Conditions: Migraine
Keywords: Acute Migraine phonophobia photophobia nausea
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 2154
Healthy volunteers: no

Brief summary:
The purpose of the study is to evaluate the safety and efficacy of three different intranasal dose levels of zavegepant (BHV-3500), relative to placebo, in the acute treatment of moderate to severe migraine.

Detailed description:

Arms:
arm 1: Participants administered a single intranasal dose of zavegepant 5 mg on occurrence of migraine that reached moderate or severe intensity within 45 days after randomization. The dose was administered using Aptar Unidose System (UDS) liquid spray device. arm 2: Participants administered a single intranasal dose of zavegepant 10 mg on occurrence of migraine that reached moderate or severe intensity within 45 days after randomization. The dose was administered using Aptar UDS liquid spray device. arm 3: Participants administered a single intranasal dose of zavegepant 20 mg on occurrence of migraine that reached moderate or severe intensity within 45 days after randomization. The dose was administered using Aptar UDS liquid spray device. arm 4: Participants administered a single intranasal dose of zavegepant-matching placebo on occurrence of migraine that reached moderate or severe intensity within 45 days after randomization. The dose was administered using Aptar UDS liquid spray device.

Interventions: intervention 1: Zavegepant intervention 2: Zavegepant matching placebo intervention 3: Intranasal Aptar Pharma Unit Dose System
Intervention descriptions: intervention 1: A single dose of zavegepant intervention 2: A single dose of placebo matched to zavegepant intervention 3: A single-dose intranasal device

Protocol document:
Prot_000.pdf: 
 
 
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DRUG: 
BHV-3500  
 
STUDY NUMBER(S): 
BHV3500-201 
 
PROTOCOL(S) TITLE: 
BHV3500-201: Phase II/III: Double-Blind, Randomized, 
Placebo Controlled, Dose-Ranging Trial of BHV-3500 for 
the Acute Treatment of Migraine  
IND NUMBER: 
134,120 
 
SPONSOR: 
Biohaven Pharmaceuticals, Inc. 
 
ORIGINAL PROTOCOL 
DATE: 
 
30 JANUARY 2019  
 
VERSION NUMBER: 
4.0  
VERSION DATE: 
08 AUGUST 2019 


 
 
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CLINICAL PROTOCOL APPROVAL FORM 
Protocol Title:  BHV3500-201: Phase II/III: Double-Blind, Randomized, Placebo Controlled, Dose-
Ranging Trial of BHV-3500 for the Acute Treatment of Migraine 
Study No: BHV3500-201 
Original Protocol Date: 30 JANUARY 2019  
Protocol Version No: V 4.0  
Protocol Version Date: 08 AUGUST 2019  
This study protocol was subject to critical review and has been approved by the appropriate 
protocol review committee of the sponsor.  The information contained in this protocol is 
consistent with: 
• The current risk-benefit evaluation of the investigational product. 
• The moral, ethical and scientific principles governing clinical research as set out in the 
Declaration of Helsinki, and principles of GCP as described in 21 CFR parts 50, 54, 56 and 
312 and according to applicable local requirements. 
The Investigator will be supplied with details of any significant or new findings, including 
adverse events, relating to treatment with the investigational product. 
 
 


 
 
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Name and Title 
Signature Approval 
Date 
Author/Protocol Writer: 
  
I confirm, QC completed for required elements 
 
 
 
Clinical Operations: 
 
 
 
 
Biostatistics: 
 
 
 
 
Medical Lead: 
 
 
 
 
 
Study Director: 
 
 
 
 
 
Regulatory Affairs: 
 
 
 
 
 
PPD
PPD
PPD
PPD
PPD
PPD


 
 
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SUMMARY OF CHANGES 
 
Change 
Page(s)  
Affected 
Summary 
Corrected Table 1: Functional 
Disability Scale  
28 
Corrected Table 1 to add a “x” under Functional 
Disability Scale at the “Onset of moderate or severe 
migraine” timepoint.  The “x” was inadvertently omitted 
previously.  As described in Section 4.3.2.1, ratings of 
functional disability are recorded at the same time points 
as the headache severity ratings.  


 
 
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BHV-3500-201 
BHV3500-201: Phase II/III: Double-Blind, Randomized, Placebo 
Controlled, Dose-Ranging Trial of BHV-3500 for the Acute Treatment 
of Migraine 
Confidentiality and Investigator Statement 
The information contained in this protocol and all other information relevant to BHV-3500 are 
the confidential and proprietary information of Biohaven Pharmaceuticals, Inc., 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 Pharmaceuticals, Inc. 
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 Pharmaceuticals, Inc. 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:  
BHV3500-201: Phase II/III: Double-Blind, Randomized, Placebo 
Controlled, Dose-ranging Trial of BHV-3500 for the Acute Treatment of 
Migraine 
Rationale: 
BHV-3500 is being developed for the treatment of migraine by the 
intranasal (IN) route.  Nonclinical evidence suggests that BHV-3500, a 
CGRP receptor antagonist, possesses pharmacological properties suitable 
for the acute treatment of migraine. Intranasal administration of BHV-
3500 in the single ascending dose study BHV3500-101 produced plasma 
levels predicted to be within the therapeutic range for compounds of this 
class. 
 
This study will evaluate the safety and efficacy of three different intranasal 
dose levels (5 mg, 10 mg, 20 mg) of BHV-3500, relative to placebo, in the 
acute treatment of moderate to severe migraine.  
 
This study was designed to identify at least one dose of BHV-3500 that is 
safe, well tolerated, and meets the registrational co-primary endpoints of 
pain freedom and freedom from the most bothersome symptom (MBS) 
associated with migraine at 2 hours post-dose.  This information will be 
used in future trials to further define the safety and efficacy of the selected 
dose or doses.  
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,1 including an age of onset prior to 50, 
migraine attacks that last 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 1900 subjects will be screened to randomize approximately 
1600 subjects (approximately 400 per arm).  The subjects will be 
randomized in a 3:1 ratio to the BHV-3500 or matching placebo treatment 
groups.  The randomization will be stratified by the use of prophylactic 
migraine medications (yes or no).  
Objectives:  
Primary:  To evaluate the efficacy of BHV-3500 compared with placebo in 
the acute treatment of migraine as measured by co-primary endpoints of 
pain freedom and freedom from the most bothersome symptom 
(MBS), associated with migraine, at two hours post dose, while identifying 
an optimal dose for evaluation in the Phase 3 clinical trials. 
 


 
 
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STUDY SCHEMATIC 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
End of Treatment 
Visit: 
Subjects will return to 
investigational site for 
end of study procedures 
(this includes subjects 
who do not experience a 
migraine of moderate to 
severe intensity).  
[EOT visit will occur (after  
assessments in the handheld 
are completed) within 7 (+2) 
days after dosing with study 
medication.] 
Treatment Phase 
Screening and 
Baseline  
Screening 
Visit  
Baseline/ 
Randomization 
Visit  
Randomization 
(Day 1): 
Occurs at the 
Baseline Visit. 
One dose of 
study medication 
or matching 
placebo is 
dispensed for 
later migraine 
treatment. 
Treatment: 
Treatment of 
one migraine 
of moderate 
or severe 
intensity with 
BHV-3500 or 
matching 
placebo. 
Assessments:  
Using eCOA 
Handheld 
device, subjects 
will treat from 
onset of 
migraine to 48 
hours post dose 
of migraine for 
assessments of 
pain, disability, 
associated 
symptoms.   
End of Treatment  
[Treatment of migraine must occur within 45 days of randomization 
(Baseline Visit/Day 1)] 
Total study duration is approximately 11 weeks 
Arm 2: 
BHV-3500 
10mg 
Arm 1: 
BHV-3500 
5mg  
Arm 3: 
BHV-3500  
20mg 
Arm 4: 
Placebo 
Screening phase is 3-28 days 


 
 
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TABLE OF CONTENTS 
SUMMARY OF CHANGES ............................................................................................ 4 
STUDY SUMMARY (SYNOPSIS) .................................................................................. 6 
STUDY SCHEMATIC ...................................................................................................... 7 
TABLE OF CONTENTS .................................................................................................. 8 
LIST OF ABBREVIATIONS ......................................................................................... 12 
1 
INTRODUCTION AND RATIONALE ................................................................. 15 
1.1 
THERAPEUTIC AREA BACKGROUND ....................................................... 15 
1.2 
PRODUCT DEVELOPMENT BACKGROUND ............................................. 15 
1.2.1 
NON-CLINICAL PHARMACOLOGY ...................................................... 16 
1.2.1.1 
NONCLINICAL PHARMACOKINETICS AND 
PHARMACODYNAMICS ..................................................................... 16 
1.2.1.2 
NONCLINICAL TOXICOLOGY ......................................................... 16 
1.2.2 
CLINICAL EXPERIENCE .......................................................................... 16 
1.2.2.1 
SINGLE ASCENDING DOSE (BHV3500-101) ................................... 16 
1.2.3 
OTHER CLINICAL/ NON-CLINICAL STUDIES ................................... 17 
1.2.3.1 
CYP AND TRANSPORTER STUDIES ................................................ 17 
1.2.3.2 
PHASE 1 STUDIES ................................................................................. 17 
1.2.4 
CLINICAL ADVERSE EVENT PROFILE ............................................... 18 
1.3 
STUDY RATIONALE ........................................................................................ 18 
1.3.1 
STUDY DESIGN RATIONALE .................................................................. 18 
1.3.2 
DOSE SELECTION RATIONALE ............................................................. 18 
1.3.3 
OTHER RATIONALE RELATED TO THE COMPOUND/STUDY ..... 19 
1.4 
RESEARCH HYPOTHESIS .............................................................................. 19 
2 
STUDY OBJECTIVES ............................................................................................ 20 
2.1 
PRIMARY ............................................................................................................ 20 
2.2 
SECONDARY ...................................................................................................... 20 
2.3 
EXPLORATORY ................................................................................................ 21 
3 
STUDY ENDPOINTS .............................................................................................. 22 
3.1 
PRIMARY ............................................................................................................ 22 
3.2 
SECONDARY ...................................................................................................... 22 
3.3 
MEASURES OF INTEREST ............................................................................. 23 
4 
STUDY PLAN .......................................................................................................... 24 
4.1 
STUDY DESIGN AND DURATION ................................................................. 24 
4.2 
STUDY SCHEMATIC ........................................................................................ 25 
4.3 
SCHEDULE OF ASSESSMENTS ..................................................................... 26 
4.3.1 
SCREENING PHASE (3-28 DAYS) ............................................................ 30 
4.3.2 
RANDOMIZATION PHASE (45 DAYS) ................................................... 30 
4.3.2.1 
ECOA HANDHELD DEVICE DATA COLLECTION ...................... 31 
4.3.3 
EXTENSION PHASE ................................................................................... 31 


 
 
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4.3.4 
END OF TREATMENT VISIT ................................................................... 31 
4.4 
POST STUDY ACCESS TO THERAPY .......................................................... 32 
5 
POPULATION ......................................................................................................... 33 
5.1 
NUMBER OF SUBJECTS .................................................................................. 33 
5.2 
INCLUSION CRITERIA ................................................................................... 33 
5.3 
EXCLUSION CRITERIA .................................................................................. 35 
5.4 
PROHIBITED CONCOMITANT MEDICATION ......................................... 38 
5.4.1 
RESCUE MEDICATIONS ........................................................................... 39 
5.5 
WOMEN OF CHILDBEARING POTENTIAL ............................................... 40 
5.6 
OTHER RESTRICTIONS AND PRECAUTIONS (IF APPLICABLE) ....... 41 
5.7 
DEVIATION FROM INCLUSION/EXCLUSION CRITERIA ..................... 41 
6 
STUDY CONDUCT AND DESCRIPTION OF STUDY PROCEDURES ......... 42 
6.1 
STUDY MATERIALS ........................................................................................ 42 
6.2 
SAFETY ASSESSMENTS .................................................................................. 43 
6.2.1 
VITAL SIGNS AND PHYSICAL MEASUREMENTS (HEIGHT AND 
WEIGHT) ....................................................................................................... 43 
6.2.2 
ELECTROCARDIOGRAM (ECG) ............................................................ 43 
6.2.3 
PHYSICAL EXAM ....................................................................................... 43 
6.2.3.1 
NASAL INSPECTION ............................................................................ 43 
6.2.4 
LABORATORY ASSESSMENTS ............................................................... 44 
6.2.4.1 
SAFETY LABORATORY TESTING ................................................... 44 
6.2.4.2 
PREGNANCY TESTING ....................................................................... 44 
6.2.5 
SHEEHAN SUICIDALITY TRACKING SCALE (S-STS) ...................... 44 
6.3 
EFFICACY ASSESSMENTS ............................................................................. 45 
6.3.1 
PAIN ............................................................................................................... 45 
6.3.2 
NAUSEA, PHONOPHOBIA AND PHOTOPHOBIA ............................... 45 
6.3.3 
RESCUE MEDICATION ............................................................................. 45 
6.3.4 
FUNCTIONAL DISABILITY ...................................................................... 45 
6.3.5 
MIGRAINE QUALITY OF LIFE QUESTIONNAIRE ............................ 46 
6.3.6 
MIGRAINE PREFERENCE OF MEDICINE ........................................... 46 
6.4 
EARLY DISCONTINUATION FROM THE STUDY .................................... 46 
7 
STUDY DRUG MANAGEMENT .......................................................................... 47 
7.1 
DESCRIPTION OF STUDY DRUG ................................................................. 47 
7.1.1 
INVESTIGATIONAL PRODUCT .............................................................. 47 
7.1.2 
NON-INVESTIGATIONAL PRODUCT .................................................... 47 
7.1.3 
PACKAGING, SHIPMENT AND STORAGE ........................................... 47 
7.2 
DOSE AND ADMINISTRATION ..................................................................... 47 
7.2.1 
METHOD OF ASSIGNING SUBJECT IDENTIFICATION ................... 47 
7.2.2 
SELECTION AND TIMING OF DOSE AND ADMINISTRATION ...... 48 
7.2.3 
DOSE MODIFICATIONS ............................................................................ 48 
7.3 
BLINDING AND UNBLINDING ...................................................................... 48 
7.4 
TREATMENT COMPLIANCE ......................................................................... 49 
7.5 
DESTRUCTION AND RETURN OF STUDY DRUG .................................... 49 


 
 
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8 
ADVERSE EVENTS ................................................................................................ 50 
8.1 
SERIOUS ADVERSE EVENT ........................................................................... 50 
8.1.1 
DEFINITION OF SERIOUS ADVERSE EVENT (SAE) ......................... 50 
8.1.2 
COLLECTION AND REPORTING SERIOUS ADVERSE EVENTS ... 51 
8.1.3 
OVERDOSE ................................................................................................... 53 
8.1.3.1 
DOSE MISADMINISTRATION AND APTAR UDS 
MALFUNCTION .................................................................................... 53 
8.1.4 
PREGNANCY ................................................................................................ 53 
8.1.5 
POTENTIAL DRUG INDUCED LIVER INJURY (DILI) ....................... 54 
8.2 
NON-SERIOUS ADVERSE EVENTS .............................................................. 54 
8.2.1 
COLLECTION AND REPORTING OF NON-SERIOUS ADVERSE 
EVENTS ......................................................................................................... 54 
8.2.2 
LABORATORY TEST ABNORMALITIES .............................................. 55 
9 
STATISTICS ............................................................................................................ 56 
9.1 
GENERAL PROCEDURES ............................................................................... 56 
9.2 
SAMPLE SIZE .................................................................................................... 56 
9.3 
POPULATIONS FOR ANALYSIS .................................................................... 56 
9.4 
STATISTICAL METHODS ............................................................................... 57 
9.4.1 
PRIMARY ENDPOINT(S) ........................................................................... 57 
9.4.2 
SECONDARY ENDPOINT(S) ..................................................................... 57 
9.4.3 
ANALYSIS OF SAFETY .............................................................................. 57 
9.4.4 
DEMOGRAPHIC AND BASELINE CHARACTERISTICS ................... 57 
9.5 
INTERIM ANALYSIS ........................................................................................ 57 
10 ETHICS AND RESPONSIBILITIES ..................................................................... 58 
10.1 
GOOD CLINICAL PRACTICE ........................................................................ 58 
10.2 
DATA AND SAFETY MONITORING COMMITTEE .................................. 58 
10.3 
INSTITUTIONAL REVIEW BOARD/INDEPENDENT ETHICS 
COMMITTEE ..................................................................................................... 58 
10.4 
INFORMED CONSENT ..................................................................................... 59 
10.5 
CASE REPORT FORMS ................................................................................... 59 
10.6 
RECORDS MANAGEMENT AND RETENTION .......................................... 60 
10.7 
SOURCE DOCUMENTATION ......................................................................... 61 
10.8 
STUDY FILES AND RECORD RETENTION ................................................ 61 
11 AMENDMENTS ....................................................................................................... 62 
12 STUDY REPORT AND PUBLICATIONS ............................................................ 62 
13 STUDY DISCONTINUATION ............................................................................... 62 
14 CONFIDENTIALITY .............................................................................................. 63 
15 APPENDICES .......................................................................................................... 64 
15.1 
APPENDIX I – NAMES OF STUDY PERSONNEL ....................................... 64 
15.2 
APPENDIX II – STRONG CYP3A4 INHIBITORS AND INDUCERS (NOT 
ALL INCLUSIVE) .............................................................................................. 65 
16 REFERENCES ......................................................................................................... 66 


 
 
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LIST OF TABLES 
Table 1:  
Schedule of Assessments ......................................................................... 26 
 
 
 


 
 
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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 
AT 
AUC 
Aminotransferase 
Area Under the Curve 
BHV 
Biohaven Pharmaceuticals, Inc. 
BP 
Blood Pressure 
BUN 
Blood Urea Nitrogen 
Cmax 
Cmin 
CGRP 
Maximum Plasma Concentration 
Minimum Concentration 
Calcitonin gene-related peptide 
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 
eCOA 
eCRF 
EDC 
eDiary 
eGFR 
EOT 
ePRO 
FDA 
Ethics Committee 
Electrocardiogram 
Electronic clinical outcome assessment 
Electronic case report forms 
Electronic Data Capture 
Electronic Diary 
Glomerular Filtration Rate 
End of Treatment  
Electronic Patient Reported Outcome 
Food and Drug Administration 
FSH 
Follicle Stimulating Hormone 
GCP 
Good Clinical Practice 
CCI


 
 
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GLP 
HIV 
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 
IN 
IP 
International Headache Society 
Independent Ethics Committee 
Intranasal 
Investigational Product 
IRB 
Institutional Review Board 
IV 
IWRS 
LDH 
LDL 
Intravenous 
Interactive Web Response System 
Lactate Dehydrogenase 
Low-density lipoprotein 
kg 
Kilogram 
MBS 
MDRD 
MedRA 
mITT 
mg 
Most Bothersome Symptom 
Modification of Diet in Renal Disease 
Medical Dictionary for Regulatory Activities  
Modified Intent to Treat  
Milligram 
MI 
Min 
MQoL 
Myocardial Infarction  
Minute 
Migraine Quality of Life Questionnaire 
msecs 
MTD 
NOAEL 
NSAIDs 
NRS 
Milliseconds 
Maximum tolerated dose 
No-observable-adverse effect level 
Non-Steroidal Anti-Inflammatories 
Numeric Rating Scale  
OTC 
PCI 
Over the counter 
Percutaneous Coronary Intervention 
PCP 
Phencyclidine 


 
 
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PK 
PoM 
PVG 
Pharmacokinetic 
Preference of Medication  
Pharmacovigilance 
QTc 
Interval between Q-wave and T-wave in the cardiac cycle 
SAD 
SAE 
S-STS 
TBL 
TIA 
Tmax 
Single Ascending Dose  
Serious Adverse Event 
Sheehan Suicidality Tracking Scale 
Total Bilirubin  
Transient Ischemic Attack 
Time of observed Cmax 
UDS 
ULN 
USPI 
WBC 
Unit Dose System 
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. Migraine 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.2 Triptans 
have been used to treat migraine attacks with varying results including incomplete and 
inconsistent relief at 2 hours, and the recurrence of migraine within 24-48 hours after treatment. 
In addition, triptans are contraindicated in patients with cardiovascular events (e.g., myocardial 
infarction), conditions (e.g., angina) and procedures (e.g., carotid endarterectomy) due to 
vasoconstrictive properties. Recent estimates indicate that there are 2.6 million Americans with 
migraine who have a cardiovascular event, condition or procedure, demonstrating the need for 
non-vasoactive migraine treatments.3 
BHV-3500 is a selective, competitive CGRP receptor antagonist being developed for the 
treatment of migraine. BHV-3500 is being developed for IN administration. The CGRP receptor 
is located within pain-signaling pathways, intracranial arteries and mast cells4 and its activation 
is thought to play a causal role in migraine pathophysiology.5 For example, research and clinical 
studies have shown that serum levels of CGRP are elevated during migraine attacks,6 infusion of 
intravenous CGRP produces persistent pain in migraine sufferers and non-migraine sufferers,7,8  
and treatment with anti-migraine drugs normalizes CGRP levels.9 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.10 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™]).11  
A summary of the nonclinical investigational programs can be found in the current Investigator’s 
Brochure (IB).12 
1.2 
Product Development Background 
Details of the clinical and preclinical studies are provided in the most current version of the 
Investigator’s Brochure. A summary of the relevant data are presented below.  


 
 
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1.2.1 
Non-clinical Pharmacology 
1.2.1.1 
Nonclinical Pharmacokinetics and Pharmacodynamics 
A series of in vitro and in vivo pharmacokinetic (PK) and metabolism studies were conducted 
with BHV-3500 in rats, dogs, rabbits, mice and monkeys. 
1.2.1.2 
Nonclinical Toxicology 
Safety studies in animals were performed by the IN route in rat and monkey to determine 
tolerability and potential for local irritation, and by the subcutaneous (SC) route in both species 
to assess systemic toxicity.
 
 
1.2.2 
Clinical Experience 
1.2.2.1 
Single Ascending Dose (BHV3500-101) 
Preliminary blinded data to date has shown BHV-3500 to be safe and well tolerated. No deaths or 
serious AEs have been reported in the study.  No subjects have been discontinued due to AEs. 
Dose escalation to the highest planned dose of 40mg has been completed and no dose limiting 
toxicity has been observed. A Maximum Tolerated Dose (MTD) has not been identified. 
 
CCI
CCI
CCI


 
 
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All doses of BHV-3500 administered in the SAD study as of 07 March 2019 have been generally 
well tolerated, and all AEs graded as at least possibly related to study drug were mild in severity. 
 
 
Thus far in the development of BHV-3500, clinical pharmacokinetic information is obtained from 
the SAD study.    
1.2.3 
Other Clinical/ Non-clinical Studies 
1.2.3.1 
CYP and Transporter Studies  
BHV-3500 is not expected to cause any significant CYP-mediated drug interactions within the 
projected human dose range. 
 
 
 
 
 
 
 
 
BHV-3500 was examined for effects in a transporter study.15 
 
 
 
 
 
 
1.2.3.2 
Phase 1 Studies 
There is a planned series of clinical pharmacology studies with BHV-3500.  Relevant 
information will be provided in the Investigator Brochure or protocol when available. 
CCI
CCI
CCI


 
 
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1.2.4 
Clinical Adverse Event Profile 
 
Preliminary blinded data to date has shown BHV-3500 to be safe and well tolerated. No deaths 
or serious AEs have been reported in the study.  No subjects have been discontinued due to AEs. 
The majority of AEs have been mild in severity.  A Maximum Tolerated Dose has not been 
identified to date.  
1.3 
Study Rationale 
BHV-3500 is being developed for the treatment of migraine by the intranasal route.  Nonclinical 
evidence suggests that BHV-3500, a CGRP receptor antagonist, possesses pharmacological 
properties suitable for the acute treatment of migraine. Intranasal administration of BHV-3500 in 
the single ascending dose study produced plasma levels predicted to be within the therapeutic 
range for compounds of this class. 
This study will characterize of the safety and efficacy of 3 different intranasal dose levels (5mg, 
10mg, 20mg) of BHV-3500, relative to placebo, in the acute treatment of moderate to severe 
migraine.  
This study is designed to identify at least one dose of BHV-3500 that is safe, well tolerated, and 
that meets the registrational co-primary endpoints of pain freedom and freedom from the most 
bothersome symptom (MBS) associated with migraine at 2 hours post-dose.  This information 
will be used in future trials to further define the safety and efficacy of the selected dose or doses. 
1.3.1 
Study Design Rationale 
This is a double-blind, randomized, multicenter, outpatient evaluation of the safety and efficacy 
of BHV-3500 as compared to placebo in the treatment of moderate or severe migraine. The study 
drug will be intranasal BHV-3500 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 1600 subjects in a 1:1:1:1 ratio across the 4 treatment 
groups [3:1 ratio of the BHV-3500 groups to the placebo group]. The randomization will be 
stratified by the use of prophylactic migraine medications (yes or no). 
1.3.2 
Dose Selection Rationale  
Preclinical data predicts an effective human IN dose range of 2mg to 20mg.   Clinical data to 
date from the BHV3500-101 study suggests the doses selected for this protocol will produce 
systemic exposures within the range predicted to have clinical efficacy. 
CCI


 
 
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The existing human safety data, and animal toxicity data, support these doses for inclusion in a 
single dose trial for the acute treatment of migraine. Given that acute migraine agents such as 
triptans and CGRP inhibitors often have step-function like dose-response curves, it is expected 
that the low dose, or doses, may have no effect, while a higher dose, or doses, will have full 
effect.  This study is adequately powered to find a dose or doses of BHV-3500 that have strong 
effects in the treatment of acute migraine. If a dose is identified as safe and effective, the dose 
selected will be retested in a subsequent confirmatory trial.  
Given the tolerability of BHV-3500 across a wide dose range, and in order to determine the 
optimal efficacious doses, this trial will study the efficacy and dose-response of BHV-3500 
across a wide dose range in patients with a migraine attack.  
1.3.3 
Other Rationale related to the compound/study 
Not Applicable  
1.4 
Research Hypothesis 
The exploration of a range of BHV-3500 doses will reveal at least one dose that is safe and 
clinically superior to placebo in the acute treatment of migraine. 


 
 
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2 STUDY OBJECTIVES 
2.1 
Primary 
To evaluate the efficacy of BHV-3500 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, while 
identifying an optimal dose to support the Phase 3 clinical trials. 
2.2 
Secondary 
1. To evaluate BHV-3500 compared to placebo on pain relief at 2 hours post-dose.  
2. To evaluate the effect of BHV-3500 relative to placebo on the patient’s ability to function 
normally at 2 hours post dose according to the Functional Disability scale.  
3. To evaluate BHV-3500 compared to placebo on the probability of requiring rescue 
medication within 24 hours of initial treatment.  
4. To evaluate BHV-3500 compared to placebo on freedom from photophobia at 2 hours post-
dose.  
5. To evaluate BHV-3500 compared to placebo on freedom from phonophobia at 2 hours post-
dose. 
6. To evaluate BHV-3500 compared to placebo on pain relief at 60 minutes post-dose.  
7. To evaluate the effect of BHV-3500 relative to placebo on the patient’s ability to function 
normally at 60 minutes post dose according to the Functional Disability scale.  
8. To evaluate BHV-3500 compared to placebo on pain relief at 30 minutes post-dose.  
9. To evaluate the effect of BHV-3500 relative to placebo on the patient’s ability to function 
normally at 30 minutes post dose according to the Functional Disability scale.  
10. To evaluate BHV-3500 compared to placebo on sustained pain relief from 2 to 24 hours post-
dose.  
11. To evaluate BHV-3500 compared to placebo on sustained pain freedom from 2 to 24 hours 
post-dose.   
12. To evaluate BHV-3500 compared to placebo on sustained pain relief from 2 to 48 hours post-
dose.  


 
 
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13. To evaluate BHV-3500 compared to placebo on sustained pain freedom from 2 to 48 hours 
post-dose. 
14. To evaluate BHV-3500 compared to placebo on freedom from nausea at 2 hours post-dose. 
15. To evaluate BHV-3500 compared to placebo for the incidence of pain relapse from 2 to 48 
hours post-dose  
2.3 
Exploratory  
1. To evaluate the effect of BHV-3500 relative to placebo on the patients ability to function 
normally at 24 hours post dose according to the Functional Disability scale.  
2. To evaluate the effect of BHV-3500 relative to placebo on the Migraine Preference of 
Medication (PoM).  
3. To evaluate BHV-3500 relative to placebo for pain freedom at all scheduled time points post 
dose.  
4. To evaluate BHV-3500 relative to placebo for pain relief at all scheduled time points post 
dose.  
5. To evaluate BHV-3500 relative to placebo for freedom from MBS at all scheduled time 
points post dose.  
6. To evaluate BHV-3500 relative to placebo for freedom from functional disability at all 
scheduled time points post dose.  
7. To evaluate the effect of BHV-3500 relative to placebo on the Migraine Quality of Life 
Questionnaire (MQoL).  
8. To evaluate the tolerability and safety of BHV-3500 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.  
9. To evaluate the effect of BHV-3500 relative to placebo on the Sheehan Suicidality Tracking 
Scale (S-STS). 


 
 
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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 (aka “headache response”), at 2 hours post-dose, will be assessed using the 
number of subjects that report a pain level of none or mild (response of 0 or 1) at two hours 
post-dose.  
2. The proportion of subjects able to function normally, at 2 hours, will be assessed by 
tabulating the number of subjects that report as being able to function normally on the 
functional disability scale in the subset of subjects that reported any level of disability at the 
migraine baseline. 
3. 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. 
4. 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 the migraine baseline.  
5. 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 the migraine baseline. 
6. Pain Relief at 60 minutes post-dose, will be assessed using the number of subjects that report 
a pain level of none or mild (response of 0 or 1). 
7. The proportion of subjects able to function normally, at 60 minutes, will be assessed by 
tabulating the number of subjects that report as being able to function normally on the 
functional disability scale at 60 minutes in the subset of subjects that reported any level of 
disability at the migraine baseline. 
8. Pain Relief at 30 minutes post-dose, will be assessed using the number of subjects that report 
a pain level of none or mild (response of 0 or 1). 


 
 
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9. The proportion of subjects able to function normally, at 30 minutes, will be assessed by 
tabulating the number of subjects that report as being able to function normally on the 
functional disability scale at 30 minutes in the subset of subjects that reported any level of 
disability at the migraine baseline. 
10. Sustained pain relief, from 2 to 24 hours will be assessed using the number of subjects that 
do not experience any moderate or severe migraine pain through the time period of interest.  
11. Sustained pain freedom, from 2 to 24 hours, will be assessed using the number of subjects 
that do not experience any migraine pain through the time period of interest.  
12. Sustained pain relief from 2 to 48 hours, will be assessed using the number of subjects that 
do not experience any moderate or severe migraine pain through the time period of interest.  
13. Sustained pain freedom, from 2 to 48 hours, will be assessed using the number of subjects 
that do not experience any migraine pain through the time period of interest.  
14. 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 migraine baseline.  
15. Pain relapse will be assessed using the number of subjects that are pain free at 2 hours post-
dose and then have migraine pain of any severity (response of 1, 2 or 3 on the 4 point scale) 
within 48 hours after administration of study medication. 
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 Quality of Life Questionnaire (MQoL) 
• Nasal Inspection  


 
 
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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 BHV-3500 as compared to placebo in the treatment of moderate or severe migraine. Subjects 
will be dispensed one Aptar Unit Dose System (UDS) liquid spray device containing a single 
dose of study medication BHV-3500 or a matching placebo. The total duration of the study will 
be approximately 11 weeks.  This includes a 3-28 day Screening Period, a Treatment Phase that 
can last up to 45 days or until the subject has a migraine that reaches moderate or severe 
intensity, followed by an End of Treatment Visit 7 (+2) days after the administration of study 
medication.  
 


 
 
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4.2 
Study Schematic 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
End of Treatment 
Visit: 
Subjects will return to 
investigational site for 
end of study procedures 
(this includes subjects 
who do not experience a 
migraine of moderate to 
severe intensity).  
[EOT visit will occur (after  
assessments in the handheld 
are completed) within 7 (+2) 
days after dosing with study 
medication.] 
Treatment Phase 
Screening and 
Baseline  
Screening 
Visit  
Baseline/ 
Randomization 
Visit  
Randomization 
(Day 1): 
Occurs at the 
Baseline Visit. 
One dose of 
study medication 
or matching 
placebo is 
dispensed for 
later migraine 
treatment. 
Treatment: 
Treatment of 
one migraine 
of moderate 
or severe 
intensity with 
BHV-3500 or 
matching 
placebo. 
Assessments:  
Using eCOA 
Handheld 
device, 
subjects will 
treat from 
onset of 
migraine to 48 
hours post 
dose of 
migraine for 
assessments of 
pain, 
disability, 
associated 
symptoms.   
End of Treatment  
[Treatment of migraine must occur within 45 days of randomization 
(Baseline Visit/Day 1)] 
Total study duration is approximately 11 weeks 
Arm 2: 
BHV-3500 
10mg 
Arm 1: 
BHV-3500 
5mg  
Arm 3: 
BHV-3500  
20mg 
Arm 4: 
Placebo 
Screening phase is 3-28 days 


 
 
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4.3 
Schedule of Assessments 
Table 1:  
Schedule of Assessments 
Procedure 
Screening Visit1 
Baseline/ 
Randomization 
Visit 
(Day 1)2 
Onset of moderate or 
severe migraine3 
Post Study Medication 
Administration: 
15, 30, 45, 60 and 90 minutes 
2, 3, 4, 6, 8, 24 and 48 hours 
End of Treatment 
Visit14 
Eligibility Assessments 
Informed Consent 
X 
 
 
 
 
Inclusion/ 
Exclusion Criteria 
X 
X 
 
 
 
Medical History 
X 
 
 
 
 
Migraine History 
Assessment  
(signs/ symptoms/ prior 
treatment/ frequency/ 
intensity) 
 
X 
 
 
 
 
Rescue Medication paper 
diary, Concomitant 
Medication paper diary4 
 
X 
 
X 
 
X 
 
X 
 
X 
Randomize subject in 
IWRS5 
 
X 
 
 
 
Safety Assessments  
Physical Examination 
X 
 
 
 
X 
Nasal Inspection6 
X 
X 
 
 
X 
Vital Signs/ Physical 
Measurements7 
X 
X 
 
 
X 
Adverse Event and Serious 
Adverse Event 
Assessment8 
X 
X 
X 
X 
 
X 
Sheehan Suicidality 
Tracking Scale  
(S-STS)9 
X 
X 
 
 
X 
ECG 
X 
 
 
 
X 
Clinical Safety Laboratory 
Testing 
X 
 
 
 
X 


 
 
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Procedure 
Screening Visit1 
Baseline/ 
Randomization 
Visit 
(Day 1)2 
Onset of moderate or 
severe migraine3 
Post Study Medication 
Administration: 
15, 30, 45, 60 and 90 minutes 
2, 3, 4, 6, 8, 24 and 48 hours 
End of Treatment 
Visit14 
Liver Function Tests 
(LFTs) 
X 
 
 
 
X 
Lipid Panel 
X 
 
 
 
 
FSH, if applicable, to 
determine WOCBP status 
X 
 
 
 
 
Pregnancy Test10 
X (Serum) 
X (Urine) 
X (Urine) 
 
X (Serum) 
Urinalysis 
X 
 
 
 
X 
Urine drug screen for 
drugs of abuse 
X 
 
 
 
X 
Clinical Drug Supplies/Study Supplies 
eCOA Handheld device 
assigned  
 
X 
 
 
 
Dispense study 
medication11 
 
X 
 
 
 
Administer study 
medication 
 
 
X 
 
 
Patient Education:  Dose 
Administration 
 
X 
 
 
 
Patient Education: eCOA 
Handheld 
 
X 
 
 
 
Enter use of study 
medication in eCOA 
Handheld device  
 
 
X 
 
 
Return used or unused 
study medication  
 
 
 
 
X 
eCOA Handheld returned/ 
reviewed for 
completeness12 
 
 
 
 
 
X 


 
 
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Procedure 
Screening Visit1 
Baseline/ 
Randomization 
Visit 
(Day 1)2 
Onset of moderate or 
severe migraine3 
Post Study Medication 
Administration: 
15, 30, 45, 60 and 90 minutes 
2, 3, 4, 6, 8, 24 and 48 hours 
End of Treatment 
Visit14 
Efficacy Assessments12 
Assessment of migraine 
pain13 
 
 
X 
X 
 
Assessment of Migraine 
Symptoms (photophobia, 
phonophobia, and 
nausea)13 
 
 
X 
X 
 
Functional Disability 
Scale13 
 
 
X 
X 
 
MQoL (Migraine Quality 
of Life Questionnaire)13 
 
 
 
X (24-hour assessment) 
 
Preference of Medication 
(PoM)13 
 
 
 
X (24-hour assessment) 
 
1 Screening Phase will be 3 - 28 days. Subject should be entered in the IWRS once they sign the informed consent form to obtain their study subject 
identification code.  
2The Baseline/ Randomization Visit may only occur after all screening procedures are completed and the subject meets all inclusion/exclusion criteria.  If the 
subject does not meet all eligibility requirements, the subject should be screen failed in the IWRS.  
3 Subjects will use their assigned eCOA handheld device to answer questions about their migraine symptoms upon experiencing a moderate or severe migraine 
headache. The subject will administer study drug or matching placebo if the following criteria are met: 1) the headache remains moderate or severe; 2) the 
subject has completed all required migraine assessment questions in the handheld, including their current most bothersome migraine symptom, and 3) the subject 
has not already taken prohibited medications (see protocol section 5.4). 
4 Subjects should keep track of their concomitant and rescue medications on the appropriate study paper diary provided throughout the study.  These diaries 
should be returned to the investigational site for review and electronic data capture (EDC) entry.  
5 The randomization visit is considered day 1 out of the 45 days subjects have to treat and report a migraine in their handheld device. Subjects will be randomized 
in the IWRS and will be stratified by answering “yes” or “no” to prophylactic migraine medication use in the IWRS. 
6Nasal inspection – The nasal passages and turbinates will be visually inspected with a nasal speculum or otoscope at the screening, baseline and end of treatment 
visits to detect evidence of nasal inflammation or edema. 
7 Height will only be captured at the Screening Visit. Weight, body temperature, respiratory rate, blood pressure and heart rate will be collected at all time points 
where indicated. Sitting arterial systolic and diastolic blood pressure and pulse rate will be measured. 


 
 
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8 SAEs are reported from the time of signed informed consent and non-serious AEs are reported from baseline. All ongoing non-serious AEs and SAEs will be 
followed to resolution or until the 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.  
9 The S-STS will be clinician administered on site with a paper form. The source document will be provided digitally by Biohaven. The assessment period for 
completing the scale will be 30 days prior to the Screening Visit, and since the last visit for the Baseline/Randomization and End of Treatment Visits.    
10 For WOCBP: A serum pregnancy test will be collected at the Screening and End of Treatment Visits as part of the standard laboratory tests.  Confirmatory 
urine pregnancy test will 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. 
11 Subjects should be instructed that the dose should be taken once the migraine attack reaches moderate or severe pain and after the subject has completed all 
required migraine assessments in the handheld.  The handheld will prompt the subject to take study medication.   
12 Site staff to review and confirm all data points are transferred from the handheld and reset handheld for future subject use, PRIOR to the subject leaving the 
clinic. 
13 The Functional Disability, MQoL and Preference of Medication scales will be captured in the handheld device. Subjects will also be asked about their most 
bothersome symptom at the time of reporting and treating a qualifying migraine. 
14 Subjects will return to the site for their End of Treatment Visit (after assessments in the handheld are completed) within 7 (+2) days after dosing with study 
medication. The “+2” day window is included for scheduling purposes only. 


 
 
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4.3.1 
Screening Phase (3-28 days) 
Approximately 1900 subjects will be screened to randomize approximately 1600 subjects to 
study mediation (BHV-3500 or matching placebo).  
Before any study procedures are performed, subjects must sign informed consent. After informed 
consent is signed, subjects will be enrolled in the IWRS system. The subject’s migraine history 
and medical history will be collected at the Screening Visit.  Subjects will also undergo all 
screening procedures as detailed in Table 1. Within 3-28 days from the Screening Visits, subjects 
will return to the site for the Baseline/ Randomization Visit; if the subject does not meet all 
eligibility criteria, the subject will be considered a Screen Failure. 
Subjects in this study may be screened only once. Rescreening is not permitted. 
4.3.2 
Randomization Phase (45 days) 
Subjects will return to the study site for the Baseline (Randomization) Visit. 
Subjects who meet all eligibility criteria they may be randomized at the Baseline Visit.  
Randomization will occur in the IWRS. The subjects will be provided with an eCOA Handheld 
device. The study personnel will instruct the subject on the proper use of the handheld to ensure 
proper understanding and use of the tool, prior to the subject leaving the office. 
After randomization is completed in the IWRS, study medication will be dispensed to subjects to 
take home for up to 45 days. The study personnel must train the subject on the proper use of 
Aptar UDS device using instructions to be provided to each study subject.  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 handheld. 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 have answered questions about their current pain and symptoms 
and identified their currently most bothersome, migraine associated, symptom 
(phonophobia, photophobia or nausea) in the handheld. The subject will complete 
assessments 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.  


 
 
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4.3.2.1 
eCOA Handheld Device Data Collection  
The eCOA handheld device may also be referred to as a handheld or an eDiary.  Once a subject 
experiences a headache of moderate to severe intensity, they should record this in the handheld.  
The handheld will instruct the subject to take study medication after the initial assessments are 
completed in the device.  
The following will be recorded in the eCOA handheld device:  
• Onset time of headache, intensity of the headache prior to and at time of taking study 
medication 
• 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 taking study 
medication 
• Subjects will complete the migraine-specific quality-of-life questionnaire (MQoL), 
Functional Disability Scale 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.  
Subjects should be encouraged to treat their first qualifying (moderate to severe) migraine that 
occurs during the treatment phase. If subjects are unable to treat their first qualifying migraine, 
refer to section 5.4.1 Rescue Medications for a list of medications that are allowed during the 
course of this study.  
4.3.3 
Extension Phase  
Not Applicable 
4.3.4 
End of Treatment Visit  
Subjects will return to the site for their End of Treatment Visit (after assessments in the handheld 
are completed) within 7 (+2) days after dosing with study medication. The “+2” day window is 
included for scheduling purposes only. 


 
 
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At the End of Treatment Visit, medication compliance, monitoring of tolerability and safety 
assessments (including vital signs, laboratory tests, nasal inspection and electrocardiography) 
will be performed. Refer to Table 1 for a full list of assessments completed at the EOT.    
If a subject has NOT experienced a migraine headache of moderate or severe intensity within 45 
days after randomization, they are still required to complete all EOT visit procedures.  All 
subjects must return used and unused study medication and their handheld device to the 
investigational site.  
4.4 
Post Study Access to Therapy  
At the end of the study, the sponsor will not continue to supply study drug to subjects/ 
Investigators. The Investigator should ensure that the subject receives the appropriate standard of 
care to treat the condition under study.  


 
 
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5 POPULATION 
Individuals entered in this trial will be subjects who suffer from migraines. The treatment setting 
for these subjects may include clinics, institutions or private office practices. Subjects may be 
recruited through a variety of sources, including referrals from physicians and other health care 
professionals. 
5.1 
Number of Subjects 
It is anticipated that approximately 1900 subjects will need to be screened in order to randomize 
approximately 1600 subjects. The subjects will be randomized in a 3:1 ratio to the BHV-3500 or 
placebo treatment groups.  It is anticipated that enrollment will occur at approximately 80 sites in 
the United States over a period of approximately 5 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. 
b. Subjects must be able to read English or Spanish.   
2. Target Population 
Subjects with minimum 1 year history of migraines (with or without aura) consistent with a 
diagnosis according to the International Classification of Headache Disorders, 3rd Edition,1 
including the following: 
a. Migraine attacks present for more than 1 year with the age of onset prior to 50 years of 
age. 
b. Migraine attacks, on average, lasting about 4 - 72 hours if untreated. 
c. Not more than 8 attacks of moderate or severe intensity per month within last 3 months. 
d. Subjects must be able to distinguish migraine attacks from tension/cluster headaches. 
e. At least 2 consistent migraine headache attacks of moderate or severe intensity in each of 
the 3 months prior to the Screening Visit and throughout the Screening Period (subject 
self-report). 


 
 
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f. Less than 15 days with headaches (migraine or non-migraine) per month in each of the 3 
months prior to the Screening Visit and throughout the Screening Period (subject self-
report). 
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 if 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 of age. 
b. Women of childbearing potential (WOCBP) with male partners and men with women 
partners of childbearing potential must use two acceptable methods of contraception to 
avoid pregnancy throughout the study in such a manner that the risk of pregnancy is 
minimized. See Section 5.5 for the definition of WOCBP.  
c. Males with vasectomy are considered surgically sterile provided the procedure occurred 
greater than 6 months (24 weeks) prior to study participation. 
d. Women must not be lactating or breastfeeding. 
e. At the Baseline Visit prior to dispensing Investigational Study Medication, WOCBP must 
have a negative urine pregnancy test. 
4. Other Inclusion Criteria 
a. No clinically significant abnormality identified on the medical or laboratory evaluation. 
A subject with a clinical abnormality or laboratory parameters outside the reference range 
may be included if in the opinion of the Investigator the finding is not clinically 
significant, will not introduce additional risk factors or interfere with the study 
procedures (not including exclusion criteria listed in Section 5 below). 


 
 
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5.3 
Exclusion Criteria 
1. Disease Target Exclusion 
a. Subjects with 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 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 stable diabetes for at least 3 
months prior to being enrolled). A single blood pressure measurement of greater than 150 
mm Hg systolic or 100 mm Hg diastolic after 10 minutes of rest is exclusionary. 
d. Subject has a current diagnosis of major depression, other pain syndromes (e.g. chronic 
pelvic pain, chronic regional pain syndrome, fibromyalgia), 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 other disease or condition (e.g. 
chronic pancreatitis, ulcerative colitis, etc.) 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 (SAE) or interfere with assessments of 
safety or efficacy during the course of the trial. 
g. Acute or chronic treatment with OTC or prescription nasal sprays. Subjects must stop all 
OTC/Rx nasal sprays 14 days prior to the screening visit and refrain from use until study 
completion.  
h. History of nasal surgery in the 6 months preceding the screening visit. 


 
 
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i. Evidence at screening of significant nasal conditions that may affect the administration or 
absorption of the nasal product (e.g. severe septum deviation, nasal deformity or 
blockage, inflammation, perforation, mucosal erosion or ulceration, polyposis, nasal 
trauma) as evaluated by the Investigator or medically qualified delegate. 
j. Presence of piercings in the nose that, in the opinion of the Investigator, would be likely 
to interfere with positioning of the Aptar UDS device and successful completion of the 
dosing procedure. 
k. History of, treatment for, or evidence of, alcohol or drug abuse within the past 12 months 
or subjects who have met DSM-V criteria16 for any significant substance use disorder 
within the past 12 months from the date of the screening visit. 
l. 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  criteria16 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. 
m. Hematologic or solid malignancy diagnosis within 5 years prior to the screening visit. 
Subjects with a history of localized basal cell or squamous cell skin cancer are eligible 
for the study if they are cancer-free prior to the screening visit in this study.   
n. Body mass index > 35 kg/m2 
o. Patient has a history or diagnosis of Gilbert’s Syndrome or any other active hepatic or 
biliary disorder. 
3. Allergies and Adverse Drug Reactions 
a. History of drug or other allergy which, in the opinion of the Investigator, makes the 
subject unsuitable for participation in the study. 


 
 
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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 
90 days after the study. 
b. Women who are pregnant, lactating or breastfeeding.  
c. 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 or Direct) > 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). 
i. HbA1c > 7% 
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. 


 
 
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d. Subjects who have previously participated in any BHV-3500 study within the last 2 
years. 
e. Participation in clinical trial with biological investigational agents within the 90 days 
prior to Baseline visit. 
f. Score of > 0 on the Sheehan Suicidality Tracking Scale for the period of 30 days prior to 
Screening and during the study. 
g. Participation in any other investigational clinical trial while participating in this clinical 
trial. 
h. Subjects must agree to provide all requested demographic information (i.e. gender, race). 
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 up to1000mg/day is allowed as rescue 


 
 
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medication as directed in 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 BHV-3500 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 BHV-3500 should be stopped and should not start again until 14 days after the last dose 
of the strong CYP3A4 inhibitor. Refer to Section 15.2, Appendix 2. 
12. Concomitant use of strong CYP3A4 inducers with BHV-3500 is prohibited during the study. 
If use of a strong CYP3A4 inducer is required, such as use of carbamazepine, phenytoin, or 
rifampin, dosing with BHV-3500 should be stopped and should not start again until 14 days 
after the last dose of the strong CYP3A4 inducer. Refer to Section 15.2, Appendix 2. 
13. Use of OTC or prescription topical nasal steroids, oxymetazoline, topical nasal 
antihistamines, topical nasal anticholinergics, and topical nasal mast cell stabilizers should 
not be taken within 14 days prior to the screening visit and throughout the study. 
14. 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.  
15. The use of CGRP antagonists (biologic or small molecule) is prohibited during the study.  
CGRP antagonist biologics must be discontinued 6 months prior to screening. 
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 first 2 
hours post dose of study drug administration. A subject who does not experience relief of their 
migraine headache at the end of 2 hours after dosing with study medication (and after the two 
hour assessments have been completed on the handheld device), will be permitted to use 
ONLY 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.   


 
 
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If the migraine is relieved by study medication at 2 hours after dosing but then returns to a 
moderate or severe intensity level between 2 and 48 hours, the subject will be permitted to take 
the same rescue therapy as outlined above.  
If needed, 48-hours after dosing with the study medication (and before returning to the clinical 
site for the End of Treatment Visit), the 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 handheld.  
In all circumstances, the subject will always continue to complete the handheld entries through 
the 48-hour assessment after taking the study medication. Use of concomitant medication after 
randomization, including rescue medication, will be recorded by the subject on a paper diary and 
returned 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) in the EDC.  
During the 45 days of the treatment phase, 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 
handheld, if subjects experience a migraine they are allowed to take their prescribed (excluding 
prohibited medications) standard of care medication (including triptans if not contraindicated and 
acetaminophen up to 1000mg/day, this includes Excedrin Migraine). 
5.5 
Women of Childbearing Potential 
Women of childbearing potential (WOCBP) includes any female who has experienced menarche 
and who has not undergone successful surgical sterilization (hysterectomy, bilateral tubal 
ligation, or bilateral oophorectomy) or is not postmenopausal. Menopause is defined as: 
1. Amenorrhea greater than or equal to 12 consecutive months without another cause and a 
documented serum follicle stimulating hormone (FSH) level > 35mIU/mL or 
2. Woman with irregular menstrual periods and a documented serum follicle stimulating 
hormone (FSH) level > 35mIU/mL or 
3. 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 
4. Woman on hormone replacement therapy (HRT) 


 
 
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Women of childbearing potential (WOCBP) with male partners, and men with female partners of 
childbearing potential, must commit to use two acceptable methods of contraception to avoid 
pregnancy throughout the study and for up to 90 days after the last dose of investigational 
product in such a manner that risk of pregnancy is minimized. It is required to use two methods 
of contraception for the duration of the study (i.e. this study begins with signed consent form 
through 90 days after dosing with study medication). 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. All 
WOCBP must administer the home pregnancy test prior to taking Investigational Study Drug. If 
the pregnancy test is positive, subjects should not take study medication and should immediately 
contact the Investigator.  
Male subjects must be willing not to donate sperm until 90 days following the last study drug 
administration. 
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 criteria, exclusion criteria, study 
conduct, or study procedures will be documented as a protocol 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 as required by local IRB/EC 
requirements. 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/Study Binder 
• Drug Accountability Logs 
• Sample source documents 
• Concomitant and Rescue Medication Logs (take home for subject)  
• Investigator Brochure 
• Interactive Web-based Response System (IWRS) manual 
• Electronic Case Report Forms (eCRF)  
o Electronic Case Report Forms (eCRFs) will be prepared for all data collection fields  
• eCOA Handheld devices 
o One device to be kept onsite for training purposes with training materials 
o Supply of devices for each randomized subject to receive one device to use during the 
treatment phase  
• Drug administration instructions 
• Laboratory kits and laboratory manual 
• Home pregnancy test for each randomized subject of WOCBP 
• ECG Machine and instructions 
• Serious Adverse Event (SAE) forms and Serious Adverse Events (SAE) Reporting 
instructions 
• Pregnancy surveillance forms 
• S-STS source documents 


 
 
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• Single use, disposable nasal speculum provided upon request 
• Study system access:  
o Electronic Data Capture (EDC) tool to submit study data to Sponsor/ CRO 
o IWRS 
o Central Laboratory 
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.  Physical exam will include nasal inspection.  
6.2.3.1 
Nasal Inspection 
The nasal passages and turbinates will be visually inspected by the Investigator or medically 
qualified delegate with a nasal speculum or otoscope at the screening, baseline and end of 
treatment visits to detect evidence of significant nasal conditions that may affect the 
administration or absorption of the nasal product (e.g. severe septum deviation, nasal deformity 
or blockage, inflammation, perforation, mucosal erosion or ulceration, polyposis, nasal trauma). 
Nasal findings will be recorded as appropriate and followed until resolution. 


 
 
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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. 
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 (>5x ULN) may have further CK fractionation tests performed. 
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), when appropriate and 
as outlined in Table 1. 
6.2.5 
Sheehan Suicidality Tracking Scale (S-STS) 
The S-STS is a prospective clinician administered rating scale that contains questions that track 
both treatment-emergent suicidal ideation and behaviors 17,18. The S-STS will be completed on a 
paper form at the site.  At the screening visit, the recall period for completing the S-STS is within 
the last 30 days prior to the screening visit; at all other visits, the recall period for completing the 
S-STS is since the last visit.  Subjects who have a S-STS score of >0 should be evaluated by the 
Investigator.  If the Investigator determines that a subject is at risk of suicide or self-harm, 


 
 
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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 eCOA Handheld device to record their migraine pain score, on a 4-point 
numeric rating [no pain, mild pain, moderate pain, severe pain] at the time points indicated in 
Table 1.  
6.3.2 
Nausea, Phonophobia and Photophobia 
The migraine associated symptoms of photophobia, phonophobia and nausea are measured on a 
two point scale (present or absent), using the handheld, 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 assessments are done using 
the handheld. 
The subjects are also asked to identify their most bothersome symptom on the handheld (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 handheld, at the times indicated in Table 1, using a 4 point 
numeric rating scale (normal function, mild impairment, severe impairment, required bedrest).  


 
 
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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 (MQoL) version 3.0. The MQoL is a 15-item instrument that has 
been validated in migraine subjects to assess the effect of migraine and its treatment on patients’ 
health related quality of life in the following five migraine-specific domains: work functioning, 
social functioning, energy/vitality, feelings and concerns, and migraine headache symptoms.  
The handheld 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 handheld is used to evaluate the Preference of Medication 
Scale at 24 hours post-dose (see Table 1). 
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, Inc. 
• Loss of ability to freely provide consent through imprisonment or involuntary incarceration 
for treatment of either a psychiatric or physical (e.g., infectious disease) illness 
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 BHV-3500 or the matching placebo will be provided in single use Aptar UDS devices fully 
prepared and ready for administration.  The BHV-3500 and placebo solution are identical in 
appearance.   
7.1.2 
Non-investigational Product 
Other medications used as support or rescue medication for preventative, diagnostic, or 
therapeutic reasons, as components of the standard of care for a given diagnosis, may be 
considered as non-investigational products. 
In this protocol, non-investigational product(s) is/are: Not applicable for this study. 
7.1.3 
Packaging, Shipment and Storage 
The product storage manager should ensure that the study medication 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. Refer to the current Investigator Brochure 
for study medication storage requirements.  
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 throughout the 


 
 
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study through the 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 3:1 
ratio to the BHV-3500 or placebo treatment groups. The randomization will be stratified by 
the use of prophylactic migraine medications (yes or no). It is important to correctly enter 
subjects who are using prophylactic migraine medication in the IWRS system. Once a 
patient is stratified in the IWRS, this cannot be changed and will be considered a 
significant 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 kit 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 (Aptar UDS containing BHV-3500 or matching placebo) will be packaged in a 
carton. There are no dose adjustments in this study and subjects will receive study medication 
sufficient 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 Aptar UDS from the carton at the time of moderate or severe 
migraine headache onset ONLY after answering questions regarding their migraine symptoms 
in the handheld device.  Subjects will administer a single spray of the medication from the 
device.  Subjects must inform the study staff if they sneeze, if the device malfunctions or if the 
device does not dispense a complete spray. 
7.2.3 
Dose Modifications 
There will be no dose adjustments in this study. 
7.3 
Blinding and Unblinding  
Blinding is critical to the integrity of this clinical study.  However, in the event of a medical 
emergency or pregnancy in an individual subject, in which knowledge of the investigational 
product is critical to the subject’s management, the blind for that subject may be broken by the 
treating physician.  
Before breaking the blind of an individual subject’s treatment, the Investigator should have 
determined that the information is necessary, (i.e., that it will alter the subject’s immediate 
management).   In many cases, particularly when the emergency is clearly not investigational 


 
 
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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 for remaining site personnel 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 
qualifying migraine or take their study medication within 45 days of the Baseline Visit, they 
should return to the clinic for their End of Treatment Visit and return their study medication.  
7.5 
Destruction and Return of Study Drug 
If the study drug is 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 drug can only be 
destroyed after being inspected and reconciled by the responsible BHV Study monitor or the 
sponsor’s designee unless this is against institutional policy.  
All unused and/or partially used study drug may be destroyed on site providing the site has an 
applicable standard operating procedure on file.  


 
 
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8 ADVERSE EVENTS 
An Adverse Event (AE) is defined as any new untoward medical occurrence or worsening of a 
pre-existing medical condition in a 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.  
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 BHV-3500 
• Other: Important medical events that may not result in death, be life-threatening, or require 
hospitalization, may be considered an SAE when, based upon appropriate medical judgment, 
they may jeopardize the subject and may require medical or surgical intervention to prevent 
one of the outcomes listed in this definition. Examples of such events are (but not limited to): 
o Intensive treatment in an emergency room or at home for allergic bronchospasm 
o Blood dyscrasias or convulsions that do not result in inpatient hospitalization 
o Development of drug dependency or drug abuse 
o Potential drug-induced liver injury  


 
 
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Definition of Terms 
Life threatening: An AE is life threatening if the subject was at immediate risk of death from the 
event as it occurred; i.e., it does not include a reaction that if it had occurred in a more severe 
form might have caused death. For example, drug induced hepatitis that resolved without 
evidence of hepatic failure would not be considered life threatening even though drug induced 
hepatitis can be fatal. 
Hospitalization: AEs requiring hospitalization should be considered SAEs. Hospitalization for 
elective surgery or routine clinical procedures that are not the result of AE (e.g., elective surgery 
for a pre-existing condition that has not worsened) need not be considered AEs or SAEs. If 
anything, untoward is reported during the procedure, that occurrence must be reported as an AE, 
either 'serious' or 'non-serious' according to the usual criteria. 
In general, hospitalization signifies that the subject has been detained (usually involving at least 
an overnight stay) at the hospital or emergency ward for observation and/or treatment that would 
not have been appropriate in the physician's office or outpatient setting. When in doubt as to 
whether 'hospitalization' occurred or was necessary, the AE should be considered serious. 
The following hospitalizations are not considered SAEs in BHV clinical studies (but may be 
considered non-serious AEs): 
1. A visit to the emergency room or other hospital department <24 hours that does not result in 
an admission (unless considered “important medical event” or event that is life threatening); 
2. Elective surgery, planned prior to signing consent; 
3. Admissions as per protocol for a planned medical/surgical procedure; 
4. Routine health assessment requiring admission (i.e., routine colonoscopy); 
5. Admission encountered for another life circumstance that carries no bearing on health and 
requires no medical intervention (i.e., lack of housing, care-giver respite, family 
circumstances). 
Disability/incapacitating: An AE is incapacitating or disabling if the experience results in a 
substantial and/or permanent disruption of the subject's ability to carry out normal life functions. 
8.1.2 
Collection and Reporting Serious Adverse Events 
Following the subject’s written consent to participate in the study, all SAEs, whether related or 
not related to study drug, must be collected, including those thought to be associated with 
protocol-specific procedures.  All SAEs must be collected that occur during the screening period 
and throughout the course of the study up to and including the End of Treatment Visit. The 
investigator should report any SAE occurring after these time periods that is believed to be 
related to study drug or protocol-specific procedures.   


 
 
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All SAEs should be followed to resolution or stabilization. 
An SAE report should be completed for any event where doubt exists regarding its status of 
seriousness.   
If the Investigator believes that an SAE is not related to the study drug but is potentially related 
to the conditions of the study (such as a withdrawal of previous therapy or a complication related 
to study procedure), the relationship should be specified in the narrative section of the SAE 
Report 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 
  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:  
• 
 
If a form is unable to be submitted within 24 hours, the SAE may be reported by telephone via 
the Safety Hotline Number: 
• 
 
CCI
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If only limited information is initially available, follow-up reports are required. If an ongoing 
SAE changes in its intensity or relationship to study drug or if new information becomes 
available, a follow-up SAE report should be sent within 24 hours of the Investigator becoming 
aware of the updated information using the same procedure used for the transmission of the 
initial SAE and the same event term should be used. 
The minimum information required for an initial SAE report is: 
• Sender of report (Site number, Investigator name) 
• Subject identification (subject number) 
• Protocol number 
• SAE term (if an SAE is being reported) 
8.1.3 
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 
BHV-3500 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.  
8.1.3.1 
Dose misadministration and Aptar UDS malfunction  
All occurrences of dose misadministration or Aptar UDS malfunction should be communicated 
to Biohaven or a specified designee as soon as possible.  
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 
 
PVG immediately via telephone within 24 hours and in accordance with SAE reporting 
procedures as described in Section 8.1.2.  
CCI


 
 
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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) 
 
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 treatment 
visit.  


 
 
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8.2.2 
Laboratory Test Abnormalities 
The following laboratory test abnormalities should be captured on the non-serious AE CRF page 
or SAE Report Form (paper or electronic) as appropriate: 
1. Any laboratory test result that is clinically significant or meets the definition of an SAE; 
2. Any laboratory abnormality that required the 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 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 95% of the 400 subjects randomized to each arm treat a migraine on study, there will be 
roughly 380 mITT subjects in each arm. If the true response rates for pain freedom at 2 hours are 
22% and 12% in the BHV-35000 and placebo arms, then a chi-square test, at alpha=0.0167, will 
have 90% power. Similarly, if the true response rates for MBS freedom at 2 hours are 45% and 
32% in the BHV-3500 and placebo arms, then a chi-square test, at alpha=0.0167, will have 90% 
power.  Under the assumption that the endpoints are independent, the power for both endpoints 
jointly is roughly 80%. 
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 (BHV-3500 or placebo). 
• Treated subjects: Enrolled subjects who take study therapy (BHV-3500 or placebo). 
• Modified Intent to Treat (mITT) subjects: randomized subjects that take study therapy, have 
a migraine of moderate or severe baseline pain 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) 
Each of the three doses of BHV-3500 is tested for superiority against placebo, at a Bonferroni 
corrected  alpha=0.0167 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 for a dose, then the secondary endpoints are 
evaluated for that dose using a hierarchical gate-keeping procedure, with each test in the 
hierarchy conducted at alpha=0.0167.  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. 
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. 
9.5 
Interim Analysis 
There is a final analysis after the  database is locked.  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) and 
all applicable regulations, including the Federal Food, Drug and Cosmetic Act, U.S. applicable 
Code of Federal Regulations (title 21), any IRB/IEC requirements relative to clinical studies. The 
study will also be conducted in compliance with the recommendations laid down in the most 
recent version of the Declaration of Helsinki, 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., loss 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).  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 IRB/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 IRB/IEC favorable written approvals for the above-mentioned 
study documents. A properly executed written ICF shall be read, signed, and dated by each 
subject prior to entering the trial or prior to performing any study procedure. The original signed 
and dated ICF will be kept at the Investigator site and a copy will be given to the subject.  
In the event that the protocol is amended, the revised protocol must be approved by the IRB/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 IRB/IEC, prior to subsequently 
obtaining each subject’s consent.  


 
 
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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.  
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 eCRF 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.    


 
 
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The confidentiality of records that could identify subjects must be protected, respecting the 
privacy and confidentiality rules in accordance with the applicable regulatory requirement(s).  
The Investigator must retain a copy of the CRFs including records of changes and corrections.   
If EDC is being used, signatures will be obtained electronically and a copy of the electronic 
CRFs will be provided (or the data from the CRFs) for future reference.  
10.6 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 
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   


 
 
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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.  


 
 
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11 AMENDMENTS 
Protocol modifications, except those intended to reduce immediate risk to study subjects, may be 
made only by Biohaven. A protocol change intended to eliminate an apparent immediate hazard 
to subjects may be implemented immediately, provided the IRB/IEC is notified within 5 days. 
Any permanent change to the protocol must be handled as a protocol amendment. The written 
amendment must be submitted to the IRB/IEC and the investigator must await approval before 
implementing the changes. Biohaven will submit protocol amendments to the appropriate 
regulatory authorities for approval. 
If in the judgment of the IRB/IEC, the Investigator, and/or Biohaven, the amendment to the 
protocol substantially changes the study design and/or increases the potential risk to the subject 
and/or has an impact on the subject's involvement as a study participant, the currently approved 
written informed consent form will require similar modification. In such cases, informed consent 
will be renewed for subjects enrolled in the study before continued participation. 
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. 


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


 
 
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15 APPENDICES 
15.1 APPENDIX I – Names of Study Personnel 
 
Sponsor: 
Biohaven Pharmaceuticals, Inc.  
Refer to study reference manual for contact 
information 
Sponsor Medical Monitor: 
 
 
Clinical Research 
Organizations: 
  
Refer to contact list in Study Binder for contact 
information 
Central Laboratory: 
 
  
Refer to study manual for contact information 
Central ECG 
  
Refer to study manual for contact information 
eCOA 
 
Refer to study manual for contact information 
Pharmacovigilance Vendor 
 
Refer to SAE, Pregnancy Surveillance Forms and 
Study Binder for contact information.  
PPD
PPD
CCI
CCI
CCI
CCI
CCI


 
 
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15.2 APPENDIX II – 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/DrugInteracti
onsLabeling/ucm093664.htm#table3-2 
 
https://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/DrugInteracti
onsLabeling/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 
 
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Headache Classification Committee of the International Headache Society (IHS) The 
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Buse DC, Reed ML, Fanning KM, Kurth T, Lipton RB. Cardiovascular Events, 
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Durham PL, Dong PX, Belasco KT, et al. Neuronal expression and regulation of CGRP 
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Edvinsson L. The CGRP Pathway in Migraine as a Viable Target for Therapies. 
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Goadsby PJ, Edvinsson L. The trigeminovascular system and migraine: studies 
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Holland PR, Goadsby PJ. Targeted CGRP Small Molecule Antagonists for Acute 
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Calcitonin Gene-Regulated Peptide Receptor Antagonist (BHV-3500) Investigator’s 
Brochure v1.0: Biohaven Pharmaceuicals, Inc.; August 2018. 
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DT05055. BHV-3500 (BMS-742413) One Week Exploratory Intranasal Irritiation Study 
in Rats: Biohaven Pharmaceuticals, Inc; 2018. 


 
 
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14. 
1016-3803. BHV-3500: A 28-Day Subcutaneous Injection Toxicity Study Followed by a 
14-Day Recovery Period in Cynomolgus Monkeys: CiToxLAB North America;  October 30, 
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XT178113. In Vitro Evaluation of BHV-3500 as an Inhibitor of Human ABC and SLC 
Transporters: Sekisui Xenotech USA; 2018. 
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APA. Diagnostic and Statistical Manual of Mental Disorders, 5th Edition: DSM-5 5th 
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Sheehan DV, Alphs LD, Mao L, 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. Innovations in clinical neuroscience 2014;11:32-46. 
18. 
Sheehan DV, Giddens JM, Sheehan IS. Status Update on the Sheehan-Suicidality 
Tracking Scale (S-STS) 2014. Innovations in clinical neuroscience 2014;11:93-140. 
 

SAP_001.pdf: 
 
 
 
 
 
Biohaven Pharmaceuticals 
 
Protocol BHV3500-201 
 
BHV3500-201: Phase II/III: Double-Blind, Randomized, Placebo Controlled, 
Dose-Ranging Trial of BHV-3500 for the Acute Treatment of Migraine 
Statistical Analysis Plan 
 
 
Version 2.0 
Date: 15-November-2019 
 
 
 


 
 
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SIGNATURE PAGE 
 
Protocol Title: 
BHV3500-201: Phase II/III: Double-Blind, 
Randomized, Placebo Controlled, Dose-Ranging Trial 
of BHV-3500 for the Acute Treatment of Migraine 
Sponsor: 
Biohaven Pharmaceuticals, Inc. 
Protocol Number: 
BHV3500-201 
Document Version/Date: 
Version 2.0/15-November-2019 
Author: 
  
 
  
 Cytel Inc. 
Signature:____________________________________ 
Date:________________________________________ 
 
 
Sponsor Approval 
By signing this document, I acknowledge that I have read the document and approve of the 
planned statistical analyses described herein.  I agree that the planned statistical analyses are 
appropriate for this study, are in accordance with the study objectives, and are consistent with 
the statistical methodology described in the protocol, clinical development plan, and all 
applicable regulatory guidelines. 
I have discussed any questions I have regarding the contents of this document with the 
biostatistical author. 
I also understand that any subsequent changes to the planned statistical analyses, as described 
herein, may have a regulatory impact and/or result in timeline adjustments.  All changes to the 
planned analyses will be described in the clinical study report (CSR). 
Sponsor Signatories: 
 
 
 
 
Biohaven Pharmaceuticals 
Signature:____________________________________ 
Date:________________________________________ 
 
 
 Biohaven 
Pharmaceuticals  
Signature:____________________________________ 
Date:________________________________________ 
 
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD


 
 
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TABLE OF CONTENTS 
 
SIGNATURE PAGE ......................................................................................................... 2 
TABLE OF CONTENTS .................................................................................................. 3 
ABBREVIATIONS ............................................................................................................ 6 
REVISION HISTORY ...................................................................................................... 8 
1 
INTRODUCTION AND OBJECTIVES OF ANALYSIS .................................... 10 
1.1 
INTRODUCTION ............................................................................................... 10 
1.2 
STUDY OBJECTIVES ....................................................................................... 10 
1.2.1 
PRIMARY OBJECTIVES ........................................................................... 10 
1.2.2 
SECONDARY OBJECTIVES ..................................................................... 10 
1.2.3 
EXPLORATORY OBJECTIVES ................................................................ 11 
2 
STUDY DESIGN ...................................................................................................... 12 
2.1 
SYNOPSIS OF STUDY DESIGN ...................................................................... 12 
2.2 
RANDOMIZATION METHODOLOGY ......................................................... 12 
2.3 
OBJECTIVE ESTIMANDS ............................................................................... 13 
2.3.1 
PRIMARY OBJECTIVE ESTIMANDS ..................................................... 14 
2.3.2 
SECONDARY OBJECTIVE ESTIMANDS ............................................... 14 
2.3.3 
EXPLORATORY OBJECTIVE ESTIMANDS ......................................... 15 
3 
POPULATION SAMPLES FOR ANALYSES ...................................................... 17 
4 
SCHEDULE OF ANALYSES ................................................................................. 17 
5 
SAMPLE SIZE AND POWER ............................................................................... 17 
6 
STATISTICAL METHODS .................................................................................... 18 
6.1 
GENERAL METHODS ...................................................................................... 18 
6.1.1 
MISSING DATA ........................................................................................... 18 
6.1.2 
TYPE I ERROR CONTROL ....................................................................... 19 
6.1.3 
SUBGROUPS ................................................................................................. 19 
6.2 
STUDY POPULATION ...................................................................................... 20 
6.2.1 
POPULATION SAMPLES FOR ANALYSES AND RANDOMIZATION 
 ......................................................................................................................... 20 
6.2.2 
SUBJECT DISPOSITION ............................................................................ 21 
6.2.3 
PROTOCOL DEVIATIONS ........................................................................ 22 
6.2.4 
PRE-TREATMENT CHARACTERISTICS .............................................. 22 
6.2.4.1 
DEMOGRAPHICS AND BASELINE CHARACTERISTICS ........... 23 
6.2.4.2 
MEDICAL HISTORY ............................................................................ 24 
6.2.4.3 
MIGRAINE HISTORY .......................................................................... 24 
6.2.4.4 
CARDIAC AND OTHER RISK FACTORS ........................................ 25 
6.2.4.5 
PRIOR AND CURRENT TRIPTAN RESPONSE ............................... 25 
6.2.4.6 
MIGRAINE CHARACTERISTICS AT ON-STUDY MIGRAINE 
ATTACK ONSET ................................................................................... 26 
6.2.5 
EXPOSURE ................................................................................................... 26 
6.2.5.1 
STUDY MEDICATION .......................................................................... 26 
6.2.5.2 
NON-STUDY MEDICATIONS ............................................................. 27 
6.3 
EFFICACY .......................................................................................................... 28 


 
 
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6.3.1 
PRINCIPAL ANALYSIS METHODS OF HANDLING MISSING 
DATA AND INTERCURRENT EVENTS .................................................. 29 
6.3.2 
MISSING EFFICACY DATA ...................................................................... 29 
6.3.3 
PRIMARY EFFICACY ENDPOINTS ........................................................ 30 
6.3.3.1 
PAIN FREEDOM AT 2 HOURS POST-DOSE ................................... 30 
6.3.3.2 
MBS FREEDOM AT 2 HOURS POST-DOSE ..................................... 32 
6.3.4 
SECONDARY EFFICACY ENDPOINTS .................................................. 33 
6.3.4.1 
PAIN RELIEF AT 30 MINUTES, 60 MINUTES AND AT 2 HOURS 
POST-DOSE ............................................................................................ 34 
6.3.4.2 
RETURN TO NORMAL FUNCTION AT 30 MINUTES, 60 
MINUTES, AND 2 HOURS POST-DOSE ............................................ 34 
6.3.4.3 
PROBABILITY OF RESCUE MEDICATION USE WITHIN 24 
HOURS POST-DOSE ............................................................................. 35 
6.3.4.4 
FREEDOM FROM PHOTOPHOBIA, PHONOPHOBIA OR 
NAUSEA AT 2 HOURS POST-DOSE .................................................. 35 
6.3.4.5 
SUSTAINED PAIN RELIEF FROM 2 TO 24 HOURS POST-DOSE 
 ................................................................................................................... 36 
6.3.4.6 
SUSTAINED PAIN RELIEF FROM 2 TO 48 HOURS ...................... 37 
6.3.4.7 
SUSTAINED PAIN FREEDOM FROM 2 TO 24 HOURS ................. 38 
6.3.4.8 
SUSTAINED PAIN FREEDOM FROM 2 TO 48 HOURS ................. 39 
6.3.4.9 
PAIN RELAPSE FROM 2 TO 48 HOURS POST-DOSE ................... 41 
6.3.4.10 
OVERALL SUMMARY OF PRIMARY AND SECONDARY 
ENDPOINTS ............................................................................................ 42 
6.3.5 
EXPLORATORY EFFICACY ENDPOINTS ............................................ 42 
6.3.5.1 
RETURN TO NORMAL FUNCTION AT 24 HOURS ....................... 42 
6.3.5.2 
EFFICACY AT EACH POST-DOSE TIME POINT .......................... 43 
6.4 
PHARMACOKINETICS .................................................................................... 47 
6.5 
SAFETY ............................................................................................................... 47 
6.5.1 
ADVERSE E VENTS .................................................................................... 47 
6.5.1.1 
AE OVERVIEW ...................................................................................... 48 
6.5.1.2 
PRE-TREATMENT AES BY SOC AND PT ........................................ 48 
6.5.1.3 
ON-TREATMENT AES BY SOC AND PT .......................................... 48 
6.5.2 
LABORATORY TESTS ............................................................................... 48 
6.5.2.1 
LABORATORY TEST ABNORMALITIES ........................................ 49 
6.5.2.2 
LIVER FUNCTION TEST ELEVATIONS .......................................... 50 
6.5.2.3 
LABORATORY TEST CHANGE FROM BASELINE ...................... 51 
6.5.3 
VITAL SIGNS AND PHYSICAL MEASUREMENTS ............................. 52 
6.5.3.1 
VITAL SIGN AND PHYSICAL MEASUREMENT CHANGE 
FROM BASELINE .................................................................................. 52 
6.5.3.2 
VITAL SIGN AND PHYSICAL MEASUREMENT 
ABNORMALITIES ................................................................................. 52 
6.5.4 
ELECTROCARDIOGRAM ......................................................................... 52 
6.5.4.1 
ECG CHANGE FROM BASELINE ..................................................... 52 
6.5.4.2 
ECG INTERPRETATION SHIFT FROM BASELINE TO WORST 
CATEGORY ............................................................................................ 52 
6.5.4.3 
ECG ABNORMALITIES ....................................................................... 53 


 
 
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6.5.5 
SHEEHAN-SUICIDALITY TRACKING SCALE (S-STS) ...................... 53 
6.5.6 
NASAL INSPECTION .................................................................................. 53 
6.5.6.1 
NASAL INSPECTION ABNORMALITIES ........................................ 54 
6.5.6.2 
NASAL INSPECTION EVIDENCE SHIFT FROM BASELINE ...... 54 
6.5.7 
SAFETY NARRATIVES .............................................................................. 54 
6.5.8 
OUTCOMES RESEARCH ........................................................................... 54 
6.5.8.1 
POM .......................................................................................................... 54 
6.5.8.2 
MQOL ...................................................................................................... 55 
7 
CONVENTIONS ...................................................................................................... 56 
7.1 
GENERAL ........................................................................................................... 56 
7.1.1 
OUTPUT LAYOUT ...................................................................................... 56 
7.1.1.1 
TIME-TO-EVENT TABLES AND PLOTS .......................................... 56 
7.1.1.2 
BY-SUBJECT LISTINGS ...................................................................... 57 
7.1.2 
DESCRIPTIVE STATISTICS ..................................................................... 57 
7.1.3 
COUNTING RULES ..................................................................................... 58 
7.2 
SUBGROUPS ....................................................................................................... 58 
7.3 
DERIVED DATES .............................................................................................. 59 
7.4 
ANALYSIS PERIODS ........................................................................................ 60 
7.5 
ANALYSIS VISIT WINDOWS ......................................................................... 60 
7.6 
DOMAIN-SPECIFIC DERIVATIONS ............................................................. 61 
7.6.1 
ADVERSE EVENTS ..................................................................................... 61 
7.6.1.1 
IMPUTED AE START DATES ............................................................. 61 
7.6.1.2 
AE FREQUENCY TABLE ..................................................................... 62 
7.6.1.3 
TREATMENT-EMERGENT AES ........................................................ 63 
7.6.1.4 
AES OF SPECIAL INTEREST ............................................................. 63 
7.6.2 
NON-STUDY MEDICATIONS ................................................................... 64 
7.6.2.1 
IMPUTED NON-STUDY MEDICATION START DATES ............... 64 
7.6.2.2 
IMPUTED NON-STUDY MEDICATION STOP DATES .................. 65 
7.6.2.3 
NON-STUDY MEDICATION TYPES .................................................. 66 
7.6.3 
EDIARY DATA ............................................................................................. 66 
7.6.3.1 
STUDY MEDICATION .......................................................................... 66 
7.6.3.2 
MIGRAINE CHARACTERISTICS ...................................................... 67 
 
LIST OF TABLES 
 
Table 1: 
Co-Primary Objective Estimands .......................................................... 14 
Table 2: 
Secondary Objective Estimands ............................................................. 15 
Table 3: 
Exploratory Objective Estimands .......................................................... 16 
Table 4: 
Analysis Windows for Safety and Outcomes Research Parameters ... 61 
Table 5: 
eDiary Automated Efficacy Analysis Windows .................................... 68 
 
LIST OF FIGURES 
 
Figure 1: 
Study Schematic ....................................................................................... 13 
 
 


 
 
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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 
BUN 
Blood urine nitrogen  
CI 
Confidence interval 
CPK 
Creatinine phosphokinase 
CMH 
Cochran-Mantel-Haenszel 
CRF 
Case report form 
CSR 
Clinical study report 
CTCAE 
Common Technical Criteria for Adverse Events 
CV 
Cardiovascular  
DAIDS 
Division of Acquired Immune Deficiency Syndrome 
ECG 
Electrocardiogram 
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  
MBS 
Most bothersome symptom 
MDRD  
Modification of diet in renal disease 
MedDRA 
Medical Dictionary for Regulatory Activities 
mITT 
Modified Intent-to-Treat 
MQoLQ 
Migraine Specific Quality of Life Questionnaire 
NC=F 
Non-Completer = Failure 


 
 
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Abbreviation 
Definition 
NC1=F 
Non-Completer With Missing Data at More Than 1 Time Point = 
Failure 
NC=M 
Non-Completer = Missing 
NRS 
Numeric rating scale 
PID 
Patient identifier 
PoM 
Preference of medication 
PT 
Preferred term 
RM=F 
Rescue Medication = Failure 
S-STS 
Sheehan-Suicidality Tracking Scale 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SD 
Standard deviation 
SE 
Standard error 
SDS 
Sheehan Disability Scale 
SOC 
System organ class 
TBL 
Total bilirubin 
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 a revision history section. 
• 
Abbreviations: Removed ATC.  
• 
Section 6.2.3: Modified the list of significant protocol deviations.  
• 
Section 6.2.4.1: Added childbearing potential for females to the table of demographics and 
baseline characteristics. 
• 
Section 6.2.4.3: Specified that if the last migraine date is missing, then it will be imputed with 
the informed consent date. 
• 
Section 6.2.4.6: Modified contents of the 3 x 3 cross-tabulation of historical MBS versus 
MBS at on-study migraine attack onset. 
• 
Section 6.2.5.2: Replaced ATC with therapeutic class. Specified that rescue medication dates 
will not be imputed, and that rescue medication times will not be imputed, unless specified 
otherwise. 
• 
Section 6.3: Changed “95%” to “98.3” and “risk” to “percentage” throughout section. 
Specified that treatment comparisons of binary endpoints will be stratified by prophylactic 
migraine medication use at randomization except within subgroups. 
• 
Section 6.3.3.1: Added a table of pain freedom outcomes by subgroups. Removed “stratified” 
from overall percentages by treatment group. Specified that the principal analysis will be 
repeated unstratified for each subgroup level. 
• 
Section 6.3.3.2: Added a table of MBS freedom outcomes by subgroups. Specified that the 
principal analysis will be repeated unstratified for each subgroup level. 
• 
Section 6.3.4.3: Specified that analyses will be based on evaluable mITT subjects, i.e., mITT 
subjects with rescue medication start date on or before the study drug start date + 1 day and 
missing rescue medication start time will be excluded. 
• 
Section 6.3.4.5 through 6.3.4.8, 6.3.5.2: Specified that subjects who meet more than 1 failure 
criterion will be classified according to the first failure criterion met; in case of ties, the first 
failure subcategory that is met in the specified hierarchy for an endpoint will be chosen. 
• 
Section 6.3.4.9: Specified that subjects who meet more than 1 relapse criterion will be 
classified according to the first relapse criterion met; in case of ties, the first relapse 
subcategory that is met in the specified hierarchy will be chosen. 
• 
Section 6.3.4.10: Removed “stratified” from overall percentages by treatment group. 
• 
Section 6.3.5.2: Added a KM table, KM plot and time-to-event distribution table for the 
following endpoints: pain freedom through 4 hours post-dose; MBS freedom through 8 hours 
post-dose for subjects with MBS reported at on-study migraine attack onset. Modified time-
to-event algorithm to include imputed rescue medication start date/time. 
• 
Section 6.5.2: Specified that LDL cholesterol and triglycerides will be assessed by fasting 
status rather than by 8-hour fasting status. Specified that the by-subject listing of LFT values 
and ratios to ULN will display all results over time for enrolled subjects with select LFT 
elevations (ALT or AST > 3 x ULN; ALP or TBL > 2 x ULN) at any time point. 
• 
Section 6.5.1.3: Removed the table of AEs leading to death. 
• 
Section 7.1.1.1: Specified that CI levels will be 98.3% for efficacy endpoints and 95% for all 
other endpoints. 


 
 
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Version 
Description of Change 
• 
Section 7.3: Modified the definition of study drug start date/time to also use data from the 
eDiary Study Medication Intake Report. Added imputed rescue medication start date/time, 
and specified that it will be used only for time-to-event efficacy analyses in Section 6.3.5.2, 
and not for time to rescue medication use analyses in Section 6.3.4.3. 
• 
Section 7.6.3.1: Specified that subjects who took study medication without using the eDiary 
will have the study medication date and time reported by the site on the eDiary Study 
Medication Intake Report. 
 
 


 
 
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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 BHV3500-201: Phase II/III: Double-Blind, Randomized, Placebo Controlled, Dose-
Ranging Trial of BHV-3500 for the Acute Treatment of Migraine. 
This SAP is based on the BHV3500-201, V4.0, protocol dated 08-August-2019. 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 BHV-3500 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 2 hours post dose, while 
identifying an optimal dose to support the Phase 3 clinical trials. 
1.2.2 
Secondary Objectives 
The secondary objectives are: 
• To evaluate BHV-3500 compared to placebo on pain relief at 2 hours post-dose.  
• To evaluate the effect of BHV-3500 relative to placebo on the patient’s ability to function 
normally at 2 hours post-dose according to the Functional Disability scale.  
• To evaluate BHV-3500 compared to placebo on the probability of requiring rescue 
medication within 24 hours of initial treatment.  
• To evaluate BHV-3500 compared to placebo on freedom from photophobia at 2 hours post-
dose.  
• To evaluate BHV-3500 compared to placebo on freedom from phonophobia at 2 hours post-
dose.  
• To evaluate BHV-3500 compared to placebo on pain relief at 60 minutes post-dose.  
• To evaluate the effect of BHV-3500 relative to placebo on the patient’s ability to function 
normally at 60 minutes post-dose according to the Functional Disability scale.  
• To evaluate BHV-3500 compared to placebo on pain relief at 30 minutes post-dose.  
• To evaluate the effect of BHV-3500 relative to placebo on the patient’s ability to function 
normally at 30 minutes post-dose according to the Functional Disability scale.  


 
 
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• To evaluate BHV-3500 compared to placebo on sustained pain relief from 2 to 24 hours 
post-dose.  
• To evaluate BHV-3500 compared to placebo on sustained pain freedom from 2 to 24 hours 
post-dose.  
• To evaluate BHV-3500 compared to placebo on sustained pain relief from 2 to 48 hours 
post-dose. 
• To evaluate BHV-3500 compared to placebo on sustained pain freedom from 2 to 48 hours 
post-dose.  
• To evaluate BHV-3500 compared to placebo on freedom from nausea at 2 hours post-dose.  
• To evaluate BHV-3500 compared to placebo for the incidence of pain relapse from 2 to 48 
hours post-dose. 
1.2.3 
Exploratory Objectives 
The exploratory objectives are: 
• To evaluate the effect of BHV-3500 relative to placebo on the patient’s ability to function 
normally at 24 hours post dose according to the Functional Disability scale.  
• To evaluate the effect of BHV-3500 relative to placebo on the Migraine Preference of 
Medication (PoM).  
• To evaluate BHV-3500 relative to placebo for pain freedom at all scheduled time points post 
dose.  
• To evaluate BHV-3500 relative to placebo for pain relief at all scheduled time points post 
dose.  
• To evaluate BHV-3500 relative to placebo for freedom from MBS at all scheduled time 
points post dose.  
• To evaluate BHV-3500 relative to placebo for freedom from functional disability at all 
scheduled time points post dose.  
• To evaluate the effect of BHV-3500 relative to placebo on the Migraine Quality of Life 
Questionnaire (MQoLQ).  
• To evaluate the tolerability and safety of BHV-3500 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 BHV-3500 relative to placebo on the Sheehan Suicidality Tracking 
Scale (S-STS). 


 
 
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2 STUDY DESIGN 
2.1 
Synopsis of Study Design 
BHV3500-201 is a Phase II, double-blind, randomized, multicenter, outpatient evaluation of the 
safety and efficacy of BHV-3500 as compared to placebo in the treatment of moderate or severe 
migraine. 
The design of the study is illustrated in Figure 1.  As shown in the figure, after providing 
informed consent, subjects will first participate in the screening phase (3-28 day period) to 
determine eligibility for the study. Approximately 1,900 subjects will be screened to randomize 
approximately 1,600 subjects to study medication (BHV-3500 5 mg, BHV-3500 10 mg, BHV-
3500 20 mg, or matching placebo). 
After randomization, study medication will be dispensed to subjects to take home for up to 45 
days. Subjects will be dispensed one Aptar Unit Dose System (UDS) liquid spray device 
containing a single dose of study medication BHV-3500 or a matching placebo. The 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 also 
record efficacy data and outcomes research measures in their eDiary.   
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 45 days after randomization, 
they still are required to complete all EOT visit procedures and return unused study medication 
and eDiary to the investigational site. 
2.2 
Randomization Methodology 
Per protocol, subjects in this study may be randomized only once.  
The study will randomize approximately 1,600 subjects. The subjects will be randomized in a 
1:1:1:1 ratio across 4 treatment groups (BHV-3500 5 mg, BHV-3500 10 mg, BHV-3500 20 mg, 
or placebo); see Figure 1. The randomization will be stratified by prophylactic migraine 
medication use (yes or no).  
 
 


 
 
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Figure 1: 
Study Schematic 
 
 
2.3 
Objective Estimands 
An estimand is the target of estimation to address the scientific question of interest posed by a 
study objective. The four attributes of an estimand include the population of interest, endpoint 
of interest, specification of how intercurrent events are reflected in the scientific question of 
interest, and the population-level summary for the endpoint. 
For all objectives, the population of interest is defined through appropriate inclusion/exclusion 
criteria to reflect the targeted patient population for approval. Refer to the protocol for 
inclusion/exclusion criteria. 
Intercurrent events are those that occur after treatment initiation and either preclude observation 
of the endpoint or affect its interpretation. Rescue medication taken at or before the time point 
of interest defining the endpoint will be considered an intercurrent event. This event is relevant 
to all efficacy endpoints, except the secondary endpoint of rescue medication use within 24 
hours post-dose. 
For efficacy objectives, intercurrent events will be handled with a composite strategy, i.e., the 
occurrence of the intercurrent event will be integrated as a component of the endpoint. See 
Section 6.3.1 for additional details. 


 
 
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For safety and outcomes research objectives, intercurrent events will be handled with a 
treatment policy strategy, i.e., the occurrence of the intercurrent event will be considered 
irrelevant, such that all observed values of the endpoint of interest will be used regardless of 
rescue medication use. 
2.3.1 
Primary Objective Estimands 
Both co-primary objectives have efficacy endpoints. The estimands corresponding to the co-
primary objectives are shown in Table 1.  
For each objective, intercurrent events will be handled with a composite strategy described in 
Section 2.3. The population summary is the difference in the percentage of subjects achieving 
the endpoint between each BHV-3500 treatment group (5 mg, 10 mg, 20 mg) and the Placebo 
treatment group.  
Table 1: 
Co-Primary Objective Estimands 
Objective 
Pain Freedom at 2 hours post-dose 
Endpoint 
Percentage of subjects with no pain at 2 hours post-dose and no intervening rescue 
medication taken at or before 2 hours post-dose 
Objective 
MBS Freedom at 2 hours post-dose 
Endpoint 
Percentage of subjects with (1) MBS reported at on-study migraine onset before taking 
study drug, (2) MBS absent at 2 hours post-dose, (3) and no intervening rescue 
medication taken at or before 2 hours post-dose 
2.3.2 
Secondary Objective Estimands 
All secondary objectives have efficacy endpoints. The estimands corresponding to the 
secondary objectives are shown in Table 2.  
For each objective, intercurrent events are handled with a composite strategy described in 
Section 2.3, unless specified otherwise. The population summary is the difference in the 
percentage of subjects achieving the endpoint between each BHV-3500 treatment group (5 mg, 
10 mg, 20 mg) and the Placebo treatment group.  


 
 
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Table 2: 
Secondary Objective Estimands 
Objective 
Pain Relief at 30 minutes, 60 minutes, and 2 hours post-dose 
Endpoint 
Percentage of subjects with mild or no pain at the specified time point and no 
intervening rescue medication taken at or before the specified time point 
Objective 
Return to Normal Function at 30 minutes, 60 minutes, and 2 hours post-dose 
Endpoint 
Percentage of subjects with normal function at the specified time point and no 
intervening rescue medication taken at or before the specified time point; evaluated 
for subjects with functional disability at on-study migraine attack onset 
Objective 
Probability of Rescue Medication within 24 hours post-dose 
Endpoint 
Percentage of subjects taking rescue medication within 24 hours post-dose 
Intercurrent Events 
Not applicable (intercurrent event is the endpoint) 
Objective 
Photophobia Freedom at 2 hours post-dose 
Endpoint 
Percentage of subjects with photophobia absent at 2 hours post-dose and no 
intervening rescue medication taken at or before 2 hours post-dose; evaluated for 
subjects with photophobia present at on-study migraine attack onset 
Objective 
Phonophobia Freedom at 2 hours post-dose 
Endpoint 
Percentage of subjects with phonophobia absent at 2 hours post-dose and no 
intervening rescue medication taken at or before 2 hours post-dose; evaluated for 
subjects with phonophobia present at on-study migraine attack onset 
Objective 
Sustained Pain Relief  from 2 to 24 hours post-dose, and 2 to 48 hours post-dose 
Endpoint 
Percentage of subjects with (1) mild or no pain from the start to the end of the time 
period of interest, (2) missing pain data at £ 1 time point from 3 to 8 hours post-
dose, and (3) no intervening rescue medication taken at or before the end of the time 
period of interest  
Objective 
Sustained Pain Freedom from 2 to 24 hours post-dose, and from 2 to 48 hours 
post-dose 
Endpoint 
Percentage of subjects with (1) no pain from the start to the end of the time period of 
interest, (2) missing pain data at £ 1 time point from 3 to 8 hours post-dose, and (3) 
no intervening rescue medication taken at or before the end of the time period of 
interest 
Objective 
Nausea Freedom at 2 hours post-dose 
Endpoint 
Percentage of subjects with nausea absent at 2 hours post-dose and no intervening 
rescue medication taken at or before 2 hours post-dose; evaluated for subjects with 
nausea present at on-study migraine attack onset 
Objective 
Pain Relapse from 2 to 48 hours post-dose 
Endpoint 
Percentage of subjects with (1) mild, moderate, or severe pain at any time point after 
2 hours post-dose (2) missing pain data at £ 1 time point after 2 hours post-dose, and 
(3) no intervening rescue medication taken at or before 48 hours post-dose; 
evaluated for subjects with pain freedom at 2 hours post-dose 
2.3.3 
Exploratory Objective Estimands 
Exploratory objectives have efficacy, safety, and outcomes research endpoints. The estimands 
corresponding to the exploratory objectives are shown in Table 3. 


 
 
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Table 3: 
Exploratory Objective Estimands 
Objective 
Return to Normal Function at 24 hours post-dose – Efficacy 
Endpoint 
Percentage of subjects with normal function at 24 hours post-dose and no intervening 
rescue medication taken at or before 24 hours post-dose; evaluated for subjects with 
functional disability at on-study migraine attack onset 
Intercurrent Events 
Composite strategy: Intercurrent event captured in endpoint definition 
Pop. Summary 
Percentage of subjects by treatment group  
Objective 
Preference of Medication (PoM) – Outcomes Research 
Endpoint 
Percentage of subjects who prefer study medication to previous migraine medications; 
evaluated for those with PoM data 
Intercurrent Events 
Treatment policy strategy: No accounting for intercurrent events 
Pop. Summary 
Percentage of subjects by treatment group  
Objectives 
Pain Freedom at all time points post-dose – Efficacy 
Population 
mITT 
Endpoint 
Percentage of subjects with no pain at each time point post-dose and no intervening 
rescue medication taken at or before the time point 
Intercurrent Events 
Composite strategy: Intercurrent event captured in endpoint definition 
Pop. Summary 
Percentage of subjects by treatment group 
Objectives 
Pain Relief at all time points post-dose – Efficacy 
Endpoint 
Percentage of subjects with mild or no pain at each time point post-dose and no 
intervening rescue medication taken at or before the time point 
Intercurrent Events 
Composite strategy: Intercurrent event captured in endpoint definition 
Pop. Summary 
Percentage of subjects by treatment group 
Objectives 
MBS Freedom at all time points post-dose – Efficacy 
Endpoint 
Percentage of subjects with (1) MBS absent at each time point post-dose, (2) MBS 
reported at on-study migraine attack onset before study drug, and (3) no intervening 
rescue medication taken at or before the time point 
Intercurrent Events 
Composite strategy: Intercurrent event captured in endpoint definition 
Pop. Summary 
Percentage of subjects by treatment group 
Objectives 
Return to Normal Function at all time points post-dose – Efficacy 
Endpoint 
Percentage of subjects with normal function at each time point post-dose and no 
intervening rescue medication taken at or before the time point; evaluated for subjects 
with functional disability at on-study migraine attack onset 
Intercurrent Events 
Composite strategy: Intercurrent event captured in endpoint definition 
Pop. Summary 
Percentage of subjects by treatment group 
Objectives 
Migraine Quality of Life Questionnaire (MQoL) – Outcomes Research 
Endpoint 
Change from baseline in the total score at end of treatment visit 
Intercurrent Events 
Treatment policy strategy: No accounting for intercurrent events 
Pop. Summary 
Mean change from baseline in total score by treatment group  
Objective 
Safety and Tolerability 
Endpoint 
Frequency of adverse events (AEs) of at least moderate severity, serious adverse 
events (SAEs), and clinically relevant laboratory test abnormalities  
Intercurrent Events 
Treatment policy strategy: No accounting for intercurrent events 
Pop. Summary 
Number and percentage of subjects with safety events and findings 
Objective 
Sheehan Suicidality Tracking Scale – Safety 
Endpoints 
Change from baseline in the total score at end of treatment visit 
Intercurrent Events 
Treatment policy strategy: No accounting for intercurrent events 
Pop. Summary 
Percentage of subjects in each change from baseline category (< -1, -1, no change, 1, > 
1) by treatment group 


 
 
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3 POPULATION SAMPLES FOR ANALYSES 
The following population samples for analyses (“analysis sets”) 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, i.e., non-missing informed consent date. 
• Randomized subjects: Enrolled subjects who receive a randomization treatment assignment 
from the interactive web response system (IWRS), i.e., non-missing IWRS randomization 
date. 
• Treated subjects: Enrolled subjects who take study therapy (BHV-3500 or placebo), i.e., 
non-missing study drug start date/time. 
• Modified Intent-to-Treat (mITT) subjects: Treated subjects who are randomized only once, 
have moderate to severe pain at on-study migraine attack onset, and have non-missing, post-
baseline efficacy data (i.e., non-missing pain level, phonophobia status, photophobia status, 
nausea status, or functional disability level with finding date/time from the eDiary Post-Dose 
Migraine Report at any time point after the study drug start/time).  
See Section 7.3 for derived dates. 
4 SCHEDULE OF ANALYSES  
All analyses described in this SAP will be performed after the last subject completes the end of 
treatment visit or discontinues from the study, and the database has been locked. 
5 SAMPLE SIZE AND POWER 
If 95% of the 400 subjects randomized to each treatment group treat a migraine on study, then 
there will be roughly 380 mITT subjects in each treatment group.  
If the true response rates for pain freedom at 2 hours are 22% and 12% in the BHV-3500 and 
placebo groups, then a chi-square test at alpha=0.0167 will have 90% power. Similarly, if the 
true response rates for MBS freedom at 2 hours are 45% and 32% in the BHV-3500 and placebo 
groups, then a chi-square test at alpha=0.0167 will have 90% power. Under the assumption that 
the endpoints are independent, the power for both endpoints jointly is roughly 80%. 


 
 
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6 STATISTICAL METHODS 
Tables will present results by treatment group (i.e., BHV-3500 5 mg, BHV-3500 10 mg, BHV-
3500 20 mg, Placebo) and All BHV-3500 with the following exceptions: 
• Results for enrolled subjects will be presented only by overall, without treatment group and 
All BHV-3500. 
• Results for study population parameters (see Section 6.2) and pre-treatment safety will 
include overall, unless specified otherwise. 
• Efficacy results for mITT subjects will be presented only by treatment group, without All 
BHV-3500 and overall. 
The “All BHV-3500” treatment group will consist of subjects pooled across the three BHV-
3500 treatment groups. Because this group is intended mainly to support safety, it will be 
included only in tables for the population samples of randomized subjects and treated subjects. 
The population sample of treated subjects will be assessed by as-treated treatment group, i.e., by 
the treatment actually received, unless specified otherwise. Otherwise, all other population 
samples (i.e., randomized, mITT) will be assessed by as-randomized treatment group. 
All statistical analyses will be performed using SAS statistical software (Version 9.4 or higher).  
Medical history and AEs will be coded using Medical Dictionary for Regulatory Activities 
(MedDRA). Non-study medications will be coded using World Health Organization Drug 
Dictionary (WHO-DD). Refer to the latest version of Biohaven Dataset Guidelines for 
dictionary versions. 
6.1 
General Methods 
6.1.1 
Missing Data 
For all binary efficacy endpoints, principal analyses will impute missing data as failure using 
methods described in Section 6.3.1 Sensitivity analysis of the co-primary endpoints will exclude 
subjects with missing data or impute missing data using different methods (see Section 6.3.3.1  
and Section 6.3.3.2). Sensitivity analysis of exploratory efficacy endpoints will exclude subjects 
with missing data (see Section 6.3.5.2). Otherwise, all analyses will be based on observed data 
without using imputation. 


 
 
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6.1.2 
Type I Error Control  
Type I error will be controlled by a hierarchical gate-keeping procedure. First, the family of two 
co-primary endpoints will be tested. In particular, each BHV-3500 treatment group will be 
tested for superiority against placebo at a Bonferroni corrected alpha=0.0167 level for both co-
primary endpoints. If both co-primary endpoint tests are determined to be significant for a BHV-
3500 treatment group versus placebo, then the secondary endpoints will be tested for that BHV-
3500 treatment group versus placebo using a hierarchical gate-keeping procedure, with each test 
in the hierarchy conducted at alpha=0.0167.  
The secondary endpoints will be tested in the order shown in Section 1.2.2. 
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. 
6.1.3 
Subgroups  
For mITT subjects, the following efficacy subgroups are of interest: 
• Age: < 40, ³ 40 years  
• Sex: female, male 
• Race: White, Black or African American, Other including Asian, Asian   
• Ethnicity: Hispanic or Latino, Not Hispanic or Latino 
• Baseline body mass index (BMI; kg/m2): < 25, ³ 25 to < 30, ³ 30 
• Aura at on-study migraine attack onset: yes, no 
• Historical number of moderate or severe migraine attacks per month: < median, ³ median, 
where the median is calculated overall across treatment groups combined for mITT subjects 
and rounded to an integer. 
• Triptan non-responder: yes, no (see Section 7.2). 
Subgroup analyses will be performed for the co-primary efficacy endpoints only. Efficacy 
subgroup tables will present results by subgroup level for subjects with non-missing subgroup 
level data, unless specified otherwise.  
Subgroup levels may be redefined or combined based on the availability of data. 


 
 
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6.2 
Study Population 
6.2.1 
Population Samples for Analyses and Randomization 
The number of subjects in each population sample for analysis described in Section 3 will be 
presented by as-randomized or as-treated treatment group, not randomized, and overall.  
Inclusion and exclusion from the mITT population will be summarized by treatment group and 
overall as the number and percentage of randomized subjects in the following categories: 
• Included in mITT population 
• Excluded from mITT population 
o Treated 
§ Pain level of mild, none, or not reported at on-study migraine attack onset 
§ Randomized more than once 
§ No post-baseline efficacy data (i.e., missing all of the following parameters from the 
eDiary Post-Dose Migraine Report after the study drug start date/time: pain level, 
nausea status, phonophobia status, photophobia status, and functional disability level) 
o Not treated. 
A by-subject listing of population samples for analyses will be provided for enrolled subjects. 
The listing will flag subjects in population samples, and include as-treated treatment group only 
if different from as-randomized treatment group. 
A by-subject listing of subjects excluded from the efficacy analysis will be provided for 
randomized subjects not in the mITT population sample, including the reason for exclusion (e.g., 
not treated). Treated subjects may have more than one exclusion reason. 
A by-subject administrative listing of randomization scheme and codes will be provided for all 
randomization numbers and block numbers, even those not assigned to a subject. This listing 
will be sorted by randomization number and block number, and will contain the randomization 
number, site-subject ID, treatment group, randomization stratum, and randomization date. 


 
 
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6.2.2 
Subject Disposition 
Subject disposition will be based on the Study Exit Status case report form (CRF), unless noted 
otherwise. 
Subject disposition from enrollment to randomization will be summarized for enrolled subjects 
by overall as the number and percentage of subjects in the following categories: 
• Randomized 
• Not randomized 
o Reasons for not completing the study, including not reported (e.g., adverse event, death). 
For subjects whose reason is screen failure due to inclusion/exclusion criteria, the 
reasons for screen failure will be also be included from the Inclusion/Exclusion Findings 
Summary CRF. 
Subject disposition from randomization to treatment will be summarized for randomized 
subjects by as-randomized treatment group, All BHV-3500, and overall as the number and 
percentage of subjects in the following categories: 
• Treated 
• Not treated 
o Reasons for not completing the study, including not reported. 
Subject disposition during the treatment phase will be summarized for treated subjects by as-
treated treatment group, All BHV-3500, and overall as the number and percentage of subjects in 
the following categories: 
• Completed study 
• Did not complete study 
o Reasons for not completing the study, including not reported. 
Subject disposition during the treatment phase will be summarized analogously for mITT 
subjects by as-randomized treatment group and overall to support efficacy. 
The following by-subject listings will be provided for enrolled subjects: (1) subject disposition, 
including the informed consent date, randomization date, study drug start date/time, last contact 
date, and reason for not completing the study, if applicable; (2) eligibility with inclusion and 
exclusion criteria for all subjects, not just those who have non-missing criteria. 
See Section 7.3 for derived dates. 


 
 
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6.2.3 
Protocol Deviations 
A significant protocol deviation is any deviation that could impact subject safety or the integrity 
of the trial, and are defined as follows: 
• Informed Consent 
• Inclusion Criteria (Specify criteria #) 
• Exclusion Criteria (Specify criteria #) 
• Concomitant Medication 
• SAE Reporting 
• Regulatory 
• Drug Storage/ Preparation 
• Drug Administration 
• Visit Schedule 
• ePRO Diary Noncompliance 
• Noncompliance (i.e. trends, missed assessments) 
The number and percentage of treated subjects with significant protocol deviations will be 
summarized by deviation type and by as-randomized treatment group, All BHV-3500, and 
overall. Deviation types will be presented in descending order of overall frequency. 
A by-subject listing of significant protocol deviations will be provided for enrolled subjects. 
6.2.4 
Pre-Treatment Characteristics 
Demographics and baseline characteristics, medical history, migraine history, cardiac and other 
risk factors, prior triptan response, and current triptan response, and migraine characteristics at 
on-study migraine attack onset will be summarized by as-randomized treatment group and 
overall for mITT subjects to support efficacy.  These endpoints will also be summarized for 
treated subjects by as-treated treatment group, All BHV-3500, and overall to support safety. 
In addition, demographics and baseline characteristics and migraine history will be summarized 
for (1) subjects enrolled but not randomized by overall only, and (2) subjects randomized but 
not in the mITT population by as-randomized treatment group, All BHV-3500, and overall. 
Tables will display a “not reported” category for missing categorical variables, if applicable.  


 
 
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Prophylactic migraine medication use at randomization (yes, no) will be summarized by as-
randomized treatment group, All BHV-3500, and overall for randomized subjects. 
Baseline is defined according to population as follows: 
• Enrolled subjects not randomized: Last non-missing value 
• Randomized subjects not treated: Last non-missing value at or before the IWRS 
randomization date/time 
• mITT subjects and treated subjects: Last non-missing value at or before the study drug start 
date/time (i.e., in the pre-treatment analysis period; see Sections 7.4 and 7.5). 
The following by-subject listings of pre-treatment characteristics will be provided: 
• Demographics, displaying informed consent date, birth date, age, sex, race, and ethnicity. 
All reported races will be displayed comma-concatenated alphabetically for subjects who 
reported multiple races (e.g., “Asian, White”). 
• Baseline characteristics (see Section 6.2.4.1). 
• Medical history, displaying start date, stop date or ongoing, system organ class (SOC), 
preferred term (PT), and verbatim term.   
• Migraine history split into general migraine history, migraine without aura symptom history, 
and migraine with aura symptom history. 
• Cardiac and other risk factors for subjects with any risk factor present. Only records with 
“yes” responses to questions about having risk factors will be displayed. 
• Prior triptan response, displaying triptan name, route, discontinuation reason, and symptom 
frequency. 
• Current triptan response, displaying triptan name, route, and frequency of symptom relief. 
6.2.4.1 
Demographics and Baseline Characteristics 
Demographics will include the following: 
• Age (years) at informed consent calculated as: (informed consent date - birth date + 1) / 
365.25 truncated to an integer, also categorized as < 40, ³ 40, < 65, ³ 65 
• Sex (male, female) 
• Childbearing potential, if female (yes, no) 
• Race (White, Black or African American, other including Asian [i.e., American Indian or 
Alaska Native, Asian, Native Hawaiian or Other Pacific Islander, multiple]). Subjects with 
more than one race are counted only in the “multiple” category. 
• Ethnicity (Hispanic or Latino, not Hispanic or Latino). 
Baseline characteristics will include the following: 


 
 
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• Height (cm) 
• Weight (kg) 
• BMI (kg/m2), also categorized as < 25, ≥ 25 to < 30, ≥ 30 
• Prophylactic migraine medication use at randomization (yes, no), i.e., IWRS randomization 
strata. 
6.2.4.2 
Medical History 
Medical history will be summarized by SOC and PT, and displayed in descending order of 
overall frequency within SOC and PT. 
6.2.4.3 
Migraine History 
Migraine history will include the following: 
• Age (years) at migraine onset  
• Time since last migraine (days) calculated as: (informed consent date – imputed last 
migraine date) for subjects with imputed last migraine date up to 1 year before informed 
consent date. Last migraine date will be imputed for partial dates using the same 
methodology as AE start dates, but using the informed consent date as the surrogate date 
(see Section 7.6.1.1 for AE start date imputation). If the last migraine date is missing, then it 
will be imputed with the informed consent date. 
• Number of moderate to severe migraines per month, also categorized as < median and ³ 
median (see Section 6.1.3)  
• Average duration of untreated migraine attacks (hours) 
• Primary migraine type (migraine without aura, migraine with aura) 
• Most bothersome symptom (i.e., nausea, phonophobia, or photophobia) 
• Migraine symptoms (i.e., headache attacks lasting 4-72 hours, unilateral location, pulsating 
quality, moderate or severe pain level, aggravation by or causing avoidance of routine 
physical activity, during headache: nausea and/or vomiting, during headache: photophobia 
and phonophobia) 
• History of migraine without aura (yes, no) 
• History of migraine with aura (yes, no). For subjects with a “yes” response to this question: 
o Aura symptoms (i.e., visual, sensory, speech and/or language, motor, brainstem, retinal) 
o Aura characteristics (i.e., at least one aura symptom spreads gradually over ≥ 5 min, 
and/or two or more symptoms occur in succession; each individual aura symptom lasts 
5-60 min; at least one aura symptom is unilateral; the aura is accompanied, or followed 
within 60 min, by headache) 


 
 
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o Migraine with aura type (i.e., migraine with typical aura, typical aura with headache, and 
typical aura without headache). 
6.2.4.4 
Cardiac and Other Risk Factors 
Cardiac and other risk factors will include the following: 
• Any risk factor 
• Ischemic coronary artery disease along with history of: angina pectoris; myocardial 
infarction; acute coronary syndrome; documented silent ischemia; percutaneous coronary 
intervention; history of stent placemen; coronary artery bypass surgery  
• Other significant underlying cardiovascular (CV) disease (specify) 
• Coronary artery vasospasm including Prinzmetal’s angina 
• Wolff-Parkinson-White syndrome or arrhythmias associated with other cardiac accessory 
conduction pathway disorders 
• Other arrhythmias (specify) 
• Stroke or transient ischemia attack  
• Peripheral vascular disease  
• Ischemic bowel disease 
• Uncontrolled hypertension 
• Triptan hypersensitivity (specify) 
• Treated for hypertension 
• Diabetes 
• Current smoker 
• Treated with statins 
• Family history of coronary artery disease. 
6.2.4.5 
Prior and Current Triptan Response 
Prior triptan response will include historically discontinued triptan, route (e.g., intravenous, 
nasal), and reason for discontinuation (e.g., took too long to relieve headache pain) 
subcategorized as most or all of the time, some of the time, rarely, or never. 
Current triptan response will include currently used triptan, route (e.g., intravenous, nasal), and 
durability of effect (e.g., freedom from pain within 2 hours, often satisfied with speed of pain 
relief) subcategorized as never, rarely, some of the time, most of the time, or all of the time. 


 
 
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6.2.4.6 
Migraine Characteristics at On-Study Migraine Attack Onset 
Characteristics at on-study migraine attack onset will include the following, and will be 
summarized only for mITT subjects: 
• Pain level (none, mild, moderate, severe) 
• MBS (nausea, phonophobia, photophobia) 
• Nausea status (present, absent) 
• Nausea level (none, mild, moderate, severe) 
• Phonophobia status (present, absent) 
• Phonophobia level (none, mild, moderate, severe) 
• Photophobia status (present, absent) 
• Photophobia level (none, mild, moderate, severe) 
• Functional disability level (normal, mildly impaired, severely impaired, requires bedrest) 
• Aura (yes, no). 
See Section 7.6.3.2 for additional details. 
An overall 3 x 3 cross-tabulation of the historical MBS (see Section 6.2.4.3) as rows, and the 
MBS at on-study migraine attack onset as columns will be presented for mITT subjects with 
non-missing paired MBS values. The number and percentage of subjects in the following row 
and column categories will be presented: nausea, phonophobia, photophobia, marginal total. In 
addition, the following statistics will be presented: asymmetric lambda value and 95% CI; 
symmetric lambda value and 95% CI; kappa coefficient value and 95% CI; and p-value from the 
chi-square test. 
6.2.5 
Exposure 
6.2.5.1 
Study Medication 
Subjects report study drug exposure in the eDiary, whereas sites report study drug 
accountability on the Study Drug Accountability CRF. 
eDiary study drug exposure will be summarized by as-randomized treatment group, All BHV-
3500, and overall for randomized subjects, and will include the number and percentage of 
subjects in the following categories: 
• Study drug taken (i.e., study drug start date/time not missing) 
o Study drug taken mistakenly before using eDiary (see Section 7.6.3.1) 
o Study drug actually received different from randomized treatment assignment (i.e., as-
treated treatment group not equal to as-randomized treatment group). 


 
 
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• Study drug not taken (i.e., study drug start date/time missing). 
Study drug accountability will be summarized by as-randomized treatment group, All BHV-
3500, and overall for randomized subjects, and will include the number and percentage of 
subjects in the following categories: 
• Kit dispensed and returned 
o Investigational product (IP) used 
o IP not used 
o IP use unknown or not reported (i.e., missing) 
• Kit dispensed and not returned. 
Two 2 x 2 cross-tabulations of eDiary study drug exposure and study drug accountability will be 
provided for randomized subjects by overall only. The number and percentage of subjects in 
each category will be summarized follows: 
• Categories for study drug exposure in rows are “study drug taken” and “study drug not 
taken”. Categories for study drug accountability in columns are “kit dispensed and returned” 
and “kit dispensed and not returned”. 
• Categories for study drug exposure in rows are “study drug taken” and “study drug not 
taken”. Categories for study drug accountability in columns are “IP used” and “IP not 
used/unknown/not reported”.  
A by-subject listing of eDiary study drug exposure and study drug accountability will be 
provided for randomized subjects. Subjects for whom the eDiary study drug exposure and study 
drug accountability categories (as per cross-tabulations) do not match will be flagged. 
6.2.5.2 
Non-Study Medications 
Non-study medications will be summarized by therapeutic class and preferred name in 
descending order of overall frequency. For each subject, multiple records of the same 
medication will be counted only once within each therapeutic class and preferred name. Imputed 
medication start and stop dates will be used to assign non-study medication type (prior or 
concomitant) to all non-study medications except rescue medications. See Section 7.6.2 for 
details on non-study medication start and stop date imputation, and definitions of non-study 
medication types. 
The following non-study medications will be summarized by as-treated treatment group and All 
BHV-3500 for treated subjects: 
• Prior medications, including results for overall treatment group: all; prophylactic migraine 
• Current medications, including results for overall treatment group: all; prophylactic migraine 
• Concomitant medications: all; prophylactic migraine 
• Rescue medications. 


 
 
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Rescue medications will also be summarized by as-randomized treatment group for mITT 
subjects to support efficacy.  
A by-subject listing of non-study medications will be provided by therapeutic class and 
preferred name for enrolled subjects. Prophylactic migraine and rescue medications will be 
identified, as well as medication type. 
A by-subject listing of rescue medications will be provided by therapeutic class and preferred 
name for treated subjects. 
Non-study medications will be identified from the Concomitant Medication and Rescue 
Medication CRFs.  
Prophylactic migraine medications are defined as those with a “yes” response to the question 
about prophylactic migraine medication on the Concomitant Medication CRF.  
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 
start date/time, or (2) medication date at or after study drug start date if the medication time or 
study drug start time is missing. Rescue medication dates will not be imputed. Rescue 
medication times will not be imputed, unless specified otherwise (see Section 6.3.5.2). 
6.3 
Efficacy 
Efficacy analyses will be based on mITT subjects by as-randomized treatment group only 
(excluding All BHV-3500 and overall).   
Treatment comparisons of binary endpoints will be stratified by prophylactic migraine 
medication use at randomization except within subgroups. If a single cell has sparse data (< 5 
subjects), then the analysis will be performed pooled across strata.   
All CIs will be two-sided. In treatment comparisons of binary endpoints, CIs will be based on a 
normal approximation to the binomial distribution using asymptotic standard error (ASE). In 
descriptive analyses of binary endpoints, exact Clopper-Pearson CIs will be used. Otherwise, 
CIs for continuous endpoints will be based on the normal distribution. 
A by-subject listing of eDiary migraine characteristics will be provided for randomized subjects 
that displays parameters listed in Section 7.6.3.2 at migraine attack onset and over time post-
dose. The rescue medication start date/time and time to rescue medication use in hours will also 
be included (see Sections 6.3.4.3 and 7.3); data collected on or after the rescue medication start 
date/time will be flagged. 
Post-dose efficacy data will be slotted into analysis windows automatically by the eDiary (see 
Section 7.6.3.2). All efficacy endpoints will be assessed using analysis windows, unless 
specified otherwise. 


 
 
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6.3.1 
Principal Analysis Methods of Handling Missing Data and Intercurrent 
Events 
Methods of handling missing data in principal analyses of binary efficacy endpoints are defined 
as follows: 
• Non-Completer = Failure (NC=F): Subjects with missing data at a single time point will be 
classified as failures. This missing data imputation method will be applied to endpoints 
based on data from a single time point (e.g., co-primary endpoints at 2 hours post-dose). 
• Non-Completer With Missing Data at More Than 1 Time Point = Failure (NC1=F): Subjects 
with missing data at > 1 time point post-dose in a specified time period will be classified as 
failures. This missing data imputation method will be applied to endpoints that are based on 
data from multiple time points (e.g., secondary endpoint of sustained pain freedom from 2 to 
24 hours post-dose).  
• Non-Completer = Missing (NC=M): Subjects with missing data at a single time point will be 
excluded from the analysis. This missing data exclusion method will be applied to endpoints 
based on data from a single time point (e.g., co-primary endpoints at 2 hours post-dose). 
The intercurrent event of rescue medication use will be handled using Rescue Medication = 
Failure (RM=F), i.e., subjects who take rescue medication will be classified as failures for all 
efficacy evaluations that are reported at or after taking rescue medication, i.e., (1) rescue 
medication start date/time £ eDiary finding date/time if start time is not missing, or (2) rescue 
medication start date £ eDiary finding date if start time is missing; see Sections 6.2.5.2 and 7.3). 
This method will apply to all efficacy analyses, except the secondary endpoint of rescue 
medication use within 24 hours post-dose. 
6.3.2 
Missing Efficacy Data 
Missing efficacy data will be summarized by treatment group as the number and percentage of 
mITT subjects in the following categories:   
• Missing pain data at each time point from 15 minutes through 48 hours post-dose. These 
categories are not mutually exclusive because subjects may have missing data at multiple 
time points. 
• Number of time points with missing pain data from 2 hours to 48 hours post-dose: 0 (i.e., no 
missing pain data), 1, 2, 3, 4, 5, 6, 7. These categories are mutually exclusive.   
• Missing data for the following efficacy parameters at 2, 24, and 48 hours post-dose: pain 
level, nausea status, phonophobia status, photophobia status, and functional disability level. 


 
 
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In addition, missing pain data at 2 hours post-dose will be summarized by subgroup level for 
each treatment group and overall for all subgroups specified in Section 6.1.3 plus the following 
subgroups: 
• Pain level at on-study migraine attack onset (moderate or severe) 
• MBS at on-study migraine attack onset (nausea, phonophobia, or photophobia) 
• Rescue medication use: yes, no. 
6.3.3 
Primary Efficacy Endpoints 
Both co-primary efficacy endpoints will be evaluated for mITT subjects. 
A by-subject listing of pain freedom and MBS freedom outcomes at each post-dose time point 
will be provided for randomized subjects that includes prophylactic migraine medication use at 
randomization, rescue medication start date/time (see Section 7.3), time to rescue medication 
start date/time in hours (see Section 6.3.4.3), pain level at on-study migraine attack onset, MBS 
at on-study migraine attack onset, and reason for exclusion from the mITT population sample 
(see Section 6.2.1). Missing data and complete cases (see Section 6.3.5.2) will be flagged at 
each time point for each endpoint. See Section 6.3.5.2 for efficacy outcomes. 
6.3.3.1 
Pain Freedom at 2 Hours Post-Dose 
Pain freedom is defined as having a pain level of none at a single time point post-dose.  
For the co-primary endpoint, subjects who meet both of the following criteria will be classified 
as responders: 
• Pain level of none at 2 hours post-dose, i.e., in the 2-hour post-dose analysis window 
• No intervening rescue medication taken at or before 2 hours post-dose, i.e., rescue 
medication start date/time missing or > {eDiary finding date/time in the 2-hour post-dose 
analysis window}. 
Subjects who are not classified as responders and have any of the following will be classified as 
failures: 
• Intercurrent event: Rescue  medication taken at or before 2 hours post-dose (RM=F), i.e., 
(rescue medication start date/time – study drug start date/time) £ 135 minutes, the upper 
bound of the 2-hour post-dose analysis window (see Section 7.5) 
• Mild, moderate, or severe pain at 2 hours post-dose, i.e., in the 2-hour post-dose analysis 
window 
• Missing pain level at 2 hours post-dose (NC=F), i.e., in the 2-hour post-dose analysis 
window.   


 
 
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Principal Analyses 
Pain freedom outcomes at 2 hours post-dose will be summarized by treatment group (see 
Section 6.3.5.2). Outcomes will be summarized analogously for each subgroup level of all 
efficacy subgroups of interest specified in Section 6.1.3. 
The percentages of subjects with pain freedom at 2 hours post-dose will be compared pairwise 
between each BHV-3500 treatment group and placebo using Cochran-Mantel-Haenszel (CMH) 
tests stratified by prophylactic migraine medication use at randomization (yes, no). In these 
analyses, the NC=F and RM=F methods will be applied. The following statistics will be 
presented: 
• Response rate (i.e., “n/N” and percentage), ASE, and 98.3% CI by randomization stratum 
for each treatment group 
• Overall response rate (i.e., “n/N” and percentage), ASE, and 98.3% CI for each treatment 
group 
• Percentage difference between treatment groups (BHV-3500 – placebo), ASE, 98.3% CI, 
and p-value by randomization stratum 
• Stratified percentage difference between treatment groups (BHV-3500 – placebo), ASE, 
98.3% CI, and p-value. 
The stratified percentage difference between each BHV-3500 treatment group and placebo will 
be tested at a Bonferroni-corrected alpha level of 0.0167. A BHV-3500 treatment group will be 
considered to be superior to placebo for this co-primary endpoint if the p-value for the stratified 
percentage difference is < 0.0167. 
The principal analysis will be repeated unstratified for each subgroup level of all efficacy 
subgroups of interest specified in Section 6.1.3. 
Sensitivity Analyses 
Sensitivity analyses will include the following: 
• Complete cases: The principal analysis will be repeated using NC=M, i.e., subjects who 
have missing pain level in the 2-hour post-dose analysis window are excluded. First, the 
RM=F method of handling intervening rescue medication use will be applied. Next, subjects 
with missing data in the 2-hour analysis window will be excluded. The same statistics as the 
principal analysis will be presented.  
• Multiple imputation: The principal analysis will be repeated using the copy from reference 
multiple imputation approach with m=20 imputations to impute missing pain data at 2 hours 
post-dose. The fully conditional specification (FCS) method is used with a generalized logit 
distribution. Covariates may include prophylactic migraine medication use at randomization 
(yes or no), sex, pain level at on-study migraine attack onset (moderate or severe), historical 
number of moderate to severe migraine attacks per month (< median, ³ median), and MBS 
at on-study migraine attack onset (nausea, phonophobia, or photophobia). First, the RM=F 


 
 
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method of handling intervening rescue medication use will be applied. Next, missing data in 
the 2-hour post-dose analysis window will be imputed for subjects who are not missing any 
of the covariates (subjects missing any of the covariates will be considered failures). The 
same statistics as the principal analysis will be presented.  
• Varying response rate imputation: The principal analysis will be repeated by imputing 
missing pain data at 2 hours post-dose in each treatment group with varying response rates 
over the range of 0%, 10%, 20% and 30%. First, the RM=F method of handling intervening 
rescue medication use will be applied. Next, missing data in the 2-hour post-dose analysis 
window will be imputed. The following statistics will be presented: stratified percentage 
difference between treatment groups (BHV-3500 – placebo), ASE, 98.3% CI, and p-value.  
6.3.3.2 
MBS Freedom at 2 Hours Post-Dose 
MBS freedom is defined as the MBS reported at on-study migraine attack onset and being 
absent at a single time point post-dose, e.g., subjects who report nausea as the MBS at onset 
before taking study drug and have nausea absent at 2 hours post-dose.  
For the co-primary endpoint, subjects who meet both of the following criteria will be classified 
as responders: 
• MBS reported at migraine attack onset before taking study drug and being absent at 2 hours 
post-dose, i.e., in the 2-hour post-dose analysis window  
• No intervening rescue medication taken at or before 2 hours-dose, i.e., rescue medication 
start date/time missing or > {eDiary finding date/time in the 2-hour post-dose analysis 
window}. 
Subjects who are not classified as responders and have any of the following will be classified as 
failures: 
• MBS missing at on-study migraine attack onset (see Section 7.6.3.2) 
• Intercurrent event: Rescue medication taken at or before 2 hours post-dose (RM=F) i.e., 
(rescue medication start date/time – study drug start date/time) £ 135 minutes, the upper 
bound of the 2-hour post-dose analysis window (see Section 7.5) 
• MBS present at 2 hours post-dose, e.g., nausea reported as MBS at onset and nausea present 
in the 2-hour post-dose analysis window 
• MBS missing at 2 hours post-dose (NC=F), e.g., nausea reported as MBS at onset and 
nausea status missing in the 2-hour post-dose analysis window. 
Principal Analyses 
MBS freedom outcomes at 2 hours post-dose will be summarized by treatment group (see 
Section 6.3.5.2). Outcomes will be summarized analogously for each subgroup level of all 
efficacy subgroups of interest specified in Section 6.1.3 plus MBS at on-study migraine attack 
onset (nausea, phonophobia, photophobia). 


 
 
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The percentages of subjects with MBS freedom at 2 hours post-dose will be compared pairwise 
between each BHV-3500 treatment group and placebo using CMH tests stratified by 
prophylactic migraine medication use at randomization (yes, no). In these analyses, the NC=F 
and RM=F methods will be applied. The same statistics will be presented as those for the 
principal analysis of pain freedom at 2 hours post-dose (see Section 6.3.3.1). The stratified 
percentage difference between each BHV-3500 treatment group and placebo will be tested at a 
Bonferroni-corrected alpha level of 0.0167. A BHV-3500 treatment group will be considered to 
be superior to placebo for this co-primary endpoint if the p-value for the stratified percentage 
difference is < 0.0167. 
The principal analysis will be repeated unstratified for each subgroup level of all efficacy 
subgroups of interest specified in Section 6.1.3 plus MBS at on-study migraine attack onset 
(nausea, phonophobia, photophobia). 
Sensitivity Analyses 
Sensitivity analyses will include the following: 
• Complete cases: The principal analysis will be repeated using NC=M, i.e., subjects who 
have missing MBS status in the 2-hour post-dose analysis window are excluded. First, 
subjects whose MBS at on-study migraine attack onset is missing will be classified as 
failures. Next, the RM=F method of handling intervening rescue medication use will be 
applied. Finally, subjects with missing data in the 2-hour post-dose analysis window will be 
excluded. 
• Multiple imputation: The principal analysis will be repeated using the copy from reference 
multiple imputation approach with m=20 imputations to impute missing MBS status in the 
2-hour post-dose analysis window. First, subjects whose MBS at on-study migraine attack 
onset is missing will be classified as failures. Next, the RM=F method of handling 
intervening rescue medication use will be applied. Finally, missing data in the 2-hour post-
dose analysis window will be imputed.  
• Varying response rate imputation: The principal analysis will be repeated by imputing 
missing MBS at 2 hours post-dose in each treatment group with varying response rates over 
the range of 0%, 10%, 20% and 30%. First, subjects whose MBS at on-study migraine attack 
onset is missing will be classified as failures. Next, the RM=F method of handling 
intervening rescue medication use will be applied. Finally, missing data in the 2-hour post-
dose analysis window will be imputed.  
See Section 6.3.3.1 for additional details about methods and the presentation of statistics.  
6.3.4 
Secondary Efficacy Endpoints  
All secondary efficacy endpoints will be evaluated for mITT subjects, unless specified 
otherwise. 


 
 
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If the co-primary endpoint tests are both significant for a BHV-3500 treatment group versus 
placebo, then the secondary endpoints are tested for that BHV-3500 treatment group versus 
placebo using a hierarchical gate-keeping procedure, with each test in the hierarchy conducted 
at alpha=0.0167. The endpoints are tested in the order shown in Section 1.2.2. 
A by-subject listing of outcomes for pain relief, nausea freedom, phonophobia freedom, 
photophobia freedom, and return to normal function will be provided for randomized subjects at 
each time point post-dose. The listing will also include prophylactic migraine medication use at 
randomization and time to rescue medication start date/time in minutes (see Section 6.3.4.3), as 
well as nausea status, phonophobia status, photophobia status, and functional disability level at 
on-study migraine attack onset. Missing data and complete cases will be flagged at each time 
point for each endpoint. See Section 6.3.5.2 for efficacy outcomes over time. 
6.3.4.1 
Pain Relief at 30 Minutes, 60 Minutes and at 2 Hours Post-Dose 
Pain relief is defined as a pain level of none or mild at a single time point post-dose.  
Pain relief outcomes at 2 hours post-dose will be summarized by treatment group (see 
Section 6.5.3.2). 
At each time point post-dose (30 minutes, 60 minutes, and 2 hours), treatment group 
comparisons of the percentage of subjects with pain relief will use analogous methods as the 
principal analysis of the co-primary endpoint of pain freedom with NC=F and RM=F (see 
Section 6.3.3.1).  
6.3.4.2 
Return to Normal Function at 30 Minutes, 60 Minutes, and 2 Hours Post-
Dose 
Return to normal function is defined as a functional disability level of normal at a single time 
point post-dose for subjects with functional disability (mildly impaired, severely impaired, 
requires bedrest) at on-study migraine attack onset. Thus, all analyses of return to normal 
function will be based on mITT subjects with functional disability at on-study migraine attack 
onset.  
Return to normal function outcomes at 2 hours post-dose will be summarized by treatment 
group (see Section 6.3.5.2). 
At each time point post-dose (30 minutes, 60 minutes, and 2 hours), treatment group 
comparisons of the percentage of subjects with return to normal function will use analogous 
methods as the principal analysis of the co-primary endpoint of pain freedom with NC=F and 
RM=F (see Section 6.3.3.1). 


 
 
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6.3.4.3 
Probability of Rescue Medication Use within 24 Hours Post-Dose 
Analyses will be based on evaluable mITT subjects, i.e., mITT subjects with rescue medication 
start date on or before study drug start date + 1 day and missing rescue medication start time 
will be excluded. Time to rescue medication use will be measured from the study drug start 
date/time to the rescue medication start date/time. 
No analysis window around the 24-hour post-dose time point will be used. 
Rescue Medication Use Within 24 Hours Post-Dose 
Rescue medication use within 24 hours post-dose is defined as time to rescue medication use £ 
24 hours.  
Treatment group comparisons of the percentage of subjects using rescue medication within 24 
hours post-dose will use analogous methods as the principal analysis of the co-primary endpoint 
of pain freedom, except that the NC=F and RM=F methods will not be applied because they are 
not applicable to this endpoint (see Section 6.3.3.1). 
Time to Rescue Medication Use Through 24 Hours Post-Dose 
Time to rescue medication use through 24 hours post-dose will be assessed by treatment group 
as follows: 
• Kaplan-Meier (KM) plot and table using 2-hour time intervals (i.e., 0 to 2, > 2 to 4, ... , > 
24). The KM plot will display the percentage of subjects taking rescue medication within 24 
hours post-dose on the y-axis versus time in hours on the x-axis.  
• Time-to-event distribution table (hours), including a log-rank p-value (BHV-3500 versus 
placebo). 
See Section 7.1.1.1 for time-to-event plot and table attributes. Rescue medication use through 
24-hours post-dose will be considered as an event in these time-to-event analyses. Subjects who 
do not take rescue medication within 24 hours post-dose will be censored at 24 hours and 1 
minute (i.e., 1441 minutes).   
6.3.4.4 
Freedom from Photophobia, Phonophobia or Nausea at 2 Hours Post-
Dose 
Freedom from each symptom (nausea, phonophobia, photophobia) at 2 hours post-dose will be 
assessed separately. 
Symptom freedom is defined as a symptom absent at a single time point post-dose for subjects 
with the symptom present at on-study migraine attack onset. Thus, all analyses of symptom 
freedom will be based on mITT subjects with the symptom present at on-study migraine attack 
onset (see Section 7.6.3.2), e.g., nausea freedom at a post-dose time point will be based on 
subjects with nausea present at onset.  


 
 
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Symptom freedom outcomes at 2 hours post-dose will be summarized by treatment group (see 
Section 6.3.5.2). 
Treatment group comparisons of the percentage of subjects with symptom freedom at 2 hours 
post-dose will use analogous methods as the principal analysis of the co-primary endpoint of 
pain freedom with NC=F and RM=F (see Section 6.3.3.1). 
6.3.4.5 
Sustained Pain Relief from 2 to 24 Hours Post-Dose 
Sustained pain relief from 2 to 24 hours post-dose is defined as pain level of none or mild at all 
time points from 2 to 24 hours post-dose.  
Subjects who meet all of the following criteria will be classified as responders: 
• Pain level of none or mild at all time points from 2 to 24 hours post-dose, i.e., in the 2 to 24-
hour post-dose analysis windows 
• Missing data at £ 1 time point from 3 to 8 hours post-dose, i.e., in the 3, 4, 6, or 8-hour post-
dose analysis windows 
• No intervening rescue medication taken at or before 24 hours post-dose, i.e., rescue 
medication start date/time missing or > {eDiary finding date/time in the 24-hour post-dose 
analysis window}.   
Otherwise, subjects who are not responders and have any of the following will be classified as 
failures: 
• Intercurrent event: Rescue medication taken at or before 24 hours post-dose (RM=F), i.e., 
(rescue medication start date/time – study drug start date/time) £ 25 hours, the upper bound 
of the 24-hour post dose analysis window 
• Moderate or severe pain at any time point from 2 to 24 hours post-dose, i.e., in the 2, 3, 4, 6, 
8 or 24-hour post-dose analysis window 
• Missing pain level at 2 or 24 hours post-dose (NC=F), i.e., in the 2 or 24-hour post-dose 
analysis window 
• Missing pain level at > 1 time point from 3 to 8 hours post-dose (NC1=F), i.e., in the 3, 4, 6, 
or 8-hour post-dose analysis window. 
Sustained pain relief from 2 to 24 hours outcomes will be summarized by treatment group as the 
number and percentage of subjects in the following categories: 
• Responder: mild or no pain at all time points from 2 to 24 hours post-dose, missing data at £ 
1 time point from 3 to 8 hours post-dose, and no intervening rescue medication taken at or 
before 24 hours post-dose 


 
 
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• Failure 
o Rescue medication taken at or before 24 hours post-dose (RM=F) 
o Moderate or severe pain at any time point from 2 to 24 hours post-dose 
§ Severe pain 
§ Moderate pain 
o Missing pain level at 2 or 24 hours post-dose (NC=F) 
o Missing pain level at > 1 time point from 3 to 8 hours post-dose (NC1=F). 
Failure subcategories are mutually exclusive, because subjects who meet more than 1 failure 
criterion will be classified according to the first failure criterion met; in case of ties, the first 
failure subcategory that is met in the hierarchy above will be chosen. 
Treatment group comparisons of the percentage of subjects with sustained pain relief from 2 to 
24 hours post-dose will use analogous methods as the principal analysis of the co-primary 
endpoint of pain freedom with NC=F, NC1=F, and RM=F (see Section 6.3.3.1). 
6.3.4.6 
Sustained Pain Relief from 2 to 48 Hours 
Sustained pain relief from 2 to 48 hours post-dose is defined as pain level of none or mild at all 
time points from 2 to 48 hours post-dose.  
Subjects who meet all of the following criteria will be classified as responders: 
• Pain level of none or mild at all time points from 2 to 48 hours post-dose, i.e., in the 2 to 48-
hour post-dose analysis windows 
• Missing data at £ 1 time point from 3 to 8 hours post-dose, i.e., in the 3, 4, 6, or 8-hour post-
dose analysis windows 
• No intervening rescue medication taken at or before 48 hours post-dose, i.e., rescue 
medication start date/time missing or > {eDiary finding date/time in the 48-hour post-dose 
analysis window}.   
Otherwise, subjects who are not classified as responders and have any of the following will be 
classified as failures: 
• Intercurrent event: Rescue medication taken at or before 48 hours post-dose (RM=F), i.e., 
(rescue medication start date/time – study drug start date/time) £ 49 hours, the upper bound 
of the 48-hour post dose analysis window 
• Moderate or severe pain at any time point from 2 to 48 hours post-dose, i.e., in the 2, 3, 4, 6, 
8, 24, or 48-hour post-dose analysis window 
• Missing pain level at 2, 24, or 48 hours post-dose (NC=F), i.e., in the 2, 24, or 48-hour post-
dose analysis window 


 
 
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• Missing pain level at > 1 time point from 3 to 8 hours post-dose (NC1=F), i.e., in the 3, 4, 6, 
or 8-hour post-dose analysis window. 
Sustained pain relief from 2 to 48 hours outcomes will be summarized for mITT subjects by 
treatment group as the number and percentage of subjects in the following categories: 
• Responder: mild or no pain at all time points from 2 to 48 hours post-dose, missing data at £ 
1 time point from 3 to 8 hours post-dose, and no intervening rescue medication taken at or 
before 48 hours post-dose 
• Failure 
o Rescue medication taken at or before 48 hours post-dose (RM=F) 
o Moderate or severe pain at any time point from 2 to 48 hours post-dose 
§ Severe pain 
§ Moderate pain 
o Missing pain level at 2, 24, or 48 hours post-dose (NC=F) 
o Missing pain level at > 1 time point from 3 to 8 hours post-dose (NC1=F). 
Failure subcategories are mutually exclusive, because subjects who meet more than 1 failure 
criterion will be classified according to the first failure criterion met; in case of ties, the first 
failure subcategory in the hierarchy above will be chosen. 
Treatment group comparisons of the percentage of subjects with sustained pain relief from 2 to 
48 hours post-dose will use analogous methods as the principal analysis of the co-primary 
endpoint of pain freedom with NC=F, NC1=F, and RM=F (see Section 6.3.3.1). 
6.3.4.7 
Sustained Pain Freedom from 2 to 24 Hours 
Sustained pain freedom from 2 to 24 hours post-dose is defined as pain level of none at all time 
points from 2 to 24 hours post-dose.  
Subjects who meet all of the following criteria will be classified as responders: 
• Pain level of none at all time points from 2 to 24 hours post-dose, i.e., in the 2 to 24-hour 
post-dose analysis windows 
• Missing data at £ 1 time point from 3 to 8 hours post-dose, i.e., in the 3, 4, 6, or 8-hour post-
dose analysis windows 
• No intervening rescue medication taken at or before 24 hours post-dose (see Section 6.3.4.5).   
Subjects who are not classified as responders and have any of the following will be classified as 
failures: 
• Intercurrent event: Rescue medication taken at or before 24 hours post-dose (RM=F; see 
Section 6.3.4.5 ) 


 
 
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• Mild, moderate or severe pain at any time point from 2 to 24 hours post-dose, i.e., in the 2, 3, 
4, 6, 8 or 24-hour post-dose analysis window 
• Missing pain level at 2 or 24 hours post-dose (NC=F), i.e., in the 2 or 24-hour post-dose 
analysis window 
• Missing pain level at > 1 time point from 3 to 8 hours post-dose (NC1=F), i.e., in the 3, 4, 6, 
or 8-hour post-dose analysis window. 
Sustained pain freedom from 2 to 24 hours outcomes will be summarized by treatment group as 
the number and percentage of subjects in the following categories: 
• Responder: no pain at all time points from 2 to 24 hours post-dose, missing data at £ 1 time 
point from 3 to 8 hours post-dose, and no intervening rescue medication taken at or before 
24 hours post-dose 
• Failure 
o Rescue medication taken at or before 24 hours post-dose (RM=F) 
o Mild, moderate or severe pain at any time point from 2 to 24 hours post-dose 
§ Severe pain 
§ Moderate pain 
§ Mild pain 
o Missing pain level at 2 or 24 hours post-dose (NC=F) 
o Missing pain level at > 1 time point from 3 to 8 hours post-dose (NC1=F). 
Failure subcategories are mutually exclusive, because subjects who meet more than 1 failure 
criterion will be classified according to the first failure criterion met; in case of ties, the first 
failure subcategory that is met in the hierarchy above will be chosen. 
Treatment group comparisons of the percentage of subjects with sustained pain freedom from 2 
to 24 hours post-dose will use analogous methods as the principal analysis of the co-primary 
endpoint of pain freedom with NC=F, NC1=F, and RM=F (see Section 6.3.3.1). 
6.3.4.8 
Sustained Pain Freedom from 2 to 48 Hours 
Sustained pain freedom from 2 to 48 hours post-dose is defined as pain level of none at all time 
points from 2 to 48 hours post-dose.  
Subjects who meet all of the following criteria will be classified as responders: 
• Pain level of none at all time points from 2 to 48 hours post-dose, i.e., in the 2 to 48-hour 
post-dose analysis windows 
• Missing data at £ 1 time point from 3 to 8 hours post-dose, i.e., in the 3, 4, 6, or 8-hour post-
dose analysis windows 
• No intervening rescue medication taken at or before 48 hours post-dose (see Section 6.3.4.6).   


 
 
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Subjects who are not classified as responders and have any of the following will be classified as 
failures: 
• Intercurrent event: Rescue medication taken at or before 48 hours post-dose (RM=F; see 
Section 6.3.4.6) 
• Mild, moderate or severe pain at any time point from 2 to 48 hours post-dose, i.e., in the 2, 3, 
4, 6, 8, 24, or 48-hour post-dose analysis window 
• Missing pain level at 2, 24, or 48 hours post-dose (NC=F), i.e., in the 2, 24, or 48-hour post-
dose analysis window 
• Missing pain level at > 1 time point from 3 to 8 hours post-dose (NC1=F), i.e., in the 3, 4, 6, 
or 8-hour post-dose analysis window. 
Sustained pain freedom from 2 to 48 hours outcomes will be summarized for mITT subjects by 
treatment group as the number and percentage of subjects in the following categories: 
• Responder: no pain at all time points from 2 to 48 hours post-dose, missing data at £ 1 time 
point from 3 to 8 hours post-dose, and no intervening rescue medication taken at or before 
48 hours post-dose 
• Failure 
o Rescue medication taken at or before 48 hours post-dose (RM=F) 
o Mild, moderate or severe pain at any time point from 2 to 48 hours post-dose 
§ Severe pain 
§ Moderate pain 
§ Mild pain 
o Missing pain level at 2, 24, or 48 hours post-dose (NC=F) 
o Missing pain level at > 1 time point from 3 to 8 hours post-dose (NC1=F). 
Failure subcategories are mutually exclusive, because subjects who meet more than 1 failure 
criterion will be classified according to the first failure criterion met; in case of ties, the first 
failure subcategory that is met in the hierarchy above will be chosen.  
Treatment group comparisons of the percentage of subjects with sustained pain freedom from 2 
to 48 hours post-dose will use analogous methods as the principal analysis of the co-primary 
endpoint of pain freedom with NC=F, NC1=F, and RM=F (see Section 6.3.3.1). 


 
 
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6.3.4.9 
Pain Relapse from 2 to 48 Hours Post-Dose 
Pain relapse from 2 to 48 hours post-dose is defined as pain of mild, moderate, or severe at any 
time point post-dose after 2 hours post-dose for subjects with pain level of none at 2 hours post-
dose. Thus, analyses of pain relapse will be based on mITT subjects with pain freedom at 2 
hours post-dose (see Section 6.3.3.1).  
Subjects who meet all of the following criteria will be classified as non-relapsers: 
• Pain level of none at all time points after 2 hours post-dose, i.e., in the 3 to 48-hour post-
dose analysis windows 
• Missing data at £ 1 time point after 2 hours post-dose, i.e., in the 3, 4, 6, 8, 24, or 48-hour 
post-dose analysis window 
• No intervening rescue medication taken at or before 48 hours post-dose (see Section 6.3.4.6). 
Otherwise, subjects who are not classified as non-relapsers and have any of the following will 
be classified as relapsers: 
• Intercurrent event: Rescue medication taken at or before 48 hours post-dose (RM=F; see 
Section 6.3.4.6) 
• Mild, moderate or severe pain at any time point after 2 hours post-dose, i.e., in the 3, 4, 6, 8, 
24, or 48-hour post-dose analysis window 
• Missing pain level at > 1 time point after 2 hours post-dose (NC1=F), i.e., in the 3, 4, 6, 8, 
24, or 48-hour post-dose analysis window. 
Pain relapse from 2 to 48 hours outcomes will be summarized by treatment group as the number 
and percentage of subjects in the following categories: 
• Non-relapser: no pain at all time points after 2 hours post-dose, missing data at £ 1 time 
point after 2 hours post-dose, and no intervening rescue medication taken at or before 48 
hours post-dose 
• Relapser 
o Rescue medication taken at or before 48 hours post-dose (RM=F) 
o Mild, moderate or severe pain at any time point after 2 hours post-dose 
§ Severe pain  
§ Moderate pain 
§ Mild pain 
o Missing pain level at > 1 time point after 2 hours post-dose (NC1=F). 
Relapser subcategories are mutually exclusive, because subjects who meet more than 1 relapse 
criterion will be classified according to the first relapse criterion met; in case of ties, the first 
relapse subcategory that is met in the hierarchy above will be chosen.  


 
 
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Treatment group comparisons of the percentage of subjects with pain relapse from 2 to 48 hours 
post-dose will use analogous methods as the principal analysis of the co-primary endpoint of 
pain freedom with NC1=F and RM=F (see Section 6.3.3.1). 
6.3.4.10 
Overall Summary of Primary and Secondary Endpoints  
An overall summary of treatment comparisons of all primary and secondary endpoints tested 
hierarchically will present the following statistics: 
• Overall response rate (i.e., “n/N” and percentage) and 98.3% CI for each treatment group 
• Stratified percentage difference between treatment groups (BHV-3500 – placebo), 98.3% CI, 
and p-value. 
Analyses will be based on principal methods described in Sections 6.3.3 and 6.3.4. Endpoints 
will be displayed in the order presented in Sections 1.2.1 and 1.2.2. P-values that are determined 
to be significant based on the testing hierarchy will be flagged. 
A forest plot of treatment comparisons of all primary and secondary endpoints tested 
hierarchically will be produced for each treatment group comparison of BHV-3500 versus 
placebo based on the overall summary. Each plot will display the following statistics: 
• Overall response rate (i.e., “n/N” and percentage) for the BHV-3500 treatment group and 
placebo 
• Stratified percentage difference between treatment groups (BHV-3500 – placebo) and 98.3% 
CI. 
Percentage differences with p-values that are determined to be significant based on the testing 
hierarchy will be flagged. Note that each plot will display results for no intervening rescue 
medication use within 24 hours post-dose and no pain relapse from 2 to 48 hours post-dose so 
that positive percentage differences will favor BHV-3500 for these secondary endpoints. 
6.3.5 
Exploratory Efficacy Endpoints 
All exploratory efficacy endpoints will be evaluated for mITT subjects, unless specified 
otherwise. 
Any p-values presented for exploratory efficacy endpoints are for descriptive purposes only, and 
not included in the hierarchical testing. 
6.3.5.1 
Return to Normal Function at 24 Hours 
Return to normal function outcomes at 24 hours post-dose will be summarized by treatment 
group (see Section 6.3.5.2). 


 
 
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6.3.5.2 
Efficacy at Each Post-Dose Time Point 
Efficacy Outcomes Over Time: Principal Analyses 
Efficacy outcomes will be summarized for mITT subjects by treatment group as the number and 
percentage of subjects in categories (responder; failure; failure subcategories) at each time point 
from 15 minutes through 48 hours post-dose. Subjects who are not classified as responders at a 
time point will be classified as failures. Failure subcategories are mutually exclusive, because 
subjects who meet more than 1 failure criterion will be classified according to the first failure 
criterion met; in case of ties, the first failure subcategory that is met in the specified hierarchy 
for an endpoint will be chosen. Percentages for response rates will also be shown with exact 
Clopper-Pearson 98.3% CIs.   
Outcomes will be presented separately for each of the following efficacy endpoints: pain 
freedom, MBS freedom, pain relief, nausea freedom, phonophobia freedom, photophobia 
freedom, and return to normal function. These analyses will use the NC=F and RM=F methods 
to align with principal analyses of co-primary and secondary endpoints (see Sections 6.3.3.1 and 
6.3.3.2). Outcomes category nomenclature is as follows:  
• “at time point” means in the analysis window corresponding to that post-dose time point 
• “No intervening rescue medication taken at or before time point” means rescue medication 
start date/time missing or > {eDiary finding date/time in the analysis window corresponding 
to that post-dose time point} 
• “Rescue medication taken at or before time point” means (rescue medication start 
date/time – study drug start date/time) £ upper bound of the analysis window corresponding 
to that post-dose time point (see Section 7.5). 
Outcomes for mITT subjects will be presented over time as described below. Subjects who are 
not included in the mITT population sample will have the following outcomes in by-subject 
listings: 
• Randomized subjects not in the mITT population sample: “Not mITT” 
• mITT subjects with absent or missing symptom status at on-study migraine attack onset for 
nausea freedom, photophobia freedom, and photophobia freedom: “Not evaluable: symptom 
absent at onset” or “Not evaluable: symptom missing at onset” 
• mITT subjects with normal or missing functional disability level at on-study migraine attack 
onset for return to normal function: “Not evaluable: normal function at onset” or “Not 
evaluable: missing disability level at onset”.  
Pain Freedom Outcomes Over Time 
Outcomes categories are defined as: 
• Responder: No pain at time point and no intervening rescue medication taken at or before 
time point 


 
 
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• Failure 
o 
Rescue medication taken at or before time point (RM=F) 
o 
Mild, moderate or severe pain at time point 
§ Severe pain 
§ Moderate pain 
§ Mild pain 
o 
Missing pain level at time point (NC=F). 
MBS Freedom Outcomes Over Time 
Outcome categories are: 
• Responder: MBS reported at on-study migraine attack onset before taking study drug, MBS 
absent at time point, and no intervening rescue medication taken at or before time point 
• Failure 
o Missing MBS at on-study migraine attack onset 
o Rescue medication taken at or before time point (RM=F) 
o Nausea reported as MBS at on-study migraine attack onset and present at time point 
o Phonophobia reported as MBS at on-study migraine attack onset and present at time 
point 
o Photophobia reported as MBS at on-study migraine attack onset and present at time 
point 
o Missing MBS status at time point (NC=F). 
Pain Relief Outcomes Over Time 
Outcome categories are defined as: 
• Responder: Mild or no pain at time point and no intervening rescue medication taken at or 
before time point 
• Failure 
o Rescue medication taken at or before time point (RM=F) 
o Moderate or severe pain at time point 
§ Severe pain 
§ Moderate pain 
o Missing pain level at time point (NC=F). 


 
 
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Nausea Freedom, Photophobia Freedom and Phonophobia Freedom Outcomes Over Time 
Freedom from each symptom (nausea, phonophobia, and photophobia) will be evaluated 
separately. Analyses will be based on mITT subjects with the symptom present at on-study 
migraine attack onset (see Section 7.6.3.2). 
Outcomes categories are defined as: 
• Responder: symptom absent at time point and no intervening rescue medication taken at or 
before time point 
• Failure 
o Rescue medication taken at or before time point (RM=F) 
o Symptom present at time point 
o Missing symptom status at time point (NC=F). 
Return to Normal Function Outcomes Over Time 
Analyses will be based on mITT subjects with functional disability at on-study migraine attack 
onset. 
Outcomes categories are defined as: 
• Responder: normal at time point and no intervening rescue medication taken at or before 
time point 
• Failure 
o Rescue medication taken at or before time point (RM=F) 
o Functional disability at time point 
§ Requires bedrest 
§ Moderately impaired 
§ Mildly impaired 
o Missing functional disability level at time point (NC=F). 
Complete Cases Over Time: Sensitivity Analyses 
Response rates corresponding to efficacy outcomes over time will also be presented using 
complete cases for each of the following efficacy endpoints: pain freedom, MBS freedom, pain 
relief, nausea freedom, phonophobia freedom, photophobia freedom, and return to normal 
function. Percentages for response rates will also be shown with exact Clopper-Pearson 98.3% 
CIs. 
In these sensitivity analyses, subjects who are missing data in a post-dose time point analysis 
window will be excluded at that time point (NC=M). Results for the co-primary endpoints of 


 
 
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pain freedom and MBS freedom at 2 hours post-dose will be the same as those for the complete 
cases sensitivity analyses (see Sections 6.3.3.1 and 6.3.3.2). 
For MBS freedom, the following conventions will be applied: (1) first, subjects whose MBS at 
on-study migraine attack onset is missing will be classified as failures; (2) next, the RM=F 
method of handling intervening rescue medication use will be applied; (3) finally, subjects with 
missing data in the analysis window will be excluded. 
For all other endpoints, the RM=F method of handling intervening rescue medication use will be 
applied first, and then subjects with missing data in the analysis window will be excluded. 
Time-to-Event Efficacy Endpoints 
The following time-to-event endpoints will be analyzed:  
• Pain freedom through 4 hours post-dose 
• Pain freedom through 8 hours post-dose 
• MBS freedom through 8 hours post-dose for subjects with MBS reported at on-study 
migraine attack onset 
• Pain relief through 4 hours post-dose 
• Pain relief through 8 hours post-dose 
• Nausea freedom through 8 hours post-dose for subjects with nausea present at on-study 
migraine attack onset 
• Phonophobia freedom through 8 hours post-dose for subjects with phonophobia present at 
on-study migraine attack onset 
• Photophobia freedom through 8 hours post-dose for subjects with photophobia present at on-
study migraine attack onset  
• Return to normal function through 8 hours post-dose for subjects with functional disability 
at on-study migraine attack onset. 
Analyses are based on non-missing, post-dose efficacy data relevant to each endpoint.  
For a given time-to-event endpoint, subjects are considered to have an event through X hours (X 
= 4 or 8) if the first post-dose eDiary finding date/time defining response is (1) at or before the 
upper bound of the X-hour analysis window in minutes (see Table 5), and (2) is before the 
imputed rescue medication start date/time, if not missing (see Section 7.3).  
Otherwise, subjects who do not have an event through X hours will be censored at the earliest of 
the following: (1) upper bound of the X-hour analysis window + 1 minute; (2) time from the 
study drug start date/time to the imputed rescue medication start date/time, if the time is at or 
before the upper bound of the X-hour analysis window in minutes; (3) time from the study drug 
start date/time to the last non-missing finding date/time defining the endpoint, if the time was 
before the lower bound of X-hour analysis window in minutes.  


 
 
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For each endpoint listed above, time to event will be assessed by treatment group as follows: 
• KM plot and table using the following time intervals post-dose: 0 to 15, >15 to 30, > 30 to 
45, > 45 to 60, > 60 to 90, > 90 to 120, > 120 to 180, > 180 to 240, > 240 to 360, > 360 to 
495, and > 495 minutes. The KM plot will display the percentage of subjects with the event 
on the y-axis versus time in minutes on the x-axis. See Section 7.1.1.1 for KM plot and table 
attributes. 
• Time-to-event distribution table (minutes), including a log-rank p-value (BHV-3500 versus 
placebo). 
See Section 7.1.1.1 for time-to-event plot and table attributes. 
6.4 
Pharmacokinetics 
No pharmacokinetic data will be collected in this study. 
6.5 
Safety 
Safety analyses will be conducted on treated subjects by as-treated treatment group (i.e., the 
actual treatment received) and All BHV-3500.   
Safety measures will include: AEs, laboratory tests, vital signs, physical measurements, 
electrocardiograms (ECGs), S-STS, and nasal inspection. 
Analysis periods are pre-treatment and on-treatment (see Section 7.4). 
Values and changes from baseline in safety findings (e.g., laboratory tests, vital signs and 
physical measurements, ECGs) and S-STS endpoints will be summarized as continuous 
variables descriptively at baseline and the end of treatment visit. These analyses will be based 
on observed data without imputation and regardless of rescue medication use. For the change 
from baseline, subjects must have non-missing paired measurements at baseline and end of 
treatment visit to be evaluable. If a subject has multiple values in the end of treatment analysis 
window (see Section 7.5), then the last non-missing value in the analysis period will be used; in 
the case of a tie, the value collected from the central laboratory, if applicable, will be used. 
6.5.1 
Adverse E vents 
AEs will be displayed in tables and listings by SOC and PT, unless specified otherwise. AEs by 
SOC and PT will be displayed in descending order of overall frequency within SOC and PT. 
See Section 7.6.1 for AE start date imputation, AE counting rules in frequency tables, treatment-
emergent adverse events (TEAEs), and AEs of special interest. 
The following by-subject listings of all AEs will be provided for enrolled subjects: AEs; deaths; 
SAEs; and AEs leading to study drug discontinuation. TEAEs will be flagged.  


 
 
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6.5.1.1 
AE Overview 
An AE overview without SOC and PT will present the number and percentage of subjects with 
any of the following AEs: any AE; mild AE; moderate AE; severe AE; AE related to study drug; 
SAE; SAE related to study drug; AE leading to study drug discontinuation; and AE leading to 
death.  
An AE overview will be produced for each analysis period (pre-treatment, on-treatment) for 
treated subjects. 
An AE will be considered related to study drug if the relationship is not reported (missing), 
unlikely related, possibly related, or related. 
6.5.1.2 
Pre-Treatment AEs by SOC and PT 
Pre-treatment AEs will be summarized by SOC and PT for treated subjects for the following 
endpoints: 
• AEs by severity (total, mild, moderate, severe, moderate or severe, not reported) 
• SAEs. 
6.5.1.3 
On-Treatment AEs by SOC and PT 
On-treatment AEs will be summarized by SOC and PT for treated subjects for the following 
endpoints: 
• AEs by severity 
• TEAEs by severity 
• AEs related to study drug by severity  
• SAEs  
• AEs leading to study drug discontinuation  
• Hepatic-related AEs * 
• Cardiovascular AEs * 
• Suicidality AEs *.  
AEs of special interest are asterisked (“*”). 
6.5.2 
Laboratory Tests 
Laboratory tests will be analyzed using results from the central laboratory and local laboratory 
tests reported on CRFs. 
Tables, listings and figures (TLFs) will present results in both SI (Systeme Internationale) and 
United States (US) unit systems, if applicable. 


 
 
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LDL cholesterol and triglycerides will be analyzed as separate laboratory test parameters 
according to fasting status: fasting (i.e., fasting status of yes); not fasting (i.e., fasting status not 
equal to yes, including no, unknown, not reported, missing, etc.); overall.  
Clinically significant laboratory abnormalities will be identified as grade 3 to 4 laboratory test 
results according to numeric laboratory test criteria in Common Technical Criteria for Adverse 
Events (CTCAE) Version 5.0 (2017) if available; otherwise according to Division of Acquired 
Immune Deficiency Syndrome (DAIDS) Table for Grading the Severity of Adult and Pediatric 
Adverse Events Corrected Version 2.1 (2017). 
Laboratory tests of clinical interest for analyses will include the following: 
• Hematology: hemoglobin#, hematocrit, red blood cell count, white blood cell count# with 
differential (including basophils, basophils/leukocytes, eosinophils, eosinophils/leukocytes, 
lymphocytes*#, lymphocytes/leukocytes, monocytes, monocytes/leukocytes, neutrophils#, 
neutrophils/leukocytes), and platelets# 
• Serum chemistry: alanine aminotransferase (ALT)#, AST#, albumin#, alkaline phosphatase 
(ALP)#, bicarbonate#,  total bilirubin (TBL)#, calcium#*, chloride*, cholesterol (total)#, 
creatine kinase#, creatinine#, CPK (with fractionation, if available), direct bilirubin, 
estimated glomerular filtration rate (eGFR)# using the modification of diet in renal disease 
(MDRD) formula, glucose@*, HDL cholesterol, hemoglobin A1C,  indirect bilirubin, LDL 
cholesterol@, lactate dehydrogenase#, lipase, phosphorus, potassium#*,  protein,  sodium#*, 
triglycerides#, urea nitrogen, uric acid (urate)@  
• Urinalysis: pH, specific gravity, ketones, nitrites, urobilinogen, urine hemoglobin, leukocyte 
esterase, urine protein@, and urine glucose@. 
Tests marked with “*” are bidirectional, tests marked with “#” will be graded according to 
CTCAE, and tests marked with “@” will be graded according to DAIDS. 
By-subject listings of the following select laboratory test groups will be provided for enrolled 
subjects: hematology; serum chemistry; urinalysis (US units only); pregnancy (US units only); 
endocrinology, serology, drug screen, and miscellaneous laboratory tests (US units only). In 
addition, a by-subject listing of LFT values and ratios to ULN (i.e., ALT, AST, TBL and ALP) 
will also be provided for enrolled subjects for both US and SI units, which will display all LFT 
results over time for those with select LFT elevations (ALT or AST > 3 x ULN; ALP or TBL > 
2 x ULN) at any time point. Listings will display toxicity grades, if applicable. 
6.5.2.1 
Laboratory Test Abnormalities 
On-treatment laboratory test abnormalities will be summarized as the number and percentage of 
treated subjects in the following frequency tables: 
• Worst (highest) on-treatment laboratory test abnormality for each graded laboratory test. 
Toxicity grade categories will be Grade 0, Grade 1 to 2, Grade 3 to 4, Grade 3, and Grade 4. 
Bidirectional tests will be assessed separately for each component (e.g., calcium, low; 
calcium, high). 


 
 
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• Laboratory test toxicity grade shift from baseline to the worst on-treatment toxicity grade for 
each graded laboratory test. Toxicity grade categories will be Grade 0, Grade 1, Grade 2, 
Grade 3, and Grade 4. Bidirectional tests will be assessed separately for each component 
(e.g., calcium, low; calcium, high). 
• Laboratory test low/normal/high shifts from baseline to any abnormal on-treatment value for 
each laboratory test with normal ranges. Categories will be low, normal, and high. Note that 
categories do not depend on US or SI units.  Subjects with both low and high values in the 
on-treatment analysis period will be counted in both low and high categories for that period 
and given laboratory test (thus, these categories are not mutually exclusive). Subjects must 
have only normal values in the on-treatment analysis period to be counted in the normal 
category for that period and given laboratory test. 
Tables will present results by laboratory tests alphabetically within laboratory test group, as 
applicable.  
6.5.2.2 
Liver Function Test Elevations 
LFT Elevations: Cumulative, Mutually Exclusive, and Composite 
The number and percentage of subjects with LFT elevations will be summarized separately for 
each analysis period (pre-treatment, on-treatment) for treated subjects. 
The frequency table of LFT elevations will include the following endpoints: 
• Cumulative elevations: 
o ALT > 1 x, > 3 x, > 5 x, > 10 x, and > 20 x ULN 
o AST > 1 x, > 3 x, > 5 x, > 10 x, and > 20 x ULN 
o ALT or AST > 1 x, > 3 x, > 5 x, > 10 x, and > 20 x ULN 
o TBL > 1 x, > 1.5 x, and > 2 x ULN 
o ALP > 1 x, > 1.5 x, and > 2 x ULN 
• Mutually exclusive elevations: 
o ALT > ULN to £ 3 x ULN, > 3 x ULN to £ 5 x ULN, > 5 x ULN to £ 10 x ULN, > 10 x 
ULN to £ 20 x ULN, and > 20 x ULN 
o AST > ULN to £ 3 x ULN, > 3 x ULN to £ 5 x ULN, > 5 x ULN to £ 10 x ULN, > 10 x 
ULN to £ 20 x ULN, and > 20 x ULN 
o ALT or AST > ULN to £ 3 x ULN, > 3 x ULN to £ 5 x ULN, > 5 x ULN to £ 10 x ULN, 
> 10 x ULN to £ 20 x ULN, and > 20 x ULN 
o TBL > ULN to £ 1.5 x ULN, > 1.5 x ULN to £ 2 x ULN, and > 2 x ULN 
o ALP > ULN to £ 1.5 x ULN, > 1.5 x ULN to £ 2 x ULN, and > 2 x ULN 


 
 
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• Composite elevations: 
o ALT or AST > 3 x ULN and TBL > 1.5 x ULN 
o ALT or AST > 3 x ULN and TBL > 2 x ULN 
o ALT or ALT > 3 x ULN concurrent with TBL > 2 x ULN with exact Clopper-Pearson 
95% CIs. Concurrent is defined as elevations on the same laboratory test collection date. 
o ALT or ALT > 3 x ULN concurrent with TBL > 2 x ULN and ALP £ 2 x ULN with exact 
Clopper-Pearson 95% CIs. Concurrent is defined as elevations on the same laboratory test 
collection date. 
o ALT or AST > 3 x ULN concurrent with AEs of interest: nausea, vomiting, anorexia, 
abdominal pain, and fatigue. For a given analysis period, an LFT elevation is concurrent 
with an AE of interest if the imputed AE start date is +/- 7 days inclusive of the LFT 
collection date; both the LFT collection date and the imputed AE start date must also be 
in the analysis period. The following PTs will be used to identify the AEs of interest: 
nausea, vomiting, anorexia, fatigue, and those containing “abdominal pain.” 
Subjects must have non-missing on-study LFT data (i.e., ALT, AST, TBL, or ALP) to be 
included. 
LFT ULN Shifts from Baseline to Worst Elevation 
LFT ULN shifts from baseline to the worst (highest) on-treatment elevation will be summarized 
as the number and percentage of treated subjects in the following categories: £ ULN, > ULN to 
£ 3 x ULN, > 3 x ULN to £ 5 x ULN, > 5 x ULN to £ 10 x ULN, > 10 x ULN to £ 20 x ULN, 
and > 20 x ULN (US and SI units are identical, U/L). LFTs will be limited to ALT and AST. 
eDISH Scatter Plot 
An evaluation of drug-induced serious hepatotoxicity (eDISH) scatter plot will display the 
maximum TBL ratio of value to ULN on the y-axis versus the maximum ALT ratio of value to 
ULN on the x-axis by treatment group (excluding All BHV-3500), where both maxima will be 
on treatment but not necessarily concurrent. Both axes will be on the log10 scale. Ratios < 0.1 x 
ULN will be set to 0.1. Sample sizes in the legend will represent subjects with paired ratios. A 
horizontal reference line will be placed at 2 x ULN, and a vertical reference line will be placed 
at 3 x ULN. 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”, and the upper right quadrant will be labeled “Possible Hy’s Law Range.” 
6.5.2.3 
Laboratory Test Change From Baseline 
Values and changes from baseline in laboratory tests will be summarized as continuous 
variables at baseline and the end of treatment visit. 


 
 
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6.5.3 
Vital Signs and Physical Measurements 
Vital signs will include systolic blood pressure, diastolic blood pressure, heart rate, temperature, 
and respiratory rate. In tables, only vital signs measured in the sitting position will be included.  
Physical measurements will include weight and BMI. 
A by-subject listing of vital signs and physical measurements will be provided for enrolled 
subjects. 
6.5.3.1 
Vital Sign and Physical Measurement Change From Baseline 
Values and changes from baseline in vital sign and physical measurement parameters will be 
summarized as continuous variables at baseline and the end of treatment visit. 
6.5.3.2 
Vital Sign and Physical Measurement Abnormalities 
On-treatment vital sign and physical measurement abnormalities will be summarized as the 
number and percentage of subjects in the following categories: 
• Systolic blood pressure (mmHg): < 90 , > 140, > 160 
• Diastolic blood pressure (mmHg): < 50, > 90, > 100  
• Heart rate (bpm): < 60, > 100  
• Temperature (C): < 36, > 38 
• Respiratory rate (breaths/min): < 12, > 20 
• Weight change from baseline: £ -7%, ³ 7%. 
6.5.4 
Electrocardiogram 
ECG parameters will include RR, QRS, PR, QT, QTcF, and ventricular heart rate. 
A by-subject listing of ECG results will be provided for enrolled subjects. 
6.5.4.1 
ECG Change from Baseline 
Values and changes from baseline in ECG parameters will be summarized as continuous 
variables at baseline and the end of treatment visit. 
6.5.4.2 
ECG Interpretation Shift from Baseline to Worst Category 
The ECG interpretation shift from baseline to the worst on-treatment category will be 
summarized as the number and percentage of subjects with normal, abnormal, and clinically 
significant abnormal interpretations. 


 
 
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6.5.4.3 
ECG Abnormalities 
On-treatment ECG abnormalities will be summarized as the number and percentage of subjects 
in the following categories: 
• QTcB (msec): > 450, > 480, > 500 
• QTcB interval increase from baseline (msec):  > 30, > 60 
• QTcF (msec): > 450, > 480, > 500 
• QTcF interval increase from baseline (msec):  > 30, > 60 
6.5.5 
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. 
Values and changes from baseline in the self-reported S-STS ideation subscale, behavior 
subscale, and total score will be summarized as continuous variables at baseline and the end of 
treatment visit. The number and percentage of subjects in each change from baseline category 
(i.e., < -1, -1, no change, 1, > 1) will also be presented for the ideation subscale, behavior 
subscale, and total score. 
The by-subject S-STS listing will include study visit and assessment date. If the total score > 0, 
then responses to all questions will be presented; otherwise, only the ideation subscale, 
behavioral subscale, and total scores will be presented. 
6.5.6 
Nasal Inspection 
Nasal inspections will evaluate evidence of edema and inflammation in the left and right nostrils 
with yes or no responses. Abnormalities are considered to be “yes” responses. 
A by-subject listing of nasal inspection will be provided for enrolled subjects. 


 
 
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6.5.6.1 
Nasal Inspection Abnormalities 
On-treatment nasal inspection abnormalities will be summarized for each parameter as the 
number and percentage of subjects with abnormalities for the following parameters: nasal 
edema or nasal inflammation in either nostril; nasal edema in left nostril; nasal edema in right 
nostril; nasal inflammation in left nostril; nasal inflammation in right nostril. Percentages will be 
based on subjects with non-missing data for each parameter.  
6.5.6.2 
Nasal Inspection Evidence Shift from Baseline 
Nasal inspection evidence shifts from baseline to an on-treatment abnormality will be 
summarized for each parameter (nasal edema in left nostril; nasal edema in right nostril; nasal 
inflammation in left nostril; nasal inflammation in right nostril) as the number and percentage of 
subjects in each evidence category (yes or no).  
6.5.7 
Safety Narratives 
A by-subject listing of safety narrative subject identifiers will be provided for the following 
select events as columns: all deaths for enrolled subjects; all SAEs for enrolled subjects; all AEs 
leading to discontinuation of study therapy for treated subjects; on-treatment events of special 
interest for treated subjects: hepatic-related AEs; cardiovascular AEs; suicidality AEs; AST or 
ALT > 3 x ULN. The listing will flag subjects with events, as well as display total numbers of 
subjects with each event and any event in the first row.  
6.5.8 
Outcomes Research 
Outcomes research endpoints are exploratory and will be assessed at 24 hours post-dose using 
the eDiary.  
Analyses will be based on observed data without imputation and regardless of rescue medication 
use. 
6.5.8.1 
PoM 
The PoM is a 5-point rating scale that measures the patient’s preference of study medication to 
previous medications to treat migraine pain. The 5 preference categories are: much better, I 
prefer this medication; slightly better than the previous medication; about the same as the 
previous medication; slightly worse than the previous medication; and much worse, I prefer my 
previous medication.  
Combined categories will include the following: (1) prefer study medication, defined as much 
better or slightly better; (2) prefer previous medication, defined as slightly worse or much worse. 
PoM will be summarized as the number and percentage of treated subjects in each preference 
category (including combined categories) by as-treated treatment group and All BHV-3500. 


 
 
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Percentages for categories will be based on subjects with non-missing data, along with exact 
Clopper-Pearson 95% CIs for each percentage. 
PoM will also be summarized analogously by as-randomized treatment group for mITT 
subjects: (1) overall; (2) by pain freedom outcome at 2 hours post-dose (responder, failure) for 
subjects who are included in the complete cases sensitivity analysis of pain freedom at 2 hours 
post-dose (see Section 6.3.3.1).  
A by-subject listing of PoM will be provided for enrolled subjects. 
6.5.8.2 
MQoL 
Impact of treatment on patient-reported quality of life is assessed using the MQoL Version 3.0, 
which is a 15-item questionnaire that has been validated in migraine patients to measure the 
short-term impact of treatment within 24 hours. The MQoL consists of 15 items across the 
following 5 domains: (1) work functioning; (2) social functioning; (3) energy/vitality; (4) 
migraine symptoms; (5) feelings/concerns. 
Subjects will rate the negative effect of migraine headache and accompanying symptoms on 
each item on a 7-point scale, where 1 indicates maximum impairment of quality of life and 7 
indicates no impairment. 
There are 3 items within each domain. Each domain has a maximum score of 21 and a minimum 
score of 3. Items in domains are as follows: 
• Work functioning: (1) ability to do normal everyday work, (2) ability to operate machinery 
or a motor vehicle, and (3) ability to stay alert.  
• Social functioning: (1) interactions with people who are close to you *, (2) interactions with 
other people *, and (3) ability to enjoy life.  
• Energy/vitality: (1) energy level, (2) ability to have a good night's sleep, and (3) mood.  
• Migraine symptoms: (1) have throbbing head pain, (2) have increased sensitivity to light 
and/or noise, and (3) have nausea.  
• Feelings/concerns: (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. 
Responses to items asterisked (“*”) are: a very great deal; a great deal; a good deal; a moderate 
amount; some; very little; and none. Responses to all other items are: all of the time; most of the 
time; a good bit of the time; some of the time; a little of the time; hardly any of the time; or none 
of the time. 
The total score will be calculated as the sum of item scores to all 15 questions. All 15 item 
scores must be non-missing; otherwise, the total score will be considered missing. 
Each domain score will be calculated as the sum of the 3 item scores pertaining to that domain. 
All 3 item scores must be non-missing; otherwise, the domain score will be considered missing. 


 
 
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MQoL total, domain, and item scores will be summarized by as-treated treatment group and All 
BHV-3500 for treated subjects as (1) continuous variables, and (2) the number and percentage 
of subjects in the following categories: 
• Total score: 15 to 30, 31 to 45, 46 to 60, 61 to 75, 76 to 90, and 91 to 105 
• Domain score: 3 to 6, 7 to 10, 11 to 14, 15 to 18, and 19 to 21 
• Item score: 7-point scale categories defined previously 
• Overall change since dose of medication: very much better; moderately better; a little better; 
no change; a little worse moderately worse; very much worse. Combined categories will 
include: (1) very much or moderately better; (2) not very much or moderately better, defined 
as the last 5 categories combined. 
Percentages for categories will be based on subjects with non-missing data. 
MQoL total, domain, and item scores will be summarized analogously by as-randomized 
treatment group for mITT subjects. 
A by-subject listing of MQoL will be provided for enrolled subjects, and will present the total 
score, domain scores, and item scores for each domain.  
7 CONVENTIONS 
7.1 
General  
7.1.1 
Output Layout 
All programmed outputs (i.e., TLFs) will be formatted and numbered according to the latest 
version of Biohaven Standard Outputs for CSRs. 
A list of TLFs and corresponding templates will be presented separately in a mock TLF 
document corresponding to this SAP. 
7.1.1.1 
Time-to-Event Tables and Plots 
Time-to-event endpoints will be summarized with KM tables displaying the following at each 
time interval: 
• Number of subjects at risk, defined as those who did not have the event just prior to the start 
of the interval and who were not censored prior to the interval 
• Number of subjects with events, defined as those who had the event for the first time during 
the interval 
• Number of subjects censored, defined as those who did not have the event and whose 
censoring date/time is in the interval 
• Cumulative probability of having the event with lower and upper CI limits, based on the KM 
product limit method. 


 
 
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Time-to-event endpoints will also be summarized with corresponding KM plots displaying 100 
times the cumulative probability of having the event on the y-axis and time on the x-axis, 
including the number of subjects at risk at each time point below the x-axis. 
Time-to-event distributions of endpoints will be summarized with the following descriptive 
statistics: number and percentage of subjects with events; number and percentage of subjects 
censored in or before the last time interval; number and percentage of subjects censored in the 
last time interval; median time to event with CI using the method of Brookmeyer and Crowley. 
CI levels will be 98.3% for efficacy endpoints and 95% for all other endpoints. 
7.1.1.2 
By-Subject Listings 
Unless specified otherwise, by-subject listings will be sorted by randomization status 
(randomized, not randomized), site-subject ID, and additional variables such as time points, as 
applicable. Listings will display site-subject ID and as-randomized treatment group. 
By-subject listings will display site-subject ID and “(Age/Sex/Race)” stacked together in the 
same column using the following conventions:  
• Age at informed consent will be displayed truncated to an integer.  
• Sex will be displayed abbreviated as “F” for female and “M” for male.  
• Race will be displayed abbreviated as “A” for Asian”, “B” for Black or African American, 
“I” for American Indian or Alaska Native, “M” for multiple, “N” for Native Hawaiian or 
Other Pacific Islander, and “W” for White. 
A footnote will describe race abbreviations as applicable, e.g., “Race: A = Asian, B = Black or 
African American, I = American Indian or Alaska Native, M = Multiple, N = Native Hawaiian 
or Other Pacific Islander, W = White”. See Section 6.2.4.1 for multiple race. Missing age, sex, 
or race will be displayed as a single blank space.  
Note that “(Age/Sex/Race)” will not be displayed in listings of randomization scheme and codes, 
batch numbers, and demographics. 
Listings of non-study medications, eDiary migraine characteristics, safety parameters, and 
outcomes research parameters will show both study day and treatment day (see Section 7.5). 
Other listings will display study day only, if applicable. 
7.1.2 
Descriptive Statistics 
For categorical variables, summary tabulations of the number and percentage of subjects within 
each category will be presented. If applicable, a “not reported” category for missing data will 
also be presented. Percentages will be displayed as: “<0.1” if 0 < percentage < 0.1; “>99.9” if 
99.9 < percentage < 100; 0 count without a percentage; and rounded to 1 decimal place 
otherwise. Measures of variance (standard error [SE], CI) will be presented to 1 decimal place. 


 
 
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For continuous variables, descriptive statistics (e.g., n, mean, median, standard deviation (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. Measures of variance (SD, SE, CI) will be presented with the 
precision of the data + 2 decimal places.  For percent change from baseline, the minimum and 
maximum will be presented in 0 decimal places; mean and percentiles will be presented in 1 
decimal place; and measures of variance in 2 decimal places. P-values < 0.0001 will be 
presented as “<0.0001”. Otherwise, p-values will be presented in 4 decimal places. 
7.1.3 
Counting Rules 
Frequency tables of the following endpoints will present the number and percentage of unique 
subjects with an event: significant protocol deviations; medical history; non-study medications; 
AEs; laboratory test shifts from baseline; vital sign and physical measurement abnormalities; 
ECG interpretation shifts from baseline and abnormalities; nasal inspection abnormalities. Thus, 
for these endpoints, multiple occurrences of the same event will be counted only once per 
subject. 
Percentages in frequency tables will be calculated against the number of subjects in the group 
(i.e., sample sizes in column headers), unless specified otherwise. For safety findings and OR 
endpoints, percentages will be calculated on a subset of subjects as follows: 
• In analyses of the worst abnormality or category in an analysis period, subjects must have a 
non-missing measurement in the analysis period to be included for a given parameter. 
• In shift from baseline analyses of an analysis period, subjects must have a non-missing 
measurement at baseline and in the analysis period to be included for a given parameter. 
7.2 
Subgroups 
Triptan non-responders are identified using the Prior Triptan Response CRF, which captures 
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 4 efficacy-related questions are as follows: 
• 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. 
Responses to each question are “most or all of the time”, “some of the time”, and “rarely”.  A 
subject is considered to have failed a drug for efficacy reasons if they responded “most or all of 
the time” to any of the 4 questions.  


 
 
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A triptan non-responder is defined as any subject that fails 2 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. 
7.3 
Derived Dates 
Derived dates are defined as follows: 
• Study drug start date/time: Earliest study medication date and time from the eDiary 
Migraine Report or Study Medication Intake Report (see Section 7.6.3.1). This date is used 
to define analysis periods. 
o eDiary Migraine Report 
§ If the subject answered “yes” to taking study medication mistakenly already, then the 
following conventions will be applied depending when drug was reported taken: 
• Today: study drug start date will be set to the finding date, and the study drug 
start time will be set to the time of study medication taken, if available. 
• Yesterday: study drug start date will be set to the finding date – 1 day, and study 
drug start time will be set to the time of study medication taken, if available. 
• Other: study drug start date will be set to the date of study medication taken, if 
available. 
§ Otherwise, if the subject answered “no” to taking study medication mistakenly 
already and answered “yes” to confirming having taken study medication, then the 
study drug start date/time will be set to the finding date/time. 
o Study Medication Intake Report: Study medication date/time. 
• Rescue medication start date/time: Earliest rescue medication date/time (see Section 6.2.5.2). 
Missing time is considered to be earlier than non-missing time on the same date. 
• Imputed rescue medication start date/time: This will be used only for time-to-event efficacy 
analyses in Section 6.3.5.2, and not for time to rescue medication use analyses in Section 
6.3.4.3. 
o If the rescue medication start date and time are both not missing, then the imputed rescue 
medication start date/time will be set to the rescue medication start date/time. 
o If the rescue medication start time is missing and the rescue medication start date is 
equal to the study drug start date, then the imputed rescue medication start date/time will 
be set to the study drug start date/time. 
o Otherwise, if the rescue medication start time is missing and the rescue medication start 
date is equal to a post-dose eDiary finding date with non-missing efficacy data, then the 
imputed rescue medication start date/time will be set to the first eDiary finding date/time 
corresponding to non-missing efficacy data. 
o Otherwise, if the rescue medication start time is missing and rescue medication start date 
is equal to the study drug start date + 1 day, then the imputed rescue medication start 


 
 
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date/time will be set to the study drug start date/time + upper bound of the X-hour 
analysis window (see Table 5).   
• Last contact date: (1) Complete death date, if it exists; (2) otherwise, the maximum complete 
date of the following: AE start/stop; ECG; eDiary finding; eDiary study drug start; informed 
consent; IWRS randomization; laboratory collection; non-study medication start/stop; 
physical measurement; procedure; rating scale; questionnaire; study 
completion/discontinuation from Study Exit Status CRF; vital sign; visit. 
No date imputations are performed on these derived dates. Complete dates are those with valid, 
non-missing day, month, and year. 
7.4 
Analysis Periods 
Analysis periods are defined as follows: 
• Pre-treatment: measurement date/time at or before the study drug start date/time. This period 
is used to derive baseline values and to assess pre-treatment endpoints. 
• On-treatment: measurement date/time after the study drug start date/time. Note that AEs 
with imputed start date equal to the study drug start date are part of this period. 
• On-study: measurement date/time after the randomization date/time.  
See Section 7.3 for derived dates for determining analysis periods.  
If measurement time is missing or not collected for a parameter, then the measurement date will 
be compared to the derived date.  
7.5 
Analysis Visit Windows 
Study days are calculated from the IWRS randomization date as follows: 
• Measurement date - randomization date + 1, if measurement date ³ randomization date 
• Measurement date - randomization date, if measurement date < randomization date. 
Treatment days are calculated from the study drug start date as follows: 
• Measurement date - study drug start date + 1, if measurement date ³ study drug start date 
• Measurement date - study drug start date, if measurement date < study drug start date. 
Analysis windows for safety and outcomes research parameters are presented in Table 4.  
For longitudinal analyses of safety and outcomes research parameters, the end of treatment 
analysis visit window is defined as measurement date/time > study drug start date/time. 


 
 
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Table 4: 
Analysis Windows for Safety and Outcomes Research Parameters 
Evaluation 
Analysis-Specified Interval 
Screening 
£ Study Day -1 
Randomization 
Study Day 1 
Post-Randomization 
≥ Study Day 2  
See Section 7.6.3.2 for efficacy analysis windows. 
7.6 
Domain-Specific Derivations 
7.6.1 
Adverse Events 
7.6.1.1 
Imputed AE Start Dates 
Imputed AE start dates will be used to classify AEs in analysis periods, and to determine LFT 
elevations concurrent with AEs of interest. 
Complete dates are those with non-missing day, month, and year that are valid and consistent 
with the standard international calendar.  
• Examples of complete dates: 01JAN2013, 31DEC2013; 
• Example of non-complete dates: missing, 31FEB2013, MAY2013, 2013, “unknown”, 
“ongoing”, “continuing”, “NA”. 
Partially complete dates are those with either (1) missing day with complete month and year, or 
(2) missing day and month with complete year. Examples: MAY2013, 2013. 
To derive the imputed AE start date and numeric imputed start date flag, the following 
algorithm is used if the investigator term is non-missing: 
1. If the reported start date is complete, then the imputed start date is set to the reported start 
date and the numeric imputed start date flag is set to 0 (No). 
2. If the reported start date is partially complete then the following algorithm is used: 
a. Calculate a surrogate date as the first complete date from the following list (in order of 
precedence): 
i. First active study medication date of any study medication; 
ii. Informed consent date; 
iii. Visit date corresponding to the visit at which the event was reported. 
If a complete date is not available for any of these 3 dates, then the surrogate date is set 
to missing. 
b. Calculate the derived date as the earliest possible date: 
i. If only year is provided, then set the derived date to January 1st of that year.  
e.g., 2004 => 01JAN2004 


 
 
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ii. If year and month are provided, then set the derived date to the first day of the month.  
e.g., AUG2004 => 01AUG2004 
3. Compare the derived date with the surrogate date as follows: 
a. If (1) the derived date is on or after the surrogate date or (2) the surrogate date is missing, 
then set the imputed start date to the derived date. 
e.g., surrogate date = 05JAN2004, partial date = SEP2004, derived date = 01SEP2004 
=> imputed start date = 01SEP2004 
b. If the derived date is before the surrogate date and the surrogate date is consistent with 
the partial date provided for the start date, then set the imputed start date to the surrogate 
date. 
e.g., surrogate date = 05JAN2004, partial date = JAN2004, derived date = 01JAN2004 
=> imputed start date = 05JAN2004 
c. If the derived date is before the surrogate date and the surrogate date is not consistent 
with the partial date provided for the start date, then set the imputed start date to be the 
latest possible date based on the partial start date information provided. 
i. If only year is provided, then set the imputed start date to December 31st of that year.  
e.g., surrogate date = 05JAN2004, partial date = 2003, derived date = 01JAN2003, 
imputed start date = 31DEC2003 
ii. If year and month and provided, then set the imputed start date to the last day of the 
month.  
e.g., surrogate date = 05JAN2004, partial date = DEC2003, derived date = 
01DEC2003, imputed start date = 31DEC2003 
The numeric imputed start date flag is set to 1 (Yes). 
4. If the reported start date is not complete and not partially complete, then the imputed start 
date is set to the first complete date from the following list (in order of precedence): 
a. First active study medication date of any study medication;  
b. Informed consent date;  
c. Visit date corresponding to the visit at which the event was reported. 
If a complete date is not available for any of these 3 dates, then the imputed start date is set to 
missing and the numeric imputed start date flag is set to 0 (No). Otherwise, the numeric imputed 
start date flag is set to 1 (Yes). 
7.6.1.2 
AE Frequency Table 
An AE will be considered to have developed during an analysis period if the imputed AE start 
date is in the analysis period. See Section 7.6.1.1 for AE start date imputation.  
Frequency tables will present the number and percentage of subjects experiencing AEs during 
analysis periods. The following counting rules will apply: 


 
 
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• In AE tables by severity, SOC, and PT, a subject’s worst severity of a PT during the analysis 
period will be reported. A subject will contribute only once to the count for a given AE SOC 
or PT, regardless of the number of events. 
o Severities may include total (i.e., any severity including missing), mild, moderate, and 
severe. 
o Example: If subject has 1 mild rash AE and 2 moderate rash AEs, then the subject will 
be counted under rash once in both the total and moderate severities. 
• In AE tables by SOC and PT, a subject will contribute only once to the count for a given AE 
SOC or PT, regardless of the number of events.  
• In AE tables by PT, a subject will contribute only once to the count for a given AE PT, 
regardless of the number of events. 
7.6.1.3 
Treatment-Emergent AEs 
Treatment-emergent AEs (TEAEs) are those that developed, worsened, or became serious 
during the on-treatment analysis period relative to the pre-treatment analysis period. For a given 
subject and PT, the following will apply: 
• An AE developed on treatment if the first occurrence (as determined by the imputed start 
date) is on treatment.  
• An AE worsened on treatment if the worst on-treatment severity is greater than the worst 
pre-treatment severity (including not reported).  
• An AE became serious on treatment if (1) at least one on-treatment AE has serious status of 
“yes”, and (2) no pre-treatment AE has serious status of “yes”. 
Thus, TEAEs are a subset of on-treatment AEs. 
7.6.1.4 
AEs of Special Interest 
Hepatic-Related AEs 
Hepatic-related AE PTs will include the following:  
• “Hepatic disorders” SMQ: All PTs except those in “Congenital, familial, neonatal and 
genetic disorders of the liver” SMQ. 
Cardiovascular AEs 
Cardiovascular AE PTs will include the following: 
• “Conditions associated with central nervous system haemorrhages and cerebrovascular 
accidents” SMQ: Narrow PTs 


 
 
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• “Ischaemic central nervous system vascular conditions” SMQ: Narrow PTs 
• “Embolic and thrombotic events, arterial” SMQ: peripheral arterial occlusive disease; 
peripheral arterial reocclusion; peripheral artery angioplasty; peripheral artery bypass; 
peripheral artery occlusion; peripheral artery stent insertion; peripheral artery thrombosis 
• “Ischaemic colitis” SMQ: Narrow PTs 
• “Ischaemic heart disease” SMQ 
o “Myocardial infarction” SMQ: Narrow PTs 
o  “Other ischaemic heart disease” SMQ: Narrow PTs 
Suicidality AEs 
Suicidality AE PTs will include the following: completed suicide; suicide attempt; suicidal 
ideation. 
7.6.2 
Non-Study Medications 
Non-study medication imputed start and stop dates will be derived in order to categorize non-
study medications as prior or concurrent!""
See Section 7.6.1.1 for the definitions of complete dates and partially complete dates.  
7.6.2.1 
Imputed Non-Study Medication Start Dates 
To derive the imputed medication start date and numeric imputed start date flag, the following 
algorithm is used if the reported medication is non-missing: 
 
1. If reported start date is complete: 
o Imputed start date is set to reported start date. 
o Numeric imputed start date flag is set to 0 (No). 
 
2. If reported start date is partially complete: 
• Imputed start date is set to the earliest possible date based on the partial start date 
information provided. 
             e.g., SEP2018 => 01SEP2018, 2018 => 01JAN2018 
• Numeric imputed start date flag is set to 1 (Yes).  
 
3. If reported start date is not complete and not partially complete then do                                           
    if informed consent date is complete then do  
       if reported end date is at or before informed consent date then do        
          if birth date is complete then do                                                                                                           
             imputed start date is set to birth date                                                                                  


 
 
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             numeric imputed start date flag is set to 1 (Yes)                                                                       
          end                                                                                                                     
          else do (i.e., birth date is not complete)                                                                                                
            imputed start date is set to missing                                                                              
            numeric imputed start date flag is set to 0 (No)                                                                  
          end           
      else if reported end date is after informed consent date then do 
          imputed start date is set to informed consent date    
          numeric imputed start date flag is set to 1 (Yes) 
       end 
     end 
     else do (i.e., informed consent date is not complete) 
       if birth date is complete then do 
         imputed start date is set to birth date 
         numeric imputed start date flag is set to 1 (Yes) 
       end 
     else do 
       imputed start date is set to missing 
       numeric imputed start date flag is set to 0 (No) 
     end 
   end 
 end 
7.6.2.2 
Imputed Non-Study Medication Stop Dates 
To derive the imputed medication stop date and numeric stop date imputed flag, the following 
algorithm is used if the reported term is non-missing: 
1. If reported stop date is complete: 
o Imputed stop date is set to the reported stop date. 
o Numeric stop date imputed flag is set to 0 (No). 
2. If reported stop date is partially complete: 
o Imputed stop date is set to the earlier of (a) death date or (b) last possible stop date based 
on the partial reported stop date information provided.  
e.g., if death date missing, then SEP2013 => 30SEP2013, 2013 => 31DEC2013 
o Numeric stop date imputed flag is set to 1 (Yes). 
3. If reported stop date is not complete and not partially complete:  
o Imputed stop date is set to the earlier of (a) death date or (b) most recent raw database 
creation date. 
o Numeric stop date imputed flag is set to 1 (Yes). 


 
 
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7.6.2.3 
Non-Study Medication Types 
Non-study medication types will include prior, previous, current, and concomitant. 
Prior medications are defined as those taken before study drug, i.e., imputed start or stop date < 
study drug start date. These include the following subtypes: 
• Previous medications, defined as those taken before informed consent, i.e., those with an 
imputed start or stop date < informed consent date 
• Current medications, defined as those taken on or after informed consent and before study 
drug, i.e., those with (1) informed consent date £ imputed start or stop date < study drug 
start date or (2) imputed start date £ informed consent date < study drug start date - 1 £ 
imputed stop date. 
Concomitant medications are defined as those taken on or after study drug, i.e., study drug start 
date £ imputed start or stop date. 
Listings will display abbreviated medication types. Note that a medication may be classified 
into multiple types. 
7.6.3 
eDiary Data 
7.6.3.1 
Study Medication 
eDiary Migraine Report 
If the subject answered “yes” to taking study medication mistakenly already before using the 
eDiary, then the eDiary Migraine Report will collect study medication time if the subject 
reported taking it today or yesterday; otherwise, only the study medication date will be collected. 
Otherwise, if the subject answered “no” to taking study medication mistakenly already, had a 
current pain level of moderate or severe, and answered “yes” to confirming having taken study 
medication, then the eDiary Migraine Report will record the time the subject has confirmed 
taking study medication (i.e., finding date/time) as the study medication time. 
eDiary Study Medication Intake Report 
Subjects who took study medication without using the eDiary will have the study medication 
date and time reported by the site on the eDiary Study Medication Intake Report. 


 
 
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7.6.3.2 
Migraine Characteristics 
The following migraine characteristics will be collected at migraine attack onset in the eDiary 
Migraine Report and post-dose from 15 minutes through 48 hours (e.g., 15, 30, 45, 60, and 90 
minutes; 2, 3, 4, 6, 8, 24 and 48 hours) in the eDiary Post-Dose Migraine Report: 
• Pain level (none, mild, moderate, severe) 
• MBS (nausea, phonophobia, photophobia) in the Migraine Report only 
• Nausea status (present, absent) 
• Nausea level (none, mild, moderate, severe) 
• Phonophobia status (present, absent) 
• Phonophobia level (none, mild, moderate, severe) 
• Photophobia status (present, absent) 
• Photophobia level (none, mild, moderate, severe) 
• Functional disability level (normal, mildly impaired, severely impaired, requires bedrest) 
• Aura (yes, no) in the Migraine Report only. 
The eDiary will allow subjects to report one result per time point per migraine characteristics 
parameter. 
In general, if subjects answered “no” to taking study medication mistakenly already, had current 
pain level of moderate or severe, and did not use other headache medications, then the eDiary 
Migraine Report will collect all parameters listed above. 
Otherwise, if subjects answered “yes” to taking study medication mistakenly already, then the 
eDiary Migraine Report will not collect the following parameters: most bothersome symptom, 
current pain level, nausea status, phonophobia status, and photophobia status. Instead, if the 
subject provided the time of study medication taken, then the eDiary Migraine Report will 
collect nausea level, phonophobia level, photophobia level, pain level and functional disability 
level at the time study drug was taken. Thus, for these subjects at on-study migraine attack onset, 
a symptom status (nausea, phonophobia, photophobia) of absent is defined as a level of none, 
and present is defined as a level of mild, moderate, or severe. 
Windows for post-dose efficacy measurements (15, 30, 45, 60, 90 minutes; 2, 3, 4, 6, 8, 24, and 
48 hours) will be automatically assigned by the eDiary as shown in Table 5. 


 
 
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Table 5: 
eDiary Automated Efficacy Analysis Windows 
Post-Dose Evaluation 
Analysis-Specified Interval 
Target Time 
15 minutes 
10 to 20 minutes  
Study medication start time + 15 minutes 
30 minutes 
25 to 35 minutes 
Study medication start time + 30 minutes 
45 minutes 
40 to 50 minutes 
Study medication start time + 45 minutes 
60 minutes 
55 to 65 minutes 
Study medication start time + 60 minutes 
90 minutes 
85 to 95 minutes 
Study medication start time + 90 minutes 
2 hours  
1 hour 45 minutes to 2 hours 15 
i
t
Study medication start time + 2 hours 
3 hours 
2 hours 45 minutes to 3 hours 15 
i
t
Study medication start time + 3 hours 
4 hours 
3 hours 45 minutes to 4 hours 15 
i
t
Study medication start time + 4 hours 
6 hours 
5 hours 45 minutes to 6 hours 15 
i
Study medication start time + 6 hours 
8 hours 
7 hours 45 minutes to 8 hours 15 
i
t
Study medication start time + 8 hours 
24 hours 
23 to 25 hours 
Study medication start time + 24 hours 
48 hours 
47 to 49 hours 
Study medication start time + 48 hours