes, 90 minutes, or 2 hours)
Population
mITT
Variable
Percent of subjects who report mild or no pain at the specified timepoint
Intercurrent Events
NC=F;  RM=F
Objective
Functional Disability (at 60 minutes, 90 minutes, or 2 hours)
Population
mITT
Variable
Percent of subjects with a response of “normal” at the specified timepoint 
Intercurrent Events
NC=F; RM=F
Objective
Sustained Pain Relief  (2 to 24 hours; or 2 to 48 hours)
Population
mITT
Variable
Percent of subjects who report no pain or mild pain during the period of interest
Intercurrent Events
NC1=F; RM=F
Objective
Sustained Freedom from MBS  (2 to 24 hours; or 2 to 48 hours)
Population
mITT
Variable
Percent of subjects who report freedom from MBS during the period of interest
Intercurrent Events
NC1=F; RM=F
Objective
Probability of Rescue Medication within 24 hours post-dose
Population
mITT
Variable
Percent of subjects taking rescue medication within 24 hours post-dose
Intercurrent Events
None
Objective
Sustained Normal Functioning  (2 to 24 hours; or 2 to 48 hours)
Population
mITT
Variable
Percent of subjects who report normal functioning on the FDS during the period of 
interest
Intercurrent Events
NC1=F; RM=F
Objective
Photophobia Freedom at 2 hours post-dose
Population
mITT subjects with photophobia reported as present at migraine onset
Variable
Percent of subjects reporting no photophobia at 2 hours post-dose
Intercurrent Events
NC=F;  RM=F 
Objective
Sustained Pain Freedom  (2 to 24 hours; or 2 to 48 hours)
Population
mITT
Variable
Percent of subjects who report no pain during the period of interest
Intercurrent Events
NC1=F; RM=F
Objective
MBS Freedom at 90 minutes post-dose
Population
mITT subjects
Variable
Percent of subjects reporting freedom from MBS at 90 minutes post-dose
Intercurrent Events
NC=F;  RM=F 
Objective
Pain Freedom at 90 minutes post-dose
Population
mITT
Variable
Percent of subjects who report no pain at 90 minutes post-dose
Intercurrent Events
NC=F;  RM=F
Objective
Phonophobia Freedom at 2 hours post-dose
Population
mITT subjects with phonophobia reported as present at migraine onset
Variable
Percent of subjects reporting no phonophobia at 2 hours post-dose
Intercurrent Events
NC=F;  RM=F 


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Objective
Nausea Freedom at 2 hours post-dose
Population
mITT subjects with nausea reported as present at migraine onset
Variable
Percent of subjects reporting no nausea at 2 hours post-dose
Intercurrent Events
NC=F;  RM=F 
Objective
Pain Relapse (2 to 48 hours)
Population
mITT subjects who report pain freedom at 2 hours post-dose
Variable
Percent of subjects who report any pain during the period of interest
Intercurrent Events
NC1=F;  RM=F


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2.3.3
Exploratory Estimands
The estimands corresponding to the exploratory objectives are shown in Table 3.
Table 3:
Estimands for the Exploratory Efficacy Objectives
Objective
Functional Disability at 24 hours
Population
mITT
Variable
Percent of subjects with a response of “normal” at 24 hours post-dose
Intercurrent Events
NC=F; RM=F
Pop. Summary
Percentage within each treatment group (BHV3000  & Placebo)
Objectives
Pain Relief at 15 and 30 minutes post-dose
Population
mITT
Variable
Percent of subjects who report pain as mild or none at the time point of interest
Intercurrent Events
NC=F;  RM=F
Pop. Summary
Percentage within each treatment group (BHV3000  & Placebo)
Objectives
Preference of Medication
Population
Treated subjects who: 1) answer “yes” to the lead-in question (i.e. “Have you ever 
taken migraine medication?”) and provide preference of medication data
Variable
Percentage of subjects who prefer study medication to previous migraine medications
Intercurrent Events
Observed analysis. No accounting for intercurrent events.
Pop. Summary
Percentage within each treatment group (BHV3000  & Placebo)
Objectives
Pain Relief, on a 4 point scale, at all time points
Population
mITT
Variable
Percent of subjects who report pain as none, mild, moderate or severe
Intercurrent Events
NC=F;  RM=F
Pop. Summary
Percentage of each response, in each treatment group (BHV3000 & Placebo)
Objectives
Migraine Quality of Life Questionnaire
Population
mITT
Variable
Total score on the MQoLQ
Intercurrent Events
Observed analysis. No accounting for intercurrent events.
Pop. Summary
Average total score within each treatment group (BHV3000 & Placebo)
Objective
Safety and Tolerability
Population
All treated subjects
Variables
Multiple
Intercurrent Events
Subjects analyzed as treated. No accounting for intercurrent events
Pop. Summary
Multiple (discussed under section 6, “Safety Analyses”)
Objective
Sheehan Suicidality Tracking Scale
Population
All treated subjects
Variables
Change from baseline in the total score
Intercurrent Events
Subjects analyzed as treated. No accounting for intercurrent events
Pop. Summary
Percentage of subjects, by treatment group, in each of 5 categories (<-1, -1, no 
change, 1, >1)


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3
SUBJECT POPULATIONS
3.1
Population Definitions
The following subject populations will be evaluated and used for presentation and analysis of 
the data:
Enrolled subjects: subjects 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 interactive web response system (IWRS).
Treated subjects: enrolled subjects who take any amount of study therapy (rimegepant or 
placebo).
Modified Intent-to-Treat (mITT) subjects: enrolled subjects who are randomized only once,
take study therapy, have a baseline migraine of moderate to severe intensity, and who 
provide at least one post-baseline efficacy data point.
3.2
Protocol Deviations
A protocol deviation is any variance from the approved protocol, either intentional or 
unintentional.  The possible categories for all protocol deviations are as follows:

Informed Consent

Inclusion/Exclusion Criteria (specify #)

Concomitant Medication

Serious Adverse Event (SAE) Reporting

Regulatory

Drug Storage/Preparation

Drug Administration

Visit Schedule

EPro Diary Noncompliance

Noncompliance (i.e., trends, missed assessments).


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A significant protocol deviation is any deviation that could impact subject safety or the integrity 
of the trial. For the purposes of this study, significant protocol deviations will be defined as the 
following:

Inadequate informed consent or initiation of study procedures prior to completing the 
informed consent

Enrollment of subjects not meeting the inclusion/exclusion criteria

Unreported SAEs

Improper breaking of the blinding of the study

Use of prohibited medication as defined by the protocol

eDiary non-compliance with primary and secondary endpoints (2, 24, or 48-hour post-
dose assessment

Repeated deviations of the same nature for a given site or subject

Initiation of rescue medication(s) prior to primary endpoint at 2-hours
The sponsor, or designee, will be responsible for producing the final protocol deviation file 
(formatted as a Microsoft Excel file). This file will include site, subject ID, deviation date, 
deviation type, and a description of the protocol deviation.
All protocol deviations (with the exception of those related to rescue medication and missed 
eDiary assessments) will be presented in a by-subject listing.  Handling of rescue medication 
and missed eDiary assessments are described in the statistical methods section of this SAP.
4
STATISTICAL METHODS
4.1
Sample Size Justification
If roughly 85% of the 715 subjects randomized to each treatment arm have a migraine in the 
allotted time period, there will be approximately 600 treated subjects per group.
Based on data from studies BHV3000-301 and BHV3000-302, 600 treated subjects per arm 
provides 95% power to detect a difference between rimegepant and placebo on the subject’s 
self-reported most bothersome symptom.  Also, 600 subjects per arm provides 95% power to 
detect a difference in freedom from pain at 2 hours post dose.  Having 95% power on each co-
primary endpoint provides roughly 90% power to detect a difference on both endpoints jointly.


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4.2
General Statistical Methods and Data Handling
4.2.1
General Methods
All output will be incorporated into Microsoft Excel or Word files, sorted and labeled according 
to the International Conference on Harmonization (ICH) recommendations, and formatted to the 
appropriate page size(s). PDF versions of the output will also be produced.
Tabulations will be produced for appropriate demographic, baseline, efficacy, safety, and other 
parameters by as-randomized treatment group (BHV3000, Placebo) and overall, unless specified 
otherwise.  For categorical variables, summary tabulations of the number and percentage of 
subjects within each category will be presented. If applicable, a category for missing data will 
also be presented. For continuous variables, descriptive statistics (e.g., n, mean, median, SD, 
minimum, and maximum) will be presented. The minimum and maximum will be presented 
with the same precision as the data. The mean and median will be presented with the precision 
of the data + 1 decimal place. The SD will be presented with the precision of the data + 2 
decimal places.
Formal statistical hypothesis testing and summary statistics will be presented, as well as 
confidence intervals (CIs) on selected endpoints, as described in the sections below.
The default tables, listings, and figures layout will be as presented in Table 4 below:
Table 4:
Layout Specifications
Orientation
Portrait
Landscape
Paper Size
Letter
Letter
Margins
Top: 3.05 cm
Bottom: 2.54 cm
Left: 2.54 cm
Right: 2.54 cm
Top: 3.05 cm
Bottom: 2.2 cm
Left: 1.9 cm
Right: 1.9 cm
Font
Table text: Times new Roman
9 or 10 pts
Table title: Times new Roman 
12 pts
Table legend: Times new 
Roman 10 pts
Table text: Times new Roman 
8, 9 or 10 pts
Table title: Times new Roman 
12 pts
Table legend: Times new 
Roman 9 or 10 pts
The font size may be reduced as necessary to allow additional columns to be presented, but not 
at the expense of clarity. Also the orientation may be changed to portrait if appropriate.
Unless specified otherwise, by-subject listings will be sorted by site, subject ID, and additional 
variables such as time points, as applicable. Listings will display site-subject ID and as-
randomized treatment group (as-treated treatment group for safety).


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4.2.2
Computing Environment
All statistical analyses will be performed using SAS statistical software (Version 9.4).  Medical 
history and adverse events (AEs) will be coded using the latest available version of Medical 
Dictionary for Regulatory Activities (MedDRA). Concomitant medications will be coded using
the latest available version of World Health Organization Drug Dictionary (WHO-DD).
4.2.3
Methods of Pooling Data
In the case of sparse data for the stratification factor (use of prophylactic medication: yes or no),
the responses will be pooled in summary tables. Specific details on the procedures for pooling 
data are presented in the applicable sections of the document outlining the analyses.
4.2.4
Adjustments for Covariates and Stratification
The randomization of subjects is stratified by the use of prophylactic migraine medication (yes 
or no). Hence, most analyses are stratified by the use or prophylactic medication.
4.2.5
Multiple Comparisons
Type I error is controlled in this study by using a hierarchical gate-keeping procedure. First, the 
family of two co-primary endpoints is tested. If the co-primary endpoints are both found to be 
significant, then secondary endpoints are tested in a fixed sequence. In particular, each
co-primary endpoint will be tested for superiority to placebo at a two-sided alpha level of 0.05 
without further adjustment for multiplicity. If the primary endpoint tests are both significant, 
then the following secondary endpoints will be tested in a fixed sequence, in the order shown,
with each test conducted at p=0.05:
1. Pain Relief at 2 hours
2. Functional Disability at 2 hours
3. Sustained Pain Relief from 2 to 24 hours
4. Sustained Freedom from MBS from 2 to 24 hours
5. Probability of Rescue Medication within 24 hours
6. Sustained Normal Functioning (on FDS) from 2 to 24 hours
7. Sustained Pain Relief from 2 to 48 hours
8. Sustained Freedom from MBS from 2 to 48 hours
9. Sustained Normal Functioning (on FDS) from 2 to 48 hours
10. Freedom from Photophobia at 2 hours


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11. Functional Disability at 90 minutes
12. Pain Relief at 90 minutes
13. Sustained Pain Freedom from 2 to 24 hours
14. MBS Freedom at 90 minutes
15. Pain Freedom at 90 minutes
16. Freedom from Phonophobia at 2 hours
17. Sustained Pain Freedom from 2 to 48 hours
18. Pain Relief at 60 minutes
19. Functional Disability at 60 minutes
20. Freedom from Nausea at 2 hours
21. Pain Relapse from 2 to 48 hours
If a test in the hierarchy is not significant, then any further tests on endpoints in the sequence 
will have p-values presented only for descriptive purposes, and no conclusions will be drawn 
from those results. 
For exploratory endpoints, no attempt will be made to adjust for multiplicity. Any exploratory 
endpoints for which p-values are produced will be evaluated at an unadjusted two-sided alpha 
level of 0.05 and presented only for descriptive purposes.
4.2.6
Subpopulations
The subgroups of interest for this study:
Age: Categorized as < 40, ≥40 years 
Race: white, black or African American, other (including Asian) , Asian only.  Certain
tables may be created for the Asian population only; but in the subgroup analyses, Asian 
subjects will generally be included in the “other” category due to low counts.
Sex: Female/Male
Aura: Presence/Absence 
Headaches per Month: Categorized as < median, ≥median, where median is calculated 
overall across treatment groups combined for mITT subjects.
Triptan Non-Responder: Yes/No


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Cardiovascular (CV) Risk Contraindicating Triptans: Yes/No 
Subgroup analyses will be performed for the primary efficacy endpoints only.
Triptan non-responders are identified using the “Prior Triptan Response” Case Report Form 
(CRF) pages, which capture reasons for discontinuing triptans taken historically. The definition 
of triptan non-responder is based on the number of triptans that a subject failed for efficacy 
reasons. For each triptan and route of administration, the subject is asked the questions shown in
Table 5. A subject is considered to have failed a drug for efficacy reasons if they indicated 
“most or all of the time” for any of the reasons in the table. 
A triptan non-responder is defined as any subject that fails two or more molecular entities for 
efficacy reasons. To be considered a failure for a molecular entity, the subject must have failed
on all routes of administration that the subject tried for the molecular entity.
Table 5:
Questions Used to Determine Triptan Non-response
Most or All of the 
Time
Some of the 
Time
Rarely
Never
The treatment took too long to relieve my 
headache pain.
The pain returned after it was relieved 
within 24 hours
The treatment did not relieve my other 
symptoms (nausea, sensitivity to light or 
sound, for example).
I could not count on this treatment to relieve 
my pain and symptoms every time
Subjects with CV risk that contraindicates triptans are identified using the “Cardiac and Other 
Risk Factors” CRF pages. The pages are used to identify subjects with cardiovascular conditions 
cited in triptan labels as contraindications.  A subject is identified as someone with 
cardiovascular risk factors contraindicating triptans if any of the following questions are 
answered as “yes”:
Does the subject have ischemic coronary artery disease?
Does the subject have coronary artery vasospasm including Prinzmetal’s angina?
Does the subject have Wolff-Parkinson-White Syndrome or arrhythmias associated with 
other cardiac accessory conduction pathway disorders?
Does the subject have history of stroke or transient ischemic attack (TIA)? 
Does the subject have peripheral vascular disease (PVD)? 
Does the subject have ischemic bowel disease? 


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Does the subject have uncontrolled hypertension? 
4.2.7
Missing and Partial Dates
For efficacy analyses, partial or missing dates will not be imputed. The relative study days, 
where determined, will be calculated for full dates only. 
For rescue medication, if the time of rescue medication is missing, then all endpoints on or after 
the date of rescue medication will be imputed as failures.
For missing and/or partial dates regarding non-study medications, a conservative approach will 
be taken.  The medication will be assumed to be concomitant if it cannot be definitively shown 
that the medication was not taken after the period beginning 14 days prior to the taking of study 
medication.
If the start date of an AE is partially or completely missing, then the date will be compared as 
far as possible with the date of the randomization. The AE will be assumed to be on-study if it 
cannot be definitively shown that the AE did not occur or worsen during the post-randomization 
period (worst case approach). 
The following general rules will be used:
If the start day is missing, but the start month and year are complete, an AE will only be 
excluded as being on-study if the start month/year is before the month/year of randomization
or if the stop date is before randomization. 
If the start day and month are missing, but the start year is complete, an AE will only be 
excluded as being on-study if start year is before the year of randomization or if the stop 
date is before randomization. 
If the start date is completely missing, an AE will be considered on-study unless the stop 
date is before randomization.
4.2.8
Visit Windows
Windows for the timeframe around efficacy measurements (15, 30, 45, 60, 90 minutes, 2, 3, 4, 
6, 8, 24, and 48 hours) will be automated and captured in the eDiary. Refer to Table 6 for details 
on the evaluation intervals and Appendix 2 for details on the schedule of assessments.


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Table 6:
Evaluation Intervals for Efficacy Analysis
Evaluation
Protocol-Specified Interval 
Analysis-Specified Interval
Screening Phase
Screening
Day -28 to Day -3
Day -40 to Day -3
Acute (Randomization) Phase
Baseline (Randomization)
Day 1 
Day -2 to 1
Onset of Migraine
Day 1 to 45 
Day 1 to 45
15, 30, 45, 60, 90 minutes post-
dose
Time of Dose + 15, 30, 45, 60, and 
90 minutes
Time of Dose + 15, 30, 45, 60, and 90 
minutes (as captured in eDiary)
2 hours post-dose
Time of Dose + 2 hours
Time of Dose + 2 hours (as captured
in eDiary)
3 hours post-dose
Time of Dose + 3 hours
Time of Dose + 3 hours (as captured 
in eDiary)
4 hours post-dose
Time of Dose + 4 hours
Time of Dose + 4 hours (as captured 
in eDiary)
6 hours post-dose
Time of Dose + 6 hours
Time of Dose + 6 hours (as captured 
in eDiary)
8 hours post-dose
Time of Dose + 8 hours
Time of Dose + 8 hours (as captured 
in eDiary)
24 hours post-dose
Time of Dose + 24 hours
Time of Dose + 24 hours (as captured 
in eDiary)
48 hours post-dose
Time of Dose + 48 hours
Time of Dose + 48 hours (as captured 
in eDiary)
End of Treatment Visit
Time of Dose + 7 days
> Day of Dose + 2 days (as defined by 
visit)
4.3
Planned Analyses
Study Day 1 is defined as the day of randomization.  The analyses planned for endpoints that 
use data from this study only will be conducted after the last subject completes their End of 
Treatment Visit or discontinues from the study, and the database has been locked.
4.4
Subject Disposition
A summary of subject disposition will be tabulated for all enrolled subjects by treatment group 
and overall.  The disposition table will support the creation of a consort diagram, similar to that 
shown in Figure 1. The categories in the table will include:
Number of subjects screened
Number of screened subjects excluded from the study and reason for exclusion
Number of subjects randomized


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Number of subjects not treated, and the reasons for not being treated
Number of subjects treated, and their status
Completed Study
Discontinued, and reasons for discontinuation
Number of subjects in each analysis population
A by-subject listing of subject disposition information, including the reason for discontinuation, 
if applicable, will be presented.
Figure 2:        Consort Diagram
 
 
 
 
 
 
  
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
  
 
  


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4.5
Demographic and Baseline Characteristics
Demographic information, medical history by system organ class (SOC) and preferred term 
(PT), migraine history, cardiovascular risk factors, and prior/current triptan response will be 
summarized by as-randomized treatment group and overall for the mITT population to support 
efficacy. A similar set of tables will be made for the treated population by as-treated treatment 
group and overall to support safety.
A separate set of tabulations, including demographic information and migraine history, will be 
made for subjects enrolled but not randomized (overall only) and subjects randomized but not 
treated (by as-randomized treatment group and overall). 
Demographic and other baseline data will also be provided in by-subject data listings.
For each subject, multiple medical histories of the same SOC or PT will be counted only once 
within each SOC and PT. Medical histories will be presented in descending order of overall 
frequency within SOC and PT.
4.6
Missing Efficacy Data Description
Descriptions and tabulations of missing data will only be concerned with the post-baseline time 
points required for computation of the primary and secondary endpoints, and will be assessed 
as-randomized. These include the time points measured from 2 hours through 48 hours post-
dose (e.g.: 60 minutes, 90 minutes, 2, 3, 4, 6, 8, 24 and 48 hours).  The other time points (15, 30, 
45 minutes) are only required for the exploratory endpoints. Also, some tabulations focus on the 
pain endpoint as that should be generally descriptive of the other efficacy endpoints.
The number and percentage of (1) randomized subjects who do not meet the criteria for the 
mITT population, and (2) randomized and treated subjects who do not meet the criteria for the 
mITT population will be tabulated by treatment group and overall. 
For the mITT population, the items below will be tabulated by treatment group and overall. 
Number and percentage of subjects with missing pain data at each time point from 2 through 
48 hours post-dose. The categories in this tabulation are not mutually exclusive as subjects 
may have missing data at multiple time points.
Number and percentage of subjects with: no missing pain data; 1 missing time point, 2 
missing time points, 3 missing time points, 4 missing time points, 5 missing time points, 6 
missing time points, or 7 missing time points. The categories in this tabulation are mutually 
exclusive. 
The number and percentage of subjects with missing data on the following endpoints 
measured at 2-hours post-dose: pain, MBS, photophobia, phonophobia, nausea, and 
functional disability.


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In addition, the number and percentage of mITT subjects with missing pain data at 2 hours post-
dose will be displayed by treatment group and overall within the categories of each of the 
following subgroups:
Age: Categorized as < 40 or ≥40 years 
Race: white; black or African American; other (including Asian); Asian only
Sex: Female or Male
Aura for study migraine: Presence or Absence 
Headaches per Month: Categorized as < median or ≥ median (see Section 4.2.6)
Triptan Non-Responder: Yes/No
Rescue medication taken at any time during the study: Yes/No
MBS at migraine onset: photophobia, phonophobia, nausea, and not reported
4.7
Efficacy Evaluation
Unless otherwise noted, all efficacy analyses will be conducted using the mITT population as 
outlined below. Efficacy tabulations will present results by as-randomized treatment group only 
(excluding overall), unless specified otherwise. All efficacy data will be included in listings by 
subject, treatment group, and time point (as applicable).
For efficacy analyses, baseline is considered as the assessment at the onset of the treated
migraine.
4.7.1
Rescue Medication
Subjects who take rescue medication will be considered as failures for any efficacy evaluations 
that are on or after the first rescue medication date/time.  If the time of first rescue medication is 
missing, subjects will be considered as failures for any efficacy evaluations that are on or after 
the first rescue medication date.
Rescue medications are defined as non-study medications reported on the Rescue Medication 
CRF with complete medication dates, and either (1) medication date/time after the study drug 
first dose date/time, or (2) medication date equal to study drug first dose date if the medication 
time is missing.
The first rescue medication date/time is defined as the earliest rescue medication date/time, 
where missing time is considered to be earlier than non-missing time on the same date.


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4.7.2
MBS Recorded After IP is Taken
Subjects that record their MBS after taking the investigational product (IP) are considered 
failures for the analysis of MBS.
4.7.3
Primary Efficacy Endpoints
In addition to the analyses described below, data regarding the co-primary efficacy endpoints, 
pain freedom and freedom from MBS at 2 hours post-dose will be presented in a by-subject 
listing that includes treatment group, historical MBS, MBS at time of onset of study migraine,  
initial migraine severity, gender, presence or absence of aura, and use of prophylactic migraine 
medication. 
4.7.3.1
Pain Freedom at 2 Hours Post-Dose
Pain freedom is assessed using the number of mITT subjects that report pain levels of “none” at 
2 hours post-dose on a 4-point Likert scale (0=none, 1=mild, 2=moderate, 3=severe). The
information from the 4-point scale is directly summarized as follows:
A table showing descriptive statistics for the observed data, which includes the number and 
percentage of subjects reporting each of the 4 pain levels at 2 hours post-dose, and the 
percentage of subjects with missing data, for each treatment group. The table will include 
exact (Clopper-Pearson) 95% CIs for each percentage.  This table will be repeated for Asian 
subjects only.
The estimand for the primary analysis is the percentage of pain free subjects. In statistical terms, 
this percentage is arrived at by estimating the probability or the “risk” that a subject is pain free. 
The population summary, the between group difference in the percentage of pain free subjects is 
assessed by computing the “risk difference” between treatment groups. This is evaluated by 
computing the common risk difference, using Cochran-Mantel-Haenszel (CMH) weights 
(sample size weights), stratified by the use of prophylactic migraine medication (yes or no). The 
risk difference is tested at a two-sided alpha level of 0.05. Missing data at 2 hours post-dose will 
be imputed as failures (NC=F).  If a stratum (prophylactic medication use: yes or no) has sparse 
data (less than 5 subjects), then the strata will be pooled.
Results presented for the primary analysis include the following:

The number and percentage of subjects who are pain free, and those not pain free, at 2 hours 
post-dose. These are presented by stratum and treatment group, with asymptotic standard 
errors (ASE), and 95% asymptotic CIs.

Common risk difference with sample size, p-value, ASE, and 95% asymptotic CIs.

Risk difference within each stratum with sample size, p-value, ASE, and 95% asymptotic 
CIs.


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
A forest plot of the risk differences within each stratum, and common risk difference 
(similar to the risk difference plot produced by SAS Proc Freq).

Common risk for each treatment with sample size, ASE, and 95% asymptotic CIs.
The primary analysis will be repeated for the subgroups described in Section 4.2.6.  
Sensitivity analyses will be conducted as follows:
1. The primary analysis is repeated, using the mITT population, with missing data at 2 hours 
post-dose imputed using Last Observation Carried Forward (LOCF). Baseline Observation 
Carried Forward (BOCF) is permitted. 
2. The primary analysis is repeated using only data from complete cases (data present at 
baseline and 2 hours). 
3. The primary analysis is executed using the mITT population, and multiple imputation (with 
20 imputations; m=20) methods to impute missing data at 2 hours post-dose using the copy 
from reference approach. The fully conditional specification (FCS) method is used with a 
generalized logit distribution. Covariates may include use of prophylactic medication (yes or 
no), sex, migraine intensity at onset (severe or other), migraines per month (< median, 
≥median), and the subject’s MBS at time of study migraine onset (nausea, photophobia, or 
phonophobia).  
4. A series of “what if” analyses are conducted that show what the analysis results would look
like if the missing data in each treatment group were replaced with data from subjects 
having success rates that vary over the range of 0, 10, 20 and 30 percent. The results of this 
analysis are presented in a 4x4 matrix, with the rows representing the success rates for the 
placebo group and the columns representing the success rates for the BHV-3000 group. For 
example, the “30,0” cell shows the hypothetical result when a responder rate of 30% 
replaces the missing placebo data, and a responder rate of 0% replaces the missing BHV-
3000 data. Each cell in this table will show the common risk difference, asymptotic 95% CI
and uncorrected p-value. The table will be accompanied by a forest plot that displays the 
16 CIs. 
4.7.3.2
Freedom from MBS at 2 Hours Post-Dose
Freedom from each subject’s MBS is assessed using the number of mITT subjects who report 
that their MBS (reported at migraine onset) is absent at 2 hours post-dose. The symptoms that 
can be nominated as the MBS (phonophobia, photophobia or nausea) are measured using a 
binary scale (0=absent, 1=present).
Subjects who reported their MBS after taking IP, or who did not provide an MBS are considered 
failures in this analysis.
Tabulations will be presented as follows:


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The number and percentage of subjects reporting each of the migraine associated symptoms 
(phonophobia, photophobia or nausea) by treatment group and overall as most bothersome,
subjects with a missing MBS, and subjects who reported their MBS after taking study 
medication.
An overall cross tabulation of the historical MBS (reported at screening) as rows, and the 
MBS reported at the onset of the treated migraine as columns. This tabulation only includes 
subjects with both assessments. P-value from a chi-square test will be reported along with 
the values and confidence limits for both Asymmetric Lambda and Symmetric Lambda.
The estimand, difference in percentage of MBS free subjects (“risk difference”) between
treatment groups, is evaluated by computing the common risk difference, using CMH weights 
(sample size weights), stratified by the use of prophylactic migraine medication (yes or no). The 
risk difference will be tested at a two-sided alpha level of 0.05. Missing data at 2 hours post-
dose will be imputed as failure (NC=F).  Also, the use of rescue medication prior to providing 
data at the 2 hour assessment, taking IP prior to reporting the MBS, or failure to report a MBS 
are events that are imputed as treatment failures. If a stratum (prophylactic medication use: yes 
or no) has sparse data (less than 5 subjects) then the strata will be pooled.  
The results to be presented for the primary analysis of MBS include those described in items (a) 
through (e) for the primary analysis of pain freedom (Section 4.7.3.1). In this case, the “risk” is 
now the probability of being MBS free at two-hours post-dose.
The primary analysis of MBS will be repeated for the subgroups described in Section 4.2.6. 
Sensitivity analyses will be conducted as follows:
1. The primary analysis is repeated, using the mITT population, with missing data at 2 hours 
post-dose imputed using LOCF. BOCF is permitted. 
2. The primary analysis is repeated, using only data from complete cases (data present at 
baseline and 2 hours). 
3. The primary analysis is executed using the mITT analysis set, and multiple imputation (with 
20 imputations; m=20) methods to impute missing data at 2 hours post-dose using the copy 
from reference approach. The FCS method is used with a generalized logit distribution.  
Covariates may include use of prophylactic medication (yes or no), sex, migraine intensity at 
onset (severe or other), migraines per month (< median, ≥median), and the subject’s MBS at 
time of study migraine onset (nausea, photophobia, or phonophobia). 
4. A matrix of “what if” analyses, similar to that created for the co-primary endpoint of pain 
freedom, is created for freedom from the MBS.
5. The primary analysis will be repeated, using the mITT population, with the addition of a 
stratum that reflects the subject’s self-reported MBS at the time of study migraine onset 
(nausea, phonophobia, or photophobia).


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4.7.4
Secondary Efficacy Endpoints
If the co-primary endpoint tests are both significant, then the secondary endpoints are evaluated 
using a fixed sequence approach, with each test in the hierarchy conducted at p=0.05.  See 
Section 4.2.5 for the testing order.
4.7.4.1
Freedom from Photophobia, Phonophobia or Nausea at 2 Hours
Freedom from photophobia, phonophobia, and nausea are assessed, by treatment group, by 
tabulating the number of mITT subjects who reported the presence of the symptom at migraine 
onset who then report the absence of the symptom at 2 hours post-dose. Subjects who report the 
symptom at baseline, but have missing data at 2 hours post-dose will be imputed as failures
(NC=F). Also, subjects in the analysis set that take rescue medications on or before providing 
their 2 hours post-dose data are imputed as failures.
The principal measurement for the associated symptoms (phonophobia, photophobia, and 
nausea) is made on a binary scale (0 = absent; 1 = present).  An exploratory measurement of 
these symptoms was also made on a 4 point Likert scale (0=none, 1=mild, 2=moderate, 
3=severe).
For these three endpoints, the difference between treatment groups is evaluated by computing 
the common risk difference, using CMH weights (sample size weights), stratified by the use of 
prophylactic migraine medication (yes or no). The risk difference is tested at a two-sided alpha 
level of 0.05. If a stratum (prophylactic medication use: yes or no) has sparse data (less than 5 
subjects) then the strata are pooled.  
The results presented for the analysis of each symptom include those described in items (a) 
through (e) for the primary analysis of pain freedom (Section 4.7.3.1). In this case, the “risk” is
the probability of being free from the symptom of interest at 2 hours post-dose. In addition, the 
following display will be created for each of the 3 symptoms:
A table showing descriptive statistics for the 4-point scale, which includes the number and 
percentage of subjects reporting each of the 4  symptom levels at 2 hours post-dose, and the 
percentage of subjects with missing data, for each treatment group. The table will include 
exact (Clopper-Pearson) 95% CIs for each percentage.
4.7.4.2
Pain Relief (at 60 Minutes; at 90 Minutes; at 2 Hours)
Pain relief at the specified timepoint post-dose is assessed by tabulating the number of mITT 
subjects that report a pain level of none or mild (responses of 0 or 1 on the 4-point Likert scale) 
at the specified timepoint post-dose, by treatment group.  Subjects with missing data at the 
specified timepoint post-dose will be imputed as failures (NC=F). 
The results to be presented for the analysis include those described in items (a) through (e) for 
the primary analysis of pain freedom (Section 4.7.3.1). In this case, the “risk” is the probability 
of pain relief at the specified timepoint post-dose.


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4.7.4.3
Probability of Requiring Rescue Medication within 24 Hours
Whether or not a subject took rescue medication within 24 hours after the initial dose of study 
medication is tabulated by treatment group using mITT subjects, and the percentages are
compared between treatment groups.
The results are presented for the analysis include those described in items (a) through (e) for the 
primary analysis of pain freedom (Section 4.7.3.1). In this case, the “risk” is the probability of 
not requiring rescue medication within 24 hours post-dose.
Information regarding the rescue medication, including the type, date and time taken, dose, 
route and form of administration, and frequency, is presented in a listing by subject and 
treatment group.
4.7.4.4
Functional Disability Scale (at 60 Minutes; at 90 Minutes; at 2 Hours)
Impact of treatment on subject disability is assessed using a single-question, FDS. Subjects rate 
the level of disability they perceive as a result of their migraine in performing normal actions 
using a 4-point scale: Normal Function, Mild Impairment, Severe Impairment, or Required 
Bedrest.  The proportion of mITT subjects who have a response of “normal” at the specified 
timepoint post dose will be evaluated as the endpoint of interest.
The information from the 4-point scale will be directly summarized as follows:
A table showing descriptive statistics for the 4-point scale, which includes the number and 
percentage of subjects reporting each of the 4 disability levels at the specified timepoint
post-dose, and the percentage of subjects with missing data, for each treatment group, using 
the observed data. The table will include exact (Clopper-Pearson) 95% CIs for each 
percentage.
The results to be presented for the analysis include those described in items (a) through (e) for 
the primary analysis of pain freedom (Section 4.7.3.1). In this case, the “risk” is now the 
probability of a functional disability level of “normal” at the specified timepoint post-dose.
4.7.4.5
Sustained Pain Freedom from 2 to 24 Hours
Sustained pain freedom is assessed using the number of mITT subjects that experienced no 
headache pain (response of 0 on Likert scale) at all time points from 2 through 24 hours post-
dose. Subjects with missing pain scores at 1 or fewer time points, given that they have responses 
of no pain (response of 0 on 4-point Likert scale) at all other time points including the 2 and 24 
hour post-dose time points, will be considered as successes.  Subjects with responses missing at 
greater than 1 post-dose time point, missing data at the 2 or 24 hour time point, or with any pain 
score greater than 0 will be considered as failures. 
The results to be presented for the analysis include those described in items (a) through (e) for 
the primary analysis of pain freedom (Section 4.7.3.1). In this case, the “risk” is the probability 
of sustained pain freedom from 2 to 24 hours.


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4.7.4.6
Sustained Pain Freedom from 2 to 48 Hours
Sustained pain freedom is assessed using the number of mITT subjects that experienced no 
headache pain (response of 0 on Likert scale) at all time points from 2 through 48 hours post-
dose.  Subjects with missing pain scores at no more than 1 time point, given that they have 
responses of no pain (response of 0 on Likert scale) at the 2, 24, and 48 hour time points will be 
considered as successes. Subjects with responses missing at greater than 1 time point; missing 
data at the 2, 24, or 48 hour time point; or with any pain score greater than 0 will be considered 
as failures. 
The results to be presented for the analysis include those described in items (a) through (e) for 
the primary analysis of pain freedom (Section 4.7.3.1). In this case, the “risk” is the probability 
of sustained pain freedom from 2 to 48 hours.
4.7.4.7
Sustained Pain Relief from 2 to 24 Hours
Sustained pain relief is assessed using the number of mITT subjects who experience no or mild 
headache pain (responses of  either 0 or 1 on 4-point Likert scale) at all time points from 
2 through 24 hours post-dose.  Subjects with missing pain scores at no more than 1 time point, 
given that they have responses of no or mild pain at the 2 and 24 hour time points will be 
considered as successes.  Subjects with responses missing at more than 1 time point, with 
missing data at the 2 or 24 hour time points, or with any pain score greater than 1 will be 
considered as failures. 
The results to be presented for the analysis include those described in items (a) through (e) for 
the primary analysis of pain freedom (Section 4.7.3.1). In this case, the “risk” is the probability 
of sustained pain relief from 2 to 24 hours.
4.7.4.8
Sustained Pain Relief from 2 to 48 Hours
Sustained pain relief will be assessed using the number of subjects that experience no or mild 
headache pain (response of 0 or 1 on the 4-point Likert scale) at all time points from 2 through 
48 hours post-dose. Subjects with missing pain scores at no more than 1 time point, given that 
they have responses of no or mild pain at all other time points including the 2, 24, and 48 hour 
time points will be considered as successes. Subjects with responses missing at more than 1 time 
point; with missing data at the 2, 24, or 48 hour time point; or with any pain score greater than 1 
will be considered as failures. 
The results to be presented for the analysis include those described in items (a) through (e) for 
the primary analysis of pain freedom (Section 4.7.3.1). In this case, the “risk” is the probability 
of sustained pain relief from 2 to 48 hours.
4.7.4.9
Sustained MBS Freedom from 2 to 24 Hours
Sustained MBS freedom is assessed using the number of mITT subjects that experienced 
freedom from their MBS at all time points from 2 through 24 hours post-dose. Subjects with 
missing MBS scores at 1 or fewer time points, given that they have responses of freedom from 


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MBS at all other time points including the 2 and 24 hour post-dose time points will be 
considered as successes.  Subjects with responses missing at greater than 1 post-dose time point, 
missing data at the 2 or 24 hour time point, or with any report of presence of MBS will be 
considered as failures. 
The results to be presented for the analysis include those described in items (a) through (e) for 
the primary analysis of pain freedom (Section 4.7.3.1). In this case, the “risk” is the probability 
of sustained MBS freedom from 2 to 24 hours.
4.7.4.10
Sustained MBS Freedom from 2 to 48 Hours
Sustained MBS freedom is assessed using the number of mITT subjects that experienced 
freedom from their MBS at all time points from 2 through 48 hours post-dose. Subjects with 
missing MBS scores at 1 or fewer time points, given that they have responses of freedom from 
MBS at all other time points including the 2, 24, and 48 hour post-dose time points will be 
considered as successes.  Subjects with responses missing at greater than 1 post-dose time point, 
missing data at the 2, 24, or 48 hour time point, or with any report of presence of MBS will be 
considered as failures. 
The results to be presented for the analysis include those described in items (a) through (e) for 
the primary analysis of pain freedom (Section 4.7.3.1). In this case, the “risk” is the probability 
of sustained MBS freedom from 2 to 48 hours.
4.7.4.11
Sustained Normal Functioning from 2 to 24 Hours
Sustained normal functioning is assessed using the number of mITT subjects that experienced 
normal functioning on the FDS at all time points from 2 through 24 hours post-dose. Subjects 
with missing FDS scores at 1 or fewer time points, given that they have responses of normal at 
all other time points including the 2 and 24 hour post-dose time points will be considered as 
successes.  Subjects with responses missing at greater than 1 post-dose time point, missing data 
at the 2 or 24 hour time point, or with any report of non-normal functioning will be considered 
as failures. 
The results to be presented for the analysis include those described in items (a) through (e) for 
the primary analysis of pain freedom (Section 4.7.3.1). In this case, the “risk” is the probability 
of sustained normal functioning from 2 to 24 hours.
4.7.4.12
Sustained Normal Functioning from 2 to 48 Hours
Sustained normal functioning is assessed using the number of mITT subjects that experienced 
normal functioning on the FDS at all time points from 2 through 48 hours post-dose. Subjects 
with missing FDS scores at 1 or fewer time points, given that they have responses of normal at 
all other time points including the 2, 24, and 48 hour post-dose time points will be considered as 
successes.  Subjects with responses missing at greater than 1 post-dose time point, missing data 
at the 2, 24, or 48 hour time point, or with any report of non-normal functioning will be 
considered as failures. 


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The results to be presented for the analysis include those described in items (a) through (e) for 
the primary analysis of pain freedom (Section 4.7.3.1). In this case, the “risk” is the probability 
of sustained normal functioning from 2 to 48 hours.
4.7.4.13
Pain Freedom at 90 Minutes
Pain freedom at 90 minutes post-dose is assessed by tabulating the number of mITT subjects 
that report a pain level of none (response of 0 on the 4-point Likert scale) at 90 minutes post-
dose, by treatment group.  Subjects with missing data at 90 minutes post-dose will be imputed 
as failures (NC=F). 
The results to be presented for the analysis include those described in items (a) through (e) for 
the primary analysis of pain freedom (Section 4.7.3.1). In this case, the “risk” is the probability 
of pain freedom at 90 minutes post-dose.
4.7.4.14
MBS Freedom at 90 Minutes
MBS freedom at 90 minutes post-dose is assessed by tabulating the number of mITT subjects 
that report an absence of their MBS at 90 minutes post-dose, by treatment group.  Subjects with 
missing data at 90 minutes post-dose will be imputed as failures (NC=F). 
The results to be presented for the analysis include those described in items (a) through (e) for 
the primary analysis of pain freedom (Section 4.7.3.1). In this case, the “risk” is the probability 
of MBS freedom at 90 minutes post-dose.
4.7.4.15
Pain Relapse from 2 to 48 Hours
Pain relapse is assessed using the number of mITT subjects that are pain free at 2 hours post-
dose as the denominator.  The numerator is the number of these subjects that then have a relapse 
of pain at any severity (response of 1, 2, or 3 on the 4-point Likert scale) within 48 hours after 
administration of study medication. Subjects with more than 1 time point with missing data or 
with missing data at the 2, 24, or 48 hour time point are classified as relapsers.
The results to be presented for the analysis include those described in items (a) through (e) for 
the primary analysis of pain freedom (Section 4.7.3.1). In this case, the “risk” is the probability 
of sustained pain relapse from 2 to 48 hours.
4.7.5
Exploratory Efficacy Endpoints
Any p-values presented for exploratory efficacy endpoints are for descriptive purposes only.
4.7.5.1
Functional Disability Scale at 24 Hours
Data will be analyzed in the same manner as described in Section 4.7.4.4. However, in this case 
the analysis will use the data from the 24 hour post-dose time point.  


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4.7.5.2
Pain Relief at 15, 30, 60 and 90 Minutes Post-Dose
Pain relief at 15, 30, 60, and 90 minutes post-dose will be assessed by tabulating the number of 
mITT subjects that report a pain level of none or mild (responses of 0 or 1 on the 4-point Likert 
scale) at the specified post-dose time point by treatment group. Subjects with missing data at the 
specified post-dose time point will be imputed as failures (NC=F). 
First, the data will be evaluated at each time point for each time point, using the first analysis 
methods described in Section 4.7.3.1.
Pain relief over time up to 8 hours will be analyzed using Kaplan-Meier methods.  Kaplan-
Meier estimates will be tabulated using the following time periods (0 through 15 minutes, >15 
through 30 minutes, > 30 through 60 minutes, > 60 through 90 minutes, > 90 through 120 
minutes, >120 minutes through 180 minutes, >180 minutes though 240 minutes, >240 minutes 
though 360 minutes, >360 minutes though 495 minutes, and > 495 minutes). For each time 
period, the number of subjects at risk, with an event (pain freedom), censored, and survival 
probability estimate (with 95% CI), will be presented by treatment group. Subjects who fail to 
reach no pain by 495 minutes, will be censored at 496 minutes. Additionally, subjects who take 
rescue medication prior to 495 minutes will be censored at the date/time associated with their 
rescue medication. Note that the probability of survival corresponds to the probability of NOT 
having pain relief.  Survival estimates are calculated using the Kaplan-Meier product-limit 
method and median survival (time to pain freedom), and will be presented along with 95% CIs 
calculated using the method of Brookmeyer and Crowley.
To support the analysis, a Kaplan-Meier plot, with time in minutes on the x-axis and probability 
of survival on the y-axis, will be presented by treatment group. The number at risk at each time 
point (0, 15, 30, 45, 60, 90, 120, 180, 240, 360, and 495) minutes will be presented below the
figure. In this analysis, being at risk corresponds to not yet having achieved pain relief; 
therefore, the subject is still “at risk” of having pain freedom. Once a subject has pain relief or is 
censored, then the subject is no longer in the risk pool. If a subject has missing data at an earlier 
time point, then the time point with missing data is not considered. The subject is still 
considered at risk of failure at a future time point if data are available. Subjects are censored as 
described above.
4.7.5.3
Preference of Medication (PoM)
The PoM 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. 
Responses at 24 hours post-dose for all subjects who provided a response, and answered “yes” 
to the lead-in question (i.e. “Have you ever taken migraine medication”), will be tabulated. The 
number and percentage of subjects preferring the study medication, along with 95% asymptotic 
CIs, are presented by treatment group.  The tabulations will be repeated for the subset of 
subjects considered as responders or non-responders by treatment group without imputation, 
where responders are those subjects who reported a pain score of 0 or 1 at 2 hours post-dose and 
who did not require rescue medication at or prior to 2 hours post-dose.


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4.7.5.4
Migraine Quality of Life Questionnaire (MQoLQ)
Impact of treatment on patient-reported quality of life is assessed using the MQoLQ, which is a 
15-item instrument that has been validated in migraine patients to measure the short-term impact 
of treatment (within 24 hours). The MQoLQ consists of 15 items across the following five 
domains: (1) work functioning, (2) social functioning, (3) energy/vitality, (4) migraine 
symptoms, and (5) feelings/concerns. There are three items within each domain. Response 
options for each of the items are on a 7-point scale where 1 indicates maximum impairment of 
QoL and 7 indicates no impairment. Each domain has a maximum score of 21 and a minimum 
score of 3. The items in the work functioning domain are: (1) ability to do normal everyday 
work, (2) ability to operate machinery or a motor vehicle, and (3) ability to stay alert. The items 
in the social functioning domain are: (1) interactions with people who are close to you, (2) 
interactions with other people, and (3) ability to enjoy life. The items in the energy/vitality 
domain are: (1) energy level, (2) ability to have a good night's sleep, and (3) mood. The items in 
the migraine symptoms domain are: (1) have throbbing head pain, (2) have increased sensitivity 
to light and/or noise, and (3) have nausea. Lastly, the items in the feelings/concerns domain are: 
(1) feel upset about having migraine headaches, (2) feel physically uncomfortable, and (3) feel 
concern that your migraine medication wouldn't relieve your migraine headache symptoms.
The observed responses at 24 hours post-dose will be presented for each item, each domain, and 
as a total score, by treatment group. The observed responses at 24 hours will also be 
summarized as a continuous response for each item, domain, and for the total score.  Responses 
will also be presented in a by-subject listing along with treatment group, historical MBS
collected at screening, MBS reported at migraine onset, migraine severity just prior to study 
medication, and migraine severity at 24 hours post-dose.
4.7.5.5
Efficacy at Each Pose-Dose Time Point
Pain freedom, pain relief, freedom from MBS, and functional disability score will be tabulated
by treatment group at each post-dose time point. Success for each of these endpoints will be 
tabulated using the mITT subjects. 
Freedom from nausea, freedom from phonophobia, freedom from photophobia, and FDS
response will be tabulated by treatment group at each post-dose time point.  The tabulation will 
include: the total number of subjects reporting each of the above symptoms at baseline, success 
as the percentage of the total number of subjects reporting the symptoms at baseline, and the
number of subjects that reported the symptom but with missing data at the post-dose time point
as a percentage of the number reporting the symptom at baseline.
4.7.5.6
Pain Freedom to 8 Hours Post-Dose
Pain freedom over time up to 8 hours will be analyzed using Kaplan-Meier methods.  Kaplan-
Meier estimates will be tabulated using the following time periods (0 through 15 minutes, >15 
through 30 minutes, > 30 through 60 minutes, > 60 through 90 minutes, > 90 through 120 
minutes, >120 minutes through 180 minutes, >180 minutes though 240 minutes, >240 minutes 
though 360 minutes, >360 minutes though 495 minutes, and > 495 minutes). For each time 
period, the number of subjects at risk, with an event (pain freedom), censored, and survival 


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probability estimate (with 95% CI), will be presented by treatment group. Subjects who fail to 
reach no pain by 495 minutes, will be censored at 496 minutes. Additionally, subjects who take 
rescue medication prior to 495 minutes will be censored at the date/time associated with their 
rescue medication. Note that the probability of survival corresponds to the probability of NOT 
having pain freedom.  Survival estimates are calculated using the Kaplan-Meier product-limit 
method and median survival (time to pain freedom), and will be presented along with 95% CIs 
calculated using the method of Brookmeyer and Crowley.
To support the analysis, a Kaplan-Meier plot, with time in minutes on the x-axis and probability 
of survival on the y-axis, will be presented by treatment group. The number at risk at each time 
point (0, 15, 30, 45, 60, 90, 120, 180, 240, 360, and 495) minutes will be presented below the 
figure. In this analysis, being at risk corresponds to not yet having achieved pain freedom; 
therefore, the subject is still “at risk” of having pain freedom. Once a subject has pain freedom
or is censored, then the subject is no longer in the risk pool. If a subject has missing data at an 
earlier time point, then the time point with missing data is not considered. The subject is still 
considered at risk of failure at a future time point if data are available. Subjects are censored as 
described above.
4.8
Pharmacokinetic Evaluation
No pharmacokinetic data will be collected in this study.
4.9
Safety Evaluation
Safety analyses will be conducted on the treated population by as-treated treatment group (i.e., 
the actual treatment received) and overall. All safety data will be presented in by-subject listings
and will indicate which values are on-study or on-treatment.  
Safety outcome measures include: AEs, laboratory assessments including liver toxicity, vital 
signs, physical measurements, electrocardiograms (ECGs), concomitant and rescue medications, 
and suicidal ideation and behaviors.  Unless otherwise noted, baseline is considered as last non-
missing assessment on or prior to study drug randomization.
4.9.1
Extent of Exposure
Extent of exposure is measured by subjects providing self-reported study drug exposure 
information in their eDiaries. As a check on this exposure data, study drug accountability data 
are provided by the study center on the “Drug Accountability” CRF page.
The self-reported study drug exposure data will be tabulated by treatment group and overall for 
randomized subjects who had an on-study migraine, and will include:

The number (and percentage) of randomized subjects that took study medication  
o
The number and percentage who took the medication prior to providing baseline 
study migraine characteristics


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o
The number and percentage that took study medication after providing baseline 
study migraine characteristics

The number and percentage of randomized subjects who reported not taking study 
medication 

The number and percentage of randomized subjects for whom no exposure data was 
reported 
The study drug accountability will be tabulated by treatment group and overall for randomized 
subjects who had an on-study migraine, and will include:

The number and percentage of randomized subjects to whom kits were dispensed 

The number and percentage of kits returned
o
The number and percentage of kits returned from which the IP was used  
o
The number and percentage of kits returned from which the IP was not used  

The number and percentage of kits not returned
A cross tabulation of exposure and accountability data will be prepared. This will be done 
overall for randomized subjects who had an on-study migraine. For the exposure and 
accountability data, the categories are: Took IP, Did not Take IP, and Unknown.
A by-subject listing will be prepared that indicates the study drug exposure and accountability
status of all randomized subjects.  A patient identifier (PID) listing will be prepared if subjects 
had unknown exposure data, unknown accountability data, or for whom the exposure and 
accountability data did not match.
4.9.2
Adverse Events
AEs will be coded using MedDRA and displayed in tables and listings by SOC and PT, unless 
specified otherwise.
On-study AEs are those with a start (onset) date on or after the randomization date.
Adverse events are summarized by subject incidence rates; therefore, in any tabulation, a subject 
contributes only once to the count for a given AE (SOC or PT).  The number and percentage of 
subjects with any on-study AE, with any on-study AE related to treatment (unlikely related, 
possibly related, or related), with any on-study SAE, with any on-study SAE related to 
treatment, with any on-study severe AE, with any on-study AE leading to study drug 
discontinuation and with any on-study AE leading to death will be summarized by treatment 
group and overall. 


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The number and percentage of subjects with on-study AEs will also be summarized by SOC and 
PT for the following: any AE; AEs related to study drug; SAEs; severe AEs; and AEs leading to 
study drug discontinuation. AEs will be displayed in descending order of overall frequency 
within SOC and PT.
In these tabulations, each subject will contribute only once (i.e., the most related occurrence or 
the most intense occurrence) to each of the incidence rates in the descriptive analysis, regardless 
of the number of episodes. All AEs will be listed and indicate whether or not the AE was 
serious, occurred on study, or potentially occurred on treatment. Additional listings will be 
provided including: deaths; SAEs; and AEs leading to study drug discontinuation.  
Potentially on-treatment AEs are those with a start date on or after the first dose of study drug
date.  Given that the AEs do not have recorded onset times, these on-study events are considered 
to be potentially on-treatment. (Thus, potentially on-treatment AEs are a subset of on-study 
AEs).
4.9.3
Laboratory Data
Clinical laboratory evaluations include:
Hematology: hemoglobin, hematocrit, red blood cell count, white blood cell count with 
differential, and platelets
Serum Chemistry: 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 fractionation, if available)
Lipid Panel: Cholesterol, LDL, HDL, triglycerides (screening only)
Estimated glomerular filtration rate (eGFR) using the estimated modification of diet in renal 
disease (MDRD) formula will be calculated and reported by the central lab at each visit that
the clinical laboratory test is collected.
Urinalysis: pH, specific gravity, protein, ketones, nitrites, urobilinogen, leukocyte esterase, 
protein, glucose, microalbuminuria, and blood.  If blood, protein, or leukocytes are positive, 
reflex to microscopic examination.
Urine drug screen: for drugs of abuse
Clinical laboratory values will be expressed using both Standard US units and SI units.
Tabulations, listings, and graphics will be provided to show the data in both systems, unless 
specified otherwise.
The observed value and change from baseline will be summarized for select continuous 
laboratory parameters at baseline and the end of treatment visit. In addition, the shift from 
baseline in laboratory tests will be summarized as the number and percentage of subjects with 
each category (low, normal, high) at baseline and the end of treatment visit.  Note that shift 


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categories are independent of US and SI units. For AST and ALT, the shift tables will use the 
following categories (SI and US units are the same): Normal, >ULN, >3x ULN, and >5x ULN.  
In the event of repeat values from the same post-baseline visit, the non-missing value closest to 
the target date for the visit will be used. In the case of a tie, the latest record will be used.
All laboratory data will be provided in by-subject listings that indicate which values are on 
study or on treatment. Additional listings will be presented for all abnormal laboratory values.  
On-study laboratory values are those with collection date/time after the randomization
date/time.
On-treatment laboratory values are those with collection date/time after the first dose of study 
drug date/time. (Thus, on-treatment laboratory values are a subset of on-study values.)
These definitions of on-study/on-treatment apply to vital signs, physical measurements, ECGs, 
and suicidal ideation and behaviors.
4.9.3.1
Liver Toxicity Evaluation
Potential drug induced liver injury (DILI) are those events meeting Hy’s Law, defined as:
1. Aminotransferases (AT) ALT or AST elevation > 3 times the upper limit of normal (ULN);
2. Total bilirubin (TBL) > 2 times ULN, without initial findings of cholestasis (elevated serum 
alkaline phosphatase); and
3. No other immediately apparent possible causes of AT elevation and hyperbilirubinemia, 
included but not limited to: viral hepatitis, pre-existing chronic or acute liver disease, or the 
administration of other drug(s) known to be hepatotoxic.
Any on-study potential DILI, meeting the above defined criteria, will be reported as SAEs in the 
SAE summary table (see Section 4.9.2). A by-subject listing of potential DILI will be prepared 
that shows the AT and TBL values for all subjects that experience either AT > 3 times the upper 
limit of normal or TBL > 2 times the upper limit of normal at any time.
Additionally, a table will be created that summarizes the on-study incidence (as the number and 
percentage of subjects with an elevation) of the following:

>3x, >5x, >10x, and >20x ULN elevations of AST, ALT, and either ALT or AST

Any elevations of bilirubin >1x ULN and >2x ULN

Any elevations of ALP > 1.5x ULN

Elevation of AST or ALT (>3x ULN) accompanied by elevated bilirubin (>1.5x ULN 
and >2x ULN)


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
Elevation of AST or ALT along with an on-study AE of nausea, vomiting, anorexia, 
abdominal pain, or fatigue
An evaluation of on-study Drug-Induced Serious Hepatotoxicity (eDISH) plot will be created by 
plotting the maximum total bilirubin against maximum ALT and presenting these data points by 
treatment group.  The maximum values for each subject during the study will be identified as 
the maximum values that occur on study, but not necessarily concurrently. Maximum total 
bilirubin (presented as xULN) will be plotted on a log scale on the y-axis and maximum ALT 
(presented as xULN) will be plotted on a log scale on the x-axis.  A horizontal reference line 
will be placed at 2x ULN for maximum total bilirubin, and a vertical reference line will be 
placed at 3x ULN for maximum ALT. The lower left quadrant will be labeled “Normal Range”. 
The upper left quadrant will be labeled “Hyperbilirubinemia”. The lower right quadrant will be 
labeled “Temple’s Corollary”. The upper right quadrant will be labeled “Possible Hy’s Law 
Range”. 
4.9.4
Vital Signs and Physical Measurements
The observed value and change from baseline in vital signs will be summarized at baseline and 
the end of treatment visit.
4.9.5
Electrocardiogram
The shift from baseline in ECG parameters will be summarized as the number and percentage of 
subjects with normal and abnormal results at baseline and the end of treatment visit. The 
observed value and change from baseline in ECG interval data (e.g., RR, QRS, PR, QT, QTcF), 
and ventricular heart rate will also be summarized at baseline and the end of treatment visit.
4.9.6
Non-Study Medications
Concomitant medications will be coded using the WHO-DD. Results will be tabulated by 
Anatomic Therapeutic Class (ATC) and PT in descending order of overall frequency. For each 
subject, multiple records of the same medication will be counted only once within each ATC 
and/or PT. 
The following non-study medications will be tabulated:

Prior medications, defined as non-study medications with start or stop date < randomization 
date – 14 days.

Concomitant medications, defined as non-study medications with start or stop date 
randomization date – 14 days.

Prophylactic medications taken at or after informed consent and before randomization, 
defined as those with (1) informed consent date start or stop date < randomization date, or 
(2) start date informed consent date and randomization date – 1 day stop date 


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
Prophylactic medications taken at or after randomization, defined as those with start or stop 
date randomization date.

Rescue medications (see Section 4.7.1).
4.9.7
Sheehan-Suicidality Tracking Scale (S-STS)
The S-STS is a prospective, self-reported rating scale that contains 16 questions to track both 
treatment-emergent suicidal ideation and behaviors. In the event the subject is unavailable, the 
S-STS clinician-administered rating scale will be completed that contains 6 yes/no questions.
Self-reported S-STS scores are calculated as follows:
Ideation subscale score: Sum of scores (0 – 4) for Questions 2 – 11
Behavior subscale score: Sum of scores (0 – 4) for Questions 1a, (highest of 12 or any row 
of 16), (highest of 14 or any row of 15), 17, and 20
Total score: Sum of the ideation and behavior subscale scores
The self-reported S-STS ideation subscale, behavior subscale, and total score will be 
summarized at baseline, and the number and percentage of subjects in change from baseline 
categories (i.e., <-1, -1, no change, 1, >1) will be summarized at the end of treatment visit.


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APPENDIX 1:
TABLES, LISTINGS, AND FIGURES
Table Number
Title
Population
Topline
14.1.1
Subject Disposition
Enrolled Subjects
Y
14.1.2.1
Demographic and Baseline Characteristics
mITT Subjects
Y
14.1.2.2
Demographic and Baseline Characteristics
Subjects Enrolled but Not Randomized
14.1.2.3
Demographic and Baseline Characteristics
Subjects Randomized but Not Treated
14.1.2.4
Demographic and Baseline Characteristics
Treated Subjects
14.1.3.1
Medical History by System Organ Class and Preferred Term
mITT Subjects
14.1.3.2
Medical History by System Organ Class and Preferred Term
Treated Subjects
14.1.4.1
Migraine History
mITT Subjects
Y
14.1.4.2
Migraine History
Subjects Enrolled but Not Randomized
14.1.4.3
Migraine History
Subjects Randomized but Not Treated
14.1.4.4
Migraine History
Treated Subjects
14.1.5.1
Cardiac and Other Risk Factors
mITT Subjects
14.1.5.2
Cardiac and Other Risk Factors
Treated Subjects
14.1.6.1
Prior Triptan Response
mITT Subjects
14.1.6.2
Prior Triptan Response
Treated Subjects
14.1.7.1
Current Triptan Response
mITT Subjects
14.1.7.2
Current Triptan Response
Treated Subjects
14.1.8
Subgroup Summary
mITT Subjects
Y
14.1.9.1
Missing Data Summary for Primary and Secondary Efficacy Endpoints
Randomized Subjects
14.1.9.2
Missing Pain Data at 2 Hours Post Dose Summary by Subgroup
mITT Subjects
14.2.1.1.1.1
Pain Freedom at 2 Hours Post Dose: Observed Data
mITT Subjects
14.2.1.1.1.2
Pain Freedom at 2 Hours Post Dose: Asian Subjects Only
mITT Subjects
14.2.1.1.2
Pain Freedom at 2 Hours Post Dose: Primary Analysis
mITT Subjects
Y
14.2.1.1.3.1
Pain Freedom at 2 Hours Post Dose: Subgroup Analysis by Age
mITT Subjects
14.2.1.1.3.2
Pain Freedom at 2 Hours Post Dose: Subgroup Analysis by Race
mITT Subjects
14.2.1.1.3.3
Pain Freedom at 2 Hours Post Dose: Subgroup Analysis by Sex
mITT Subjects
14.2.1.1.3.4
Pain Freedom at 2 Hours Post Dose: Subgroup Analysis by Aura
mITT Subjects
14.2.1.1.3.5
Pain Freedom at 2 Hours Post Dose: Subgroup Analysis by Headaches 
per Month
mITT Subjects
14.2.1.1.3.6
Pain Freedom at 2 Hours Post Dose: Subgroup Analysis by Prior Triptan 
Response
mITT Subjects
14.2.1.1.3.7
Pain Freedom at 2 Hours Post Dose: Subgroup Analysis by 
Cardiovascular Risk
mITT Subjects


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Table Number
Title
Population
Topline
14.2.1.1.4.1
Pain Freedom at 2 Hours Post Dose: Sensitivity Analysis 1: Applying 
Last Observation Carried Forward
mITT Subjects
14.2.1.1.4.2
Pain Freedom at 2 Hours Post Dose: Sensitivity Analysis 2: Complete 
Case Analysis
mITT Subjects
14.2.1.1.4.3
Pain Freedom at 2 Hours Post Dose: Sensitivity Analysis 3: Multiple 
Imputation
mITT Subjects
14.2.1.1.4.4
Pain Freedom at 2 Hours Post Dose: Sensitivity Analysis 4: Varying 
Success Rate Imputations
mITT Subjects
14.2.1.1.4.5
Pain Freedom at 2 Hours Post Dose: Sensitivity Analysis 5: Excluding 
Site 002
mITT Subjects Excluding Site 002
14.2.1.2
Most Bothersome Symptom at Migraine Onset: Observed Data
mITT Subjects
14.2.1.2.1.1
Historically Most Bothersome Symptom versus Most Bothersome 
Symptom at Migraine Onset
mITT Subjects
14.2.1.2.1.2
Most Bothersome Symptom Score at 2 Hours Post Dose: Observed Data
mITT Subjects
14.2.1.2.2
Freedom from Most Bothersome Symptom at 2 Hours Post Dose: 
Primary Analysis
mITT Subjects
Y
14.2.1.2.3.1
Freedom from Most Bothersome Symptom at 2 Hours Post Dose: 
Subgroup Analysis by Age
mITT Subjects
14.2.1.2.3.2
Freedom from Most Bothersome Symptom at 2 Hours Post Dose: 
Subgroup Analysis by Race
mITT Subjects
14.2.1.2.3.3
Freedom from Most Bothersome Symptom at 2 Hours Post Dose: 
Subgroup Analysis by Sex
mITT Subjects
14.2.1.2.3.4
Freedom from Most Bothersome Symptom at 2 Hours Post Dose: 
Subgroup Analysis by Aura
mITT Subjects
14.2.1.2.3.5
Freedom from Most Bothersome Symptom at 2 Hours Post Dose: 
Subgroup Analysis by Headaches per Month
mITT Subjects
14.2.1.2.3.6
Freedom from Most Bothersome Symptom at 2 Hours Post Dose: 
Subgroup Analysis by Prior Triptan Response
mITT Subjects
14.2.1.2.3.7
Freedom from Most Bothersome Symptom at 2 Hours Post Dose: 
Subgroup Analysis by Cardiovascular Risk
mITT Subjects
14.2.1.2.4.1
Freedom from Most Bothersome Symptom at 2 Hours Post Dose: 
Sensitivity Analysis 1: Applying Last Observation Carried Forward
mITT Subjects
14.2.1.2.4.2
Freedom from Most Bothersome Symptom at 2 Hours Post Dose: 
Sensitivity Analysis 2: Complete Case Analysis
mITT Subjects
14.2.1.2.4.3
Freedom from Most Bothersome Symptom at 2 Hours Post Dose: 
Sensitivity Analysis 3: Multiple Imputation
mITT Subjects
14.2.1.2.4.4
Freedom from Most Bothersome Symptom at 2 Hours Post Dose: 
Sensitivity Analysis 4: Varying Success Rate Imputations
mITT Subjects


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Table Number
Title
Population
Topline
14.2.1.2.4.5
Freedom from Most Bothersome Symptom at 2 Hours Post Dose: 
Sensitivity Analysis 5: Stratified by MBS at Study Migraine Onset
mITT Subjects
14.2.1.2.4.6
Freedom from Most Bothersome Symptom at 2 Hours Post Dose: 
Sensitivity Analysis 6: Excluding Site 002
mITT Subjects Excluding Site 002
14.2.2.1.1
Freedom from Photophobia at 2 Hours Post Dose in Subjects who 
Reported Photophobia at Study Migraine Onset: Observed Data
mITT Subjects
14.2.2.1.2
Freedom from Photophobia at 2 Hours Post Dose in Subjects who 
Reported Photophobia at Study Migraine Onset: Secondary Analysis
mITT Subjects
Y
14.2.2.1.3
Freedom from Photophobia at 2 Hours Post Dose in Subjects who 
Reported Photophobia at Study Migraine Onset: Secondary Analysis
Excluding Site 002
mITT Subjects Excluding Site 002
14.2.2.2.1
Freedom from Phonophobia at 2 Hours Post Dose in Subjects who 
Reported Phonophobia at Study Migraine Onset: Observed Data
mITT Subjects
14.2.2.2.2
Freedom from Phonophobia at 2 Hours Post Dose in Subjects who 
Reported Phonophobia at Study Migraine Onset: Secondary Analysis
mITT Subjects
Y
14.2.2.2.3
Freedom from Phonophobia at 2 Hours Post Dose in Subjects who 
Reported Phonophobia at Study Migraine Onset: Secondary Analysis
Excluding Site 002
mITT Subjects Excluding Site 002
14.2.2.3.1
Freedom from Nausea at 2 Hours Post Dose in Subjects who Reported 
Nausea at Study Migraine Onset: Observed Data
mITT Subjects
14.2.2.3.2
Freedom from Nausea at 2 Hours Post Dose in Subjects who Reported 
Nausea at Study Migraine Onset: Secondary Analysis
mITT Subjects
Y
14.2.2.3.3
Freedom from Nausea at 2 Hours Post Dose in Subjects who Reported 
Nausea at Study Migraine Onset: Secondary Analysis Excluding Site 
002
mITT Subjects Excluding Site 002
14.2.2.4.1
Pain Relief at 60 Minutes Post Dose: Observed Data
mITT Subjects
14.2.2.4.2
Pain Relief at 60 Minutes Post Dose: Secondary Analysis
mITT Subjects
Y
14.2.2.4.3
Pain Relief at 60 Minutes Post Dose: Secondary Analysis Excluding Site 
002
mITT Subjects Excluding Site 002
14.2.2.5.1
Pain Relief at 90 Minutes Post Dose: Observed Data
mITT Subjects
14.2.2.5.2
Pain Relief at 90 Minutes Post Dose: Secondary Analysis
mITT Subjects
Y
14.2.2.5.3
Pain Relief at 90 Minutes Post Dose: Secondary Analysis Excluding Site 
002
mITT Subjects Excluding Site 002
14.2.2.6.1
Pain Relief at 2 Hours Post Dose: Observed Data
mITT Subjects
14.2.2.6.2
Pain Relief at 2 Hours Post Dose: Secondary Analysis
mITT Subjects
Y
14.2.2.6.3
Pain Relief at 2 Hours Post Dose: Secondary Analysis Excluding Site 
002
mITT Subjects Excluding Site 002
14.2.2.7.1
Rescue Medication within 24 Hours Post Dose: Secondary Analysis
mITT Subjects
Y


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Table Number
Title
Population
Topline
14.2.2.7.2
Rescue Medication within 24 Hours Post Dose: Secondary Analysis
Excluding Site 002
mITT Subjects Excluding Site 002
14.2.2.8.1
Functional Disability Scale at 60 Minutes Post Dose: Observed Data
mITT Subjects
14.2.2.8.2
Functional Disability Scale at 60 Minutes Post Dose: Secondary 
Analysis
mITT Subjects
Y
14.2.2.8.3
Functional Disability Scale at 60 Minutes Post Dose: Secondary 
Analysis Excluding Site 002
mITT Subjects Excluding Site 002
14.2.2.9.1
Functional Disability Scale at 90 Minutes Post Dose: Observed Data
mITT Subjects
14.2.2.9.2
Functional Disability Scale at 90 Minutes Post Dose: Secondary 
Analysis
mITT Subjects
Y
14.2.2.9.3
Functional Disability Scale at 90 Minutes Post Dose: Secondary 
Analysis Excluding Site 002
mITT Subjects Excluding Site 002
14.2.2.10.1
Functional Disability Scale at 2 Hours Post Dose: Observed Data
mITT Subjects
14.2.2.10.2
Functional Disability Scale at 2 Hours Post Dose: Secondary Analysis
mITT Subjects
Y
14.2.2.10.3
Functional Disability Scale at 2 Hours Post Dose: Secondary Analysis
Excluding Site 002
mITT Subjects Excluding Site 002
14.2.2.11.1
Sustained Pain Freedom from 2 to 24 Hours Post Dose: Secondary 
Analysis
mITT Subjects
Y
14.2.2.11.2
Sustained Pain Freedom from 2 to 48 Hours Post Dose: Secondary 
Analysis
mITT Subjects
Y
14.2.2.11.3
Sustained Pain Relief from 2 to 24 Hours Post Dose: Secondary 
Analysis
mITT Subjects
Y
14.2.2.11.4
Sustained Pain Relief from 2 to 48 Hours Post Dose: Secondary 
Analysis
mITT Subjects
Y
14.2.2.11.5
Sustained Pain Freedom from 2 to 24 Hours Post Dose: Secondary 
Analysis Excluding Site 002
mITT Subjects Excluding Site 002
14.2.2.11.6
Sustained Pain Freedom from 2 to 48 Hours Post Dose: Secondary 
Analysis Excluding Site 002
mITT Subjects Excluding Site 002
14.2.2.11.7
Sustained Pain Relief from 2 to 24 Hours Post Dose: Secondary 
Analysis Excluding Site 002
mITT Subjects Excluding Site 002
14.2.2.11.8
Sustained Pain Relief from 2 to 48 Hours Post Dose: Secondary 
Analysis Excluding Site 002
mITT Subjects Excluding Site 002
14.2.2.12.1
Sustained MBS Freedom from 2 to 24 Hours Post Dose: Secondary 
Analysis
mITT Subjects
Y
14.2.2.12.2
Sustained MBS Freedom from 2 to 48 Hours Post Dose: Secondary 
Analysis
mITT Subjects
Y
14.2.2.12.3
Sustained MBS Freedom from 2 to 24 Hours Post Dose: Secondary 
Analysis Excluding Site 002
mITT Subjects Excluding Site 002


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Table Number
Title
Population
Topline
14.2.2.12.4
Sustained MBS Freedom from 2 to 48 Hours Post Dose: Secondary 
Analysis Excluding Site 002
mITT Subjects Excluding Site 002
14.2.2.13.1
Sustained Normal Functioning from 2 to 24 Hours Post Dose: 
Secondary Analysis
mITT Subjects
Y
14.2.2.13.2
Sustained Normal Functioning from 2 to 48 Hours Post Dose: 
Secondary Analysis
mITT Subjects
Y
14.2.2.13.3
Sustained Normal Functioning from 2 to 24 Hours Post Dose: 
Secondary Analysis Excluding Site 002
mITT Subjects Excluding Site 002
14.2.2.13.4
Sustained Normal Functioning from 2 to 48 Hours Post Dose: 
Secondary Analysis Excluding Site 002
mITT Subjects Excluding Site 002
14.2.2.14.1
Pain Freedom at 90 Minutes Post Dose: Secondary Analysis
mITT Subjects
Y
14.2.2.14.2
Pain Freedom at 90 Minutes Post Dose: Secondary Analysis Excluding 
Site 002
mITT Subjects Excluding Site 002
14.2.2.15.1
Freedom from Most Bothersome Symptom at 90 Minutes Post Dose: 
Secondary Analysis
mITT Subjects
Y
14.2.2.15.2
Freedom from Most Bothersome Symptom at 90 Minutes Post Dose: 
Secondary Analysis Excluding Site 002
mITT Subjects Excluding Site 002
14.2.2.16.1
Pain Relapse from 2 to 48 Hours Post Dose: Secondary Analysis
mITT Subjects
Y
14.2.2.16.2
Pain Relapse from 2 to 48 Hours Post Dose: Secondary Analysis
Excluding Site 002
mITT Subjects Excluding Site 002
14.2.3.1
Functional Disability Scale at 24 Hours Post Dose: Exploratory Analysis
mITT Subjects
14.2.3.2
Pain Relief at 15 and 30 Minutes Post Dose: Exploratory Analysis
mITT Subjects
14.2.3.3.1
Kaplan-Meier Time to First Report of Pain Relief up to 8 Hours Post 
Dose: Exploratory Analysis
mITT Subjects
Y
14.2.3.3.2
Median Time to First Report of Pain Relief: Exploratory Analysis
mITT Subjects
Y
14.2.3.4
Preference of Medication at 24 Hours Post Dose: Exploratory Analysis
mITT Subjects
Y
14.2.3.5.1
Migraine Quality of Life Questionnaire at 24 Hours Post Dose: 
Continuous Exploratory Analysis
mITT Subjects
14.2.3.5.2
Migraine Quality of Life Questionnaire at 24 Hours Post Dose: 
Frequency Exploratory Analysis
mITT Subjects
14.2.3.6
Pain Freedom at Every Timepoint Post Dose: Exploratory Analysis
mITT Subjects
Y
14.2.3.7
Pain Relief at Every Timepoint Post Dose: Exploratory Analysis
mITT Subjects
Y
14.2.3.8
Freedom from Most Bothersome Symptom at Every Timepoint Post 
Dose: Exploratory Analysis
mITT Subjects
Y
14.2.3.9
Freedom from Photophobia at Every Timepoint Post Dose: Exploratory 
Analysis
mITT Subjects
14.2.3.10
Freedom from Phonophobia at Every Timepoint Post Dose: Exploratory 
Analysis
mITT Subjects


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Table Number
Title
Population
Topline
14.2.3.11
Freedom from Nausea at Every Timepoint Post Dose: Exploratory 
Analysis
mITT Subjects
14.2.3.12
Functional Disability Scale at Every Timepoint Post Dose: Exploratory 
Analysis
mITT Subjects
Y
14.2.3.13.1
Kaplan-Meier Time to First Report of Pain Freedom up to 8 Hours Post 
Dose: Exploratory Analysis
mITT Subjects
Y
14.2.3.13.2
Median Time to First Report Pain Freedom: Exploratory Analysis
mITT Subjects
Y
14.3.1.1
Self-Reported Study Drug Exposure Summary
All Randomized Subjects who had a 
Study Migraine
14.3.1.2
Study Drug Accountability Summary
All Randomized Subjects who had a 
Study Migraine
14.3.1.3
Cross Tabulation of Study Drug Exposure and Accountability 
All Randomized Subjects who had a 
Study Migraine
14.3.2.1
Summary of On-Study Adverse Events
Treated Subjects
Y
14.3.2.2
Incidence of On-study Adverse Events by System Organ Class and 
Preferred Term
Treated Subjects
Y
14.3.2.3
Incidence of On-study Adverse Events Related to Study Drug by System 
Organ Class and Preferred Term
Treated Subjects
14.3.2.4
Incidence of On-study Serious Adverse Events by System Organ Class 
and Preferred Term
Treated Subjects
Y
14.3.2.5
Incidence of On-study Adverse Events with Severe Grade by System 
Organ Class and Preferred Term
Treated Subjects
Y
14.3.2.6
Incidence of On-Study Adverse Events Leading to Study Drug 
Discontinuation by System Organ Class and Preferred Term
Treated Subjects
14.4.1.1
Hematology (SI Units): Observed and Change From Baseline Values by 
Visit
Treated Subjects
14.4.1.2
Hematology (UI Units): Observed and Change From Baseline Values by 
Visit
Treated Subjects
14.4.2.1
Serum Chemistry (SI Units): Observed and Change From Baseline 
Values by Visit
Treated Subjects
14.4.2.2
Serum Chemistry (US Units): Observed and Change From Baseline 
Values by Visit
Treated Subjects
14.4.3
Hematology: Shift from Baseline by Visit
Treated Subjects
14.4.4
Serum Chemistry: Shift from Baseline by Visit
Treated Subjects
14.4.5
Urinalysis: Shift from Baseline by Visit
Treated Subjects
14.4.5.2
Urine Drug Screen: Shift from Baseline by Visit
Treated Subjects
14.4.6
Transaminases: Shift from Baseline by Visit
Treated Subjects
14.4.7
Summary of On-Study Liver Toxicity
Treated Subjects
Y


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Table Number
Title
Population
Topline
14.5.1
Vital Signs and Physical Measurements: Observed and Change from 
Baseline Values by Visit
Treated Subjects
14.5.2.1
Electrocardiogram: Observed and Change from Baseline Values by Visit
Treated Subjects
14.5.2.2
Electrocardiogram: Shift from Baseline by Visit
Treated Subjects
14.5.3.1
Prior Non-Study Medications by Therapeutic Class and Preferred Term
Treated Subjects
14.5.3.2
Concomitant Non-Study Medications by Therapeutic Class and 
Preferred Term
Treated Subjects
14.5.3.3
Non-Study Prophylactic Migraine Medications Taken at or After 
Informed Consent and Before Randomization by Therapeutic Class and 
Preferred Term
Treated Subjects
Y
14.5.3.4
Non-Study Prophylactic Migraine Medications Taken at or After 
Randomization by Therapeutic Class and Preferred Term
Treated Subjects
Y
14.5.3.5
Non-Study Rescue Medicationsby Therapeutic Class and Preferred 
Term
Treated Subjects
Y
14.5.4
Sheehan-Suicidality Tracking Scale: Exploratory Analysis 
Treated Subjects
Listing Number
Title
Population
Topline
16.2.1.1
Subject Disposition
Enrolled Subjects
16.2.1.2
Subject Eligibility
Enrolled Subjects
16.2.1.3
Significant Protocol Deviations
Enrolled Subjects
16.2.2.1
Demographic and Baseline Characteristics
Enrolled Subjects
16.2.2.2
Medical History
Enrolled Subjects
16.2.2.3
General Migraine History
Enrolled Subjects
16.2.2.4
Migraine Symptom History
Enrolled Subjects
16.2.2.5
Migraine Aura Symptom History
Enrolled Subjects
16.2.2.6
Cardiac and Other Risk Factors
Enrolled Subjects
16.2.2.7
Reasons for Discontinuation from Prior Triptans
Enrolled Subjects
16.2.2.8
Current Triptan Response
Enrolled Subjects
16.2.3
Batch Numbers
Enrolled Subjects
16.2.4
Subpopulations and Subgroups
mITT Subjects
16.2.5.1
Observed Pain and MBS Efficacy Measurements
mITT Subjects
16.2.5.2
Observed Primary Efficacy Measurements at 2 Hours Post Dose
mITT Subjects
16.2.5.3
Functional Disability Scale
mITT Subjects
16.2.5.4
Preference of Medication at 24 Hours Post Dose
mITT Subjects
16.2.5.5
Migraine Quality of Life Questionnaire at 24 Hours Post Dose
mITT Subjects
16.2.6
Study Drug Exposure and Accountability 
Randomized Subjects


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16.2.7.1
Adverse Events
Enrolled Subjects
16.2.7.2
Serious Adverse Events
Enrolled Subjects
16.2.7.3
Deaths
Enrolled Subjects
16.2.7.4
Adverse Events Leading to Study Drug Discontinuation
Treated Subjects
16.2.8.1.1
Hematology Results (SI Units)
Enrolled Subjects
16.2.8.1.2
Hematology Results (US Units)
Enrolled Subjects
16.2.8.2.1
Serum Chemistry Results (SI Units)
Enrolled Subjects
16.2.8.2.2
Serum Chemistry Results (US Units)
Enrolled Subjects
16.2.8.2.3
CK and Fractionation Results (SI Units)
Enrolled Subjects
16.2.8.2.4
CK and Fractionation Results (US Units)
Enrolled Subjects
16.2.8.3.1
Urinalysis  Results (SI Units)
Enrolled Subjects
16.2.8.3.2
Urinalysis  Results (US Units)
Enrolled Subjects
16.2.8.3.3
Urine Drug Screen Results
Enrolled Subjects
16.2.8.4.1
Endocrine  Results (SI Units)
Enrolled Subjects
16.2.8.4.2
Endocrine  Results (US Units)
Enrolled Subjects
16.2.8.5.1
Pregnancy Test Results (SI Units)
Enrolled Subjects
16.2.8.5.2
Pregnancy Test Results (US Units)
Enrolled Subjects
16.2.8.6
GC/MS Results
Enrolled Subjects
16.2.8.7.1
All Abnormal Laboratory Results  (SI Units)
Enrolled Subjects
16.2.8.7.2
All Abnormal Laboratory Results  (US Units)
Enrolled Subjects
16.2.8.8.1
Potential Drug Induced Liver Injury (SI Units)
Enrolled Subjects
16.2.8.8.2
Potential Drug Induced Liver Injury (US Units)
Enrolled Subjects
16.2.9.1
Vital Signs and Physical Measurements
Enrolled Subjects
16.2.9.2
Electrocardiogram Results
Enrolled Subjects
16.2.9.3.1
Non-Study Medications
Enrolled Subjects
16.2.9.3.2
Non-Study Prophylactic Migraine Medications
Enrolled Subjects
16.2.9.3.3
Rescue Medications
Enrolled Subjects
16.2.9.4
Procedures
Enrolled Subjects
16.2.9.5
Sheehan-Suicidality Tracking Scale Results
Enrolled Subjects
Figure Number
Title
Population
Topline
14.2.1
Forest Plot of Pain Freedom at 2 Hours Post Dose
mITT Subjects
14.2.1.1
Forest Plot of Pain Freedom at 2 Hours Post Dose: Sensitivity 
Analysis 1
mITT Subjects


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14.2.1.2
Forest Plot of Pain Freedom at 2 Hours Post Dose: Sensitivity 
Analysis 2
mITT Subjects
14.2.1.3
Forest Plot of Pain Freedom at 2 Hours Post Dose: Sensitivity 
Analysis 3
mITT Subjects
14.2.1.4
Forest Plot of Pain Freedom at 2 Hours Post Dose: Sensitivity 
Analysis 4
mITT Subjects
14.2.1.5
Forest Plot of Pain Freedom at 2 Hours Post Dose by Subgroup
mITT Subjects
14.2.2
Forest Plot of Freedom from Most Bothersome Symptom at 2 Hours 
Post Dose
mITT Subjects
14.2.2.1
Forest Plot of Freedom from Most Bothersome Symptom at 2 Hours 
Post Dose: Sensitivity Analysis 1
mITT Subjects
14.2.2.2
Forest Plot of Freedom from Most Bothersome Symptom at 2 Hours 
Post Dose: Sensitivity Analysis 2
mITT Subjects
14.2.2.3
Forest Plot of Freedom from Most Bothersome Symptom at 2 Hours 
Post Dose: Sensitivity Analysis 3
mITT Subjects
14.2.2.4
Forest Plot of Freedom from Most Bothersome Symptom at 2 Hours 
Post Dose: Sensitivity Analysis 4
mITT Subjects
14.2.2.5
Forest Plot of Freedom from Most Bothersome Symptom at 2 Hours 
Post Dose: Sensitivity Analysis 5
mITT Subjects
14.2.2.6
Forest Plot of Freedom from Most Bothersome Symptom at 2 Hours 
Post Dose by Subgroup
mITT Subjects
14.2.3
Forest Plot of Freedom from Photophobia, Phonophobia, and Nausea 
at 2 Hours Post Dose
mITT Subjects
14.2.4
Forest Plot of Pain Relief
mITT Subjects
14.2.5
Forest Plot of Probability of Requiring Rescue Medication within 24 
Hour Post Dose
mITT Subjects
14.2.6
Forest Plot of Probability of Functioning Normally According to the
Functional Disability Scale
mITT Subjects
14.2.7.1
Forest Plot of Durability of Pain Relief 
mITT Subjects
14.2.7.2
Forest Plot of Durability of Pain Freedom
mITT Subjects
14.2.7.3
Forest Plot of Durability of MBS Freedom
mITT Subjects
14.2.7.4
Forest Plot of Durability of Normal Functioning
mITT Subjects
14.2.7.5
Forest Plot of Probability of Pain Relapse
mITT Subjects
14.2.8
Kaplan-Meier Plot of Time to First Report of Pain Relief up to Eight
Hours Post Dose
mITT Subjects
Y
14.2.9
Kaplan-Meier Plot of Time to First Report of Pain Freedom to Eight 
Hours Post Dose
mITT Subjects
Y
14.3.1
Evaluation of On-Study Drug-Induced Hepatotoxicity (eDISH)
Treated Subjects
Y










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APPENDIX 3:
SUPPORTIVE ANALYSES
1
DURABILITY ENDPOINTS
New durability endpoints were defined for pain freedom, pain relief, most bothersome 
symptom, functional disability, nausea, photophobia, and phonophobia.  For each of these 
endpoints, durability was measured during six time periods:  

2 to 24 hours

3 to 24 hours

4 to 24 hours

2 to 48 hours

3 to 48 hours

4 to 48 hours
For pain freedom and pain relief, the 2 to 24 hour and 2 to 48 hour durability endpoints were 
previously defined in the SAP in Sections 5.7.4.5 - 5.7.4.8. 
Pain freedom, pain relief, most bothersome symptom, and functional disability were assessed 
using the mITT population.  Nausea, photophobia, and phonophobia were assessed using mITT 
subjects who reported the given symptom as present at the start of their treated migraine.
For all ad-hoc durability endpoints, the following were presented:

The number and percentage of subjects who are successful. These are presented by stratum 
and treatment group, with ASE and 95% asymptotic CIs.

Common risk difference with sample size, p-value, ASE, and 95% asymptotic CIs.

Risk difference within each strata with sample size, p-value, ASE and 95% asymptotic CIs.

A plot of the risk differences within each strata, and common risk difference (similar to the 
risk difference plot produced by SAS Proc Freq).

Common risk for each treatment with sample size, ASE, and 95% asymptotic CIs.
The “risk” is the probability of the given endpoint (success) through the given durability period.
1.1
Sustained Pain Freedom
The ad-hoc sustained pain freedom endpoints were:


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
Sustained Pain Freedom 3 to 24 hours

Sustained Pain Freedom 4 to 24 hours

Sustained Pain Freedom 3 to 48 hours

Sustained Pain Freedom 4 to 48 hours
Sustained pain freedom for the above time periods were defined in a manner similar to that used 
for sustained pain freedom from 2 to 24 hours and 2 to 48 hours.
Sustained pain freedom was assessed using the number of mITT subjects who experienced no 
headache pain (response of 0 on the Likert scale) at all time points from the starting time point 
(3 or 4 hours post-dose) through the ending time point (24 or 48 hours post-dose). Subjects with 
missing pain scores at 1 or fewer time points, given that they had responses of no pain at all 
other time points including the starting and ending time points (and 24 hours for periods through 
48 hours), were considered as successes.  Subjects with missing data at greater than 1 post-dose 
time point, missing data at either the starting or ending time point (or 24 hours for periods 
through 48 hours), or with any pain score greater than 0 were considered as failures. 
1.2
Sustained Pain Relief
The ad-hoc sustained pain relief endpoints were:

Sustained Pain Relief 3 to 24 hours

Sustained Pain Relief 4 to 24 hours

Sustained Pain Relief 3 to 48 hours

Sustained Pain Relief 4 to 48 hours
Sustained pain relief for the above time periods were defined in a manner similar to that used 
previously for sustained pain relief from 2 to 24 hours and 2 to 48 hours.
Sustained pain relief was assessed using the number of mITT subjects who experienced no or 
mild headache pain (response of 0 or 1 on the Likert scale) at all time points from the starting 
time point (3 or 4 hours post-dose) through the ending time point (24 or 48 hours post-dose). 
Subjects with missing pain scores at 1 or fewer time points, given that they had responses of no 
or mild pain at all other time points including the starting and ending time points (and 24 hours 
for periods through 48 hours), were considered as successes.  Subjects with missing data at 
greater than 1 post-dose time point, missing data at either the starting or ending time point (or 
24 hours for periods through 48 hours), or with any pain score greater than 1 were considered as 
failures. 


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1.3
Sustained Freedom from Most Bothersome Symptom
The ad-hoc sustained freedom from the MBS endpoints were:

Sustained Freedom from MBS 2 to 24 hours

Sustained Freedom from MBS 3 to 24 hours

Sustained Freedom from MBS 4 to 24 hours

Sustained Freedom from MBS 2 to 48 hours

Sustained Freedom from MBS 3 to 48 hours

Sustained Freedom from MBS 4 to 48 hours
Sustained freedom from MBS for these time periods is defined in a manner similar to that used 
for sustained pain freedom from 2 to 24 hours and 2 to 48 hours.
Sustained MBS freedom was assessed using the number of mITT subjects who did not have 
their MBS (response of absent) at all time points from the starting time point (2, 3 or 4 hours 
post-dose) through the ending time point (24 or 48 hours post-dose). Subjects with missing 
MBS scores at 1 or fewer time points, given that they had responses of absent MBS at all other 
time points including the starting and ending time points (and 24 hours for periods through 48 
hours), were considered as successes.  Subjects with missing data at greater than 1 post-dose 
time point, missing data at either the starting or ending time point (or 24 hours for periods 
through 48 hours), or with any MBS present at any time point in the period were considered as 
failures. 
1.4
Sustained Freedom from Functional Disability
The ad-hoc sustained freedom from functional disability endpoints were:

Sustained Freedom from Functional Disability 2 to 24 hours

Sustained Freedom from Functional Disability 3 to 24 hours

Sustained Freedom from Functional Disability 4 to 24 hours

Sustained Freedom from Functional Disability 2 to 48 hours

Sustained Freedom from Functional Disability 3 to 48 hours

Sustained Freedom from Functional Disability 4 to 48 hours


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Sustained freedom from functional disability for these time periods is defined in a manner 
similar to that used for sustained pain freedom from 2 to 24 hours and 2 to 48 hours.
Sustained freedom from functional disability was assessed using the number of mITT subjects 
who experienced normal functioning at all time points from the starting time point (2, 3 or 4 
hours post-dose) through the ending time point (24 or 48 hours post-dose). Subjects with 
missing disability scores at 1 or fewer time points, given that they have responses of no 
disability at all other time points including the starting and ending time points (and 24 hours for 
periods through 48 hours), were considered as successes.  Subjects with missing data at greater 
than 1 post-dose time point, missing data at either the starting or ending time point (or 24 hours 
for periods through 48 hours), or with any reported disability in the time period were classified 
as failures.
1.5
Sustained Freedom from Nausea
The ad-hoc sustained freedom from nausea endpoints were:

Sustained Freedom from Nausea 2 to 24 hours

Sustained Freedom from Nausea 3 to 24 hours

Sustained Freedom from Nausea 4 to 24 hours

Sustained Freedom from Nausea 2 to 48 hours

Sustained Freedom from Nausea 3 to 48 hours

Sustained Freedom from Nausea 4 to 48 hours
Sustained freedom from nausea for these time periods was defined in a manner similar to that 
used for sustained pain freedom from 2 to 24 hours and 2 to 48 hours. However, the analysis 
population was restricted to those subjects with nausea reported as present at the start of their 
treated migraine.
Sustained nausea freedom was assessed using the number of mITT subjects who had nausea 
present at baseline and did not report nausea (response of absent) at any time point from the 
starting time point (2, 3 or 4 hours post-dose) through the ending time point (24 or 48 hours 
post-dose). Subjects with missing nausea scores at 1 or fewer time points, given that they had 
responses of no nausea at all other time points including the starting and ending time points (and 
24 hours for periods through 48 hours), were considered as successes.  Subjects with missing 
data at greater than 1 post-dose time point, missing data at either the starting or ending time 
point (or 24 hours for periods through 48 hours), or with any nausea present at any time point in 
the period were considered as failures.
1.6
Sustained Freedom from Photophobia
The ad-hoc sustained freedom from photophobia endpoints are:


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
Sustained Freedom from Photophobia 2 to 24 hours

Sustained Freedom from Photophobia 3 to 24 hours

Sustained Freedom from Photophobia 4 to 24 hours

Sustained Freedom from Photophobia 2 to 48 hours

Sustained Freedom from Photophobia 3 to 48 hours

Sustained Freedom from Photophobia 4 to 48 hours
Sustained freedom from photophobia for these time periods was defined in a manner similar to 
that used for sustained freedom from nausea. The analysis population was restricted to those 
mITT subjects with photophobia reported as present at the start of their treated migraine.
Sustained photophobia freedom was assessed using the number of mITT subjects who had 
photophobia present at baseline and that did not report photophobia (response of absent) at any 
time point from the starting time point (2, 3 or 4 hours post-dose) through the ending time point 
(24 or 48 hours post-dose). Subjects with missing photophobia scores at 1 or fewer time points, 
given that they had responses of no photophobia at all other time points including the starting 
and ending time points (and 24 hours for periods through 48 hours), were considered as 
successes.  Subjects with missing data at greater than 1 post-dose time point, missing data at 
either the starting or ending time point (or 24 hours for periods through 48 hours), or with any 
photophobia present at any time point in the period were considered as failures.
1.7
Sustained Freedom from Phonophobia
The ad-hoc sustained freedom from phonophobia endpoints are:

Sustained Freedom from Phonophobia 2 to 24 hours

Sustained Freedom from Phonophobia 3 to 24 hours

Sustained Freedom from Phonophobia 4 to 24 hours

Sustained Freedom from Phonophobia 2 to 48 hours

Sustained Freedom from Phonophobia 3 to 48 hours

Sustained Freedom from Phonophobia 4 to 48 hours
Sustained freedom from phonophobia for these time periods was defined in a manner similar to 
that used for sustained freedom from nausea. The analysis population was restricted to those 
mITT subjects with phonophobia reported as present at the start of their treated migraine.


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Sustained phonophobia freedom was assessed using the number of mITT subjects who had 
phonophobia present at baseline and that did not report phonophobia (response of absent) at any 
time point from the starting time point (2, 3 or 4 hours post-dose) through the ending time point 
(24 or 48 hours post-dose). Subjects with missing phonophobia scores at 1 or fewer time points, 
given that they had responses of no phonophobia at all other time points including the starting 
and ending time points (and 24 hours for periods through 48 hours), were considered as 
successes.  Subjects with missing data at greater than 1 post-dose time point, missing data at 
either the starting or ending time point (or 24 hours for periods through 48 hours), or with any 
phonophobia present at any time point in the period were considered as failures.
2
TIME TO EVENT ANALYSES
2.1
Time to Rescue Medication
Kaplan-Meier plots were created for the time to first use of rescue medication.  The K-M plot 
covered the 24 hour period after dosing. Subjects who did not take rescue medication within 24 
hours of dosing were censored at 24 hours and 1 minute. Regardless of pain or MBS response, 
subjects were considered at risk until the first use of rescue medication, loss to follow-up (last 
contact date), or the end of the 24 hour period, whichever came first.  The analysis population 
consisted of mITT subjects.
Two tables were created to support the plot.  The first table presented the median time to rescue 
medication along with 95% CIs calculated using the method of Brookmeyer and Crowley and 
the log-rank p-value.  The second table presented the number of subjects at risk, with an event, 
censored, and the survival probability estimate (with 95% CI) for each period by treatment 
group. 
2.2
Time to First Report of Absence of Various Symptoms
For each of the following variables, two sets of Kaplan-Meier plots and tables were created:

Time to First Report of Absence of Most Bothersome Symptom

Time to First Report of Absence of Nausea

Time to First Report of Absence of Photophobia

Time to First Report of Absence of Phonophobia

Time to First Report of Return to Normal Functioning
The first set of plots and tables was similar to those created for the time to rescue medication 
(using actual time).  For the second set of plots, nominal (planned time point) as opposed to 
actual time was used for clinical event times.  Censoring was measured using actual time as in 
all previous plots.


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For both sets of analyses, the analysis population for MBS was the set of mITT subjects. The 
analysis population for nausea, phonophobia, and photophobia was the subset of mITT subjects 
that reported the symptom as present at the onset of their study migraine.  The analysis 
population for functional disability was the subset of mITT subjects that reported abnormal 
functioning at the onset of their study migraine. The y-axis for all plots represents the 
probability of the occurrence of the event of interest, and therefore are increasing from left to 
right.
2.2.1
Kaplan-Meier Plots and Tables: Actual Time for Event of Interest
The first set of K-M plots and tables were created using actual time of censoring and actual time 
for the clinical event of interest.  Subjects were censored at the actual time of their first use of 
rescue medication or last reported data point if lost to follow-up.  Subjects who did not have the 
clinical event of interest by 8 hours post dose were censored at 496 minutes (480 minutes + 15 
minute window + 1 minute).
2.2.2
Kaplan-Meier Plots and Tables: Nominal Time for Event of Interest
The second set of K-M plots and tables were created for the above variables with nominal time 
(planned time of collection, e.g., 2 hours, 3 hours, etc.) used for clinical events of interest and 
actual time used for censoring events. Subjects were censored at the actual time of their first use 
of rescue medication or last reported data point if lost to follow-up.  Subjects who did not have 
the clinical event of interest by 8 hours post dose were censored at 496 minutes (480 minutes + 
15 minute window + 1 minute).
3
PAIN AND MBS AT 3 HOURS POST DOSE
3.1
Pain Freedom at 3 Hours Post Dose
The between group difference in the percentage of subjects with pain freedom at 3 hours post-
dose was assessed by computing the “risk difference” between treatment groups. This was 
evaluated by computing the common risk difference, using CMH weights (sample size weights), 
stratified by the use of prophylactic migraine medication (yes or no). The risk difference was 
tested at a two-sided alpha level of 0.05. Missing data at 2 hours post-dose were imputed as 
failures (NC=F).  
Results presented for this analysis included the following:

Common risk difference with sample size, p-value, ASE, and 95% asymptotic CIs.

Risk difference within each strata with sample size, p-value, ASE, and 95% asymptotic CIs.

A plot of the risk differences within each strata, and common risk difference (similar to the 
risk difference plot produced by SAS Proc Freq).

Common risk for each treatment with sample size, ASE, and 95% asymptotic CIs.


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3.2
Freedom from MBS at 3 Hours Post Dose
The estimand, difference in percentage of subjects with freedom from MBS at 3 hours between 
treatment groups was evaluated by computing the common risk difference using CMH weights 
(sample size weights), stratified by the use of prophylactic migraine medication (yes or no). The 
risk difference was tested at a two-sided alpha level of 0.05. Missing data at 3 hours post-dose 
was imputed as failure (NC=F).  Also the use of rescue medication prior to providing data at the 
3 hour assessment, taking IP prior to reporting the MBS, or failure to report a MBS are events
that were imputed as treatment failures. 
Results presented for this analysis included the following:

Common risk difference with sample size, p-value, ASE, and 95% asymptotic CIs.

Risk difference within each strata with sample size, p-value, ASE, and 95% asymptotic CIs.

A plot of the risk differences within each strata, and common risk difference (similar to the 
risk difference plot produced by SAS Proc Freq).

Common risk for each treatment with sample size, ASE, and 95% asymptotic CIs.
4
OTHER ENDPOINTS AT 3 HOURS POST DOSE
4.1
Freedom from Photophobia, Phonophobia, or Nausea at 3 Hours
Freedom from photophobia, phonophobia, and nausea were assessed, by treatment group, by 
tabulating the number of mITT subjects who reported the presence of the symptom at migraine 
onset, and later reported the absence of the symptom at 3 hours post-dose. Subjects who 
reported the symptom at baseline, but have missing data at 3 hours post-dose were imputed as 
failures (NC=F).  Also, subjects in the analysis set who took rescue medications on or before 
providing their 3 hour post-dose data were imputed as failures.
The principal measurement for the associated symptoms (phonophobia, photophobia, and 
nausea) is made on a binary scale (0 = absent; 1 = present).  An exploratory measurement of 
these symptoms was also made on a 4-point Likert scale (0=none, 1=mild, 2=moderate, 
3=severe).
For these three endpoints, the difference between treatment groups, was evaluated by computing 
the common risk difference using CMH weights (sample size weights), stratified by the use of 
prophylactic migraine medication (yes or no). The risk difference was tested at a two-sided 
alpha level of 0.05. 
Results presented for these analyses included the following:

Common risk difference with sample size, p-value, ASE, and 95% asymptotic CIs.


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
Risk difference within each strata with sample size, p-value, ASE, and 95% asymptotic CIs.

A plot of the risk differences within each strata, and common risk difference (similar to the 
risk difference plot produced by SAS Proc Freq).

Common risk for each treatment with sample size, ASE, and 95% asymptotic CIs.
4.2
Pain Relief at 3 Hours Post Dose
Pain relief at 3 hours post-dose was assessed by tabulating the number of mITT subjects that 
reported a pain level of none or mild (responses of 0 or 1 on the 4-point Likert scale) at 3 hours 
post-dose by treatment group.  Subjects with missing data at 3 hours post-dose were imputed as 
failures (NC=F).  Also, subjects in the analysis set who took rescue medications on or before 
providing their 3 hour post-dose data were imputed as failures.
Results presented for this analysis included the following:

Common risk difference with sample size, p-value, ASE, and 95% asymptotic CIs.

Risk difference within each strata with sample size, p-value, ASE, and 95% asymptotic CIs.

A plot of the risk differences within each strata, and common risk difference (similar to the 
risk difference plot produced by SAS Proc Freq).

Common risk for each treatment with sample size, ASE, and 95% asymptotic CIs.
4.3
Functional Disability Scale at 3 Hours Post Dose
Impact of treatment on subject disability was assessed using a single-question, functional 
disability scale. Subjects rated the level of disability they perceived as a result of their migraine 
in performing normal actions using a 4-point scale: Normal Function, Mild Impairment, Severe 
Impairment, or Required Bedrest.  The proportion of mITT subjects who had a response of 
“normal” at 3-hours post dose was evaluated as the endpoint of interest.
Results presented for this analysis included the following:

Common risk difference with sample size, p-value, ASE, and 95% asymptotic CIs.

Risk difference within each strata with sample size, p-value, ASE, and 95% asymptotic CIs.

A plot of the risk differences within each strata, and common risk difference (similar to the 
risk difference plot produced by SAS Proc Freq).

Common risk for each treatment with sample size, ASE, and 95% asymptotic CIs.


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Statistical Analysis Plan for Protocol BHV3000-303
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APPENDIX 4:
TABLES AND FIGURES FOR SUPPORTIVE ANALYSES
Table Number
Title
Population
Topline
14.2.1.1.4.6
Pain Freedom at 3 Hours Post Dose: Ad-hoc Analysis
mITT Subjects
14.2.1.2.4.7
Freedom from Most Bothersome Symptom at 3 Hours Post Dose: Ad-hoc Analysis
mITT Subjects
14.2.2.1.4
Freedom from Photophobia at 3 Hours Post Dose: Ad-hoc Analysis
mITT Subjects
14.2.2.2.2.4
Freedom from Phonophobia at 3 Hours Post Dose: Ad-hoc Analysis
mITT Subjects
14.2.2.3.4
Freedom from Nausea at 3 Hours Post Dose: Ad-hoc Analysis
mITT Subjects
14.2.2.6.4
Pain Relief at 3 Hours Post Dose: Ad-hoc Analysis
mITT Subjects
14.2.2.7.3
Kaplan-Meier Time to Rescue Medication up to 24 hours Post Dose: Ad-hoc Analysis
mITT Subjects
Y
14.2.2.7.4
Median Time to Rescue Medication: Ad-hoc Analysis
mITT Subjects
Y
14.2.2.10.4
Functional Disability Scale at 3 Hours Post Dose: Ad-hoc Analysis
mITT Subjects
14.2.2.11.9
Sustained Pain Freedom from 3 to 24 Hours Post Dose: Ad-hoc Analysis
mITT Subjects
Y
14.2.2.11.10
Sustained Pain Freedom from 4 to 24 Hours Post Dose: Ad-hoc Analysis
mITT Subjects
Y
14.2.2.11.11
Sustained Pain Relief from 3 to 24 Hours Post Dose: Ad-hoc Analysis
mITT Subjects
Y
14.2.2.11.12
Sustained Pain Relief from 4 to 24 Hours Post Dose: Ad-hoc Analysis
mITT Subjects
Y
14.2.2.11.13
Sustained Pain Freedom from 3 to 48 Hours Post Dose: Ad-hoc Analysis
mITT Subjects
14.2.2.11.14
Sustained Pain Freedom from 4 to 48 Hours Post Dose: Ad-hoc Analysis
mITT Subjects
14.2.2.11.15
Sustained Pain Relief from 3 to 48 Hours Post Dose: Ad-hoc Analysis
mITT Subjects
14.2.2.11.16
Sustained Pain Relief from 4 to 48 Hours Post Dose: Ad-hoc Analysis
mITT Subjects
14.2.2.12.5
Sustained MBS Freedom from 3 to 24 Hours Post Dose: Ad-hoc Analysis
mITT Subjects
14.2.2.12.6
Sustained MBS Freedom from 4 to 24 Hours Post Dose: Ad-hoc Analysis
mITT Subjects
14.2.2.12.7
Sustained MBS Freedom from 3 to 48 Hours Post Dose: Ad-hoc Analysis
mITT Subjects
14.2.2.12.8
Sustained MBS Freedom from 4 to 48 Hours Post Dose: Ad-hoc Analysis
mITT Subjects
14.2.2.12.8.1
Kaplan-Meier Time to First Report of Absence of MBS up to 8 hours Post Dose: Ad-hoc Analysis
mITT Subjects
Y
14.2.2.12.8.2
Median Time to First Report of Absence of MBS: Ad-hoc Analysis
mITT Subjects
Y
14.2.2.12.8.3
Kaplan-Meier Nominal Time to First Report of Absence of MBS up to 8 hours Post Dose: Ad-hoc Analysis
mITT Subjects
14.2.2.12.8.4
Median Nominal Time to First Report of Absence of MBS: Ad-hoc Analysis
mITT Subjects
14.2.2.12.9
Sustained Nausea Freedom from 3 to 24 Hours Post Dose: Ad-hoc Analysis
mITT Subjects
14.2.2.12.10
Sustained Nausea Freedom from 4 to 24 Hours Post Dose: Ad-hoc Analysis
mITT Subjects
14.2.2.12.11
Sustained Nausea Freedom from 3 to 48 Hours Post Dose: Ad-hoc Analysis
mITT Subjects
14.2.2.12.12
Sustained Nausea Freedom from 4 to 48 Hours Post Dose: Ad-hoc Analysis
mITT Subjects
14.2.2.12.13
Sustained Photophobia Freedom from 3 to 24 Hours Post Dose: Ad-hoc Analysis
mITT Subjects
14.2.2.12.14
Sustained Photophobia Freedom from 4 to 24 Hours Post Dose: Ad-hoc Analysis
mITT Subjects
14.2.2.12.15
Sustained Photophobia Freedom from 3 to 48 Hours Post Dose: Ad-hoc Analysis
mITT Subjects
14.2.2.12.16
Sustained Photophobia Freedom from 4 to 48 Hours Post Dose: Ad-hoc Analysis
mITT Subjects
14.2.2.12.17
Sustained Phonophobia Freedom from 3 to 24 Hours Post Dose: Ad-hoc Analysis
mITT Subjects
14.2.2.12.18
Sustained Phonophobia Freedom from 4 to 24 Hours Post Dose: Ad-hoc Analysis
mITT Subjects


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Statistical Analysis Plan for Protocol BHV3000-303
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14.2.2.12.19
Sustained Phonophobia Freedom from 3 to 48 Hours Post Dose: Ad-hoc Analysis
mITT Subjects
14.2.2.12.20
Sustained Phonophobia Freedom from 4 to 48 Hours Post Dose: Ad-hoc Analysis
mITT Subjects
14.2.2.12.14.1
Kaplan-Meier Time to First Report of Absence of Nausea up to 8 hours Post Dose: Ad-hoc Analysis
mITT Subjects
14.2.2.12.14.2
Median Time to First Report of Absence of Nausea: Ad-hoc Analysis
mITT Subjects
14.2.2.12.14.3
Kaplan-Meier Nominal Time to First Report of Absence of Nausea up to 8 hours Post Dose: Ad-hoc 
Analysis
mITT Subjects
14.2.2.12.14.4
Median Nominal Time to First Report of Absence of Nausea: Ad-hoc Analysis
mITT Subjects
14.2.2.12.20.1
Kaplan-Meier Time to First Report of Absence of Photophobia up to 8 hours Post Dose: Ad-hoc Analysis
mITT Subjects
14.2.2.12.20.2
Median Time to First Report of Absence of Photophobia: Ad-hoc Analysis
mITT Subjects
14.2.2.12.20.3
Kaplan-Meier Nominal Time to First Report of Absence of Photophobia up to 8 hours Post Dose: Ad-hoc 
Analysis
mITT Subjects
14.2.2.12.20.4
Median Nominal Time to First Report of Absence of Photophobia: Ad-hoc Analysis
mITT Subjects
14.2.2.12.26.1
Kaplan-Meier Time to First Report of Absence of Phonophobia up to 8 hours Post Dose: Ad-hoc Analysis
mITT Subjects
14.2.2.12.26.2
Median Time to First Report of Absence of Photophobia: Ad-hoc Analysis
mITT Subjects
14.2.2.12.26.3
Kaplan-Meier Nominal Time to First Report of Absence of Phonophobia up to 8 hours Post Dose: Ad-hoc 
Analysis
mITT Subjects
14.2.2.12.26.4
Median Nominal Time to First Report of Absence of Photophobia: Ad-hoc Analysis
mITT Subjects
14.2.2.13.5
Sustained Functional Disability Freedom from 3 to 24 Hours Post Dose: Ad-hoc Analysis
mITT Subjects
14.2.2.13.6
Sustained Functional Disability Freedom from 4 to 24 Hours Post Dose: Ad-hoc Analysis
mITT Subjects
14.2.2.13.7
Sustained Functional Disability Freedom from 3 to 48 Hours Post Dose: Ad-hoc Analysis
mITT Subjects
14.2.2.13.8
Sustained Functional Disability Freedom from 4 to 48 Hours Post Dose: Ad-hoc Analysis
mITT Subjects
14.2.2.13.8.1
Kaplan-Meier Time to First Report of Return to Normal Functioning up to 8 hours Post Dose: Ad-hoc 
Analysis
mITT Subjects
Y
14.2.2.13.8.2
Median Time to First Report of Return to Normal Functioning: Ad-hoc Analysis
mITT Subjects
Y
14.2.2.13.8.3
Kaplan-Meier Nominal Time to First Report of Return to Normal Functioning up to 8 hours Post Dose: Ad-
hoc Analysis
mITT Subjects
14.2.2.13.8.4
Median Nominal Time to First Report of Return to Normal Functioning: Ad-hoc Analysis
mITT Subjects
Figure 
Number
Title 
Population
Topline
14.2.10
Kaplan Meier Survival Plot of Time to Rescue Medication up to 24 Hours Post Dose
mITT Subjects
Y
14.2.11
Kaplan Meier Survival Plot of Time to First Report of Absence of MBS up to 8 Hours Post Dose
mITT Subjects
14.2.12
Kaplan Meier Survival Plot of Time to First Report of Absence of Nausea up to 8 Hours Post Dose
mITT Subjects
14.2.13
Kaplan Meier Survival Plot of Time to First Report of Absence of Photophobia up to 8 Hours Post Dose
mITT Subjects
14.2.14
Kaplan Meier Survival Plot of Time to First Report of Absence of Phonophobia up to 8 Hours Post Dose
mITT Subjects
14.2.15
Kaplan Meier Survival Plot of Time to First Report of Return to Normal Functioning up to 8 Hours Post 
Dose
mITT Subjects
Y


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Statistical Analysis Plan for Protocol BHV3000-303
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CONFIDENTIAL
14.2.16
Kaplan Meier Survival Plot of Time to First Report of Absence of MBS up to 8 Hours Post Dose (Nominal 
Time)
mITT Subjects
14.2.17
Kaplan Meier Survival Plot of Time to First Report of Absence of Nausea up to 8 Hours Post Dose (Nominal 
Time)
mITT Subjects
14.2.18
Kaplan Meier Survival Plot of Time to First Report of Absence of Photophobia up to 8 Hours Post Dose
(Nominal Time)
mITT Subjects
14.2.19
Kaplan Meier Survival Plot of Time to First Report of Absence of Phonophobia up to 8 Hours Post Dose
(Nominal Time)
mITT Subjects
14.2.20
Kaplan Meier Survival Plot of Time to First Report of Return to Normal Functioning up to 8 Hours Post 
Dose (Nominal Time)
mITT Subjects
Y