Clinical trial NCT04804033
Conditions: Migraine
Keywords: Migraine Prevention Phonophobia Photophobia Nausea
Sponsor: Pfizer
Start date: 2021-03-26; Completion date: 2024-03-21
Enrollment: 1753 participants; Allocation: RANDOMIZED; Intervention model: SEQUENTIAL

Brief summary:
The purpose of this is study is to compare the efficacy of BHV-3500 (zavegepant) to placebo as a preventive treatment for migraine, as measured by the reduction in the number of migraine days per month.

Detailed description:

Arms: arm 1: Zavegepant 200mg oral soft gel capsule. arm 2: Matching placebo 200mg oral soft gel capsule. arm 3: Zavegepant 100mg oral soft gel capsule. arm 4: Matching placebo 100mg oral soft gel capsule.
Interventions: intervention 1: BHV-3500 (zavegepant) intervention 2: Placebo
Intervention descriptions: intervention 1: BHV-3500 (zavegepant) softgel capsule. intervention 2: Matching placebo softgel capsule.

Protocol documents:
Prot_000.pdf: 
Study BHV3500-302 Clinical Protocol, Version 6.0 
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DRUG:
Zavegepant (BHV-3500)
STUDY NUMBER(S):
BHV3500-302
PROTOCOL TITLE:
A Phase 2/3 Randomized, Double-Blind, Placebo-
Controlled Study to Evaluate the Efficacy and Safety 
of Oral Zavegepant in Migraine Prevention 
IND NUMBER:
151,524
SPONSOR:
Biohaven Pharmaceuticals, Inc. 
ORIGINAL PROTOCOL DATE:
15-January-2021
VERSION NUMBER:
v 6.0 
VERSION DATE:
16-May-2022
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SUMMARY OF CHANGES
Version Number
Brief Description Summary of Changes
Date
Version 1.0 – Original 
Not Applicable
15-January-2021
Version 2.0 
Updated dosing to during the DBT Phase, subjects 
will be instructed to follow one of the following 2 
dosing regimens:
!
Take four (4) 25 mg soft gelatin capsules of 
blinded study drug every calendar day, if 
randomized to the zavegepant 100 mg or 
placebo matching zavegepant 100 mg 
treatment group
!
Take eight (8) 25 mg soft gelatin capsules of 
blinded study drug every calendar day, if 
randomized to the zavegepant 200 mg or 
placebo matching zavegepant 200 mg 
treatment group. 
Updated subject screening numbers to 2900 and 
randomization to 1440. 
Updated study schematic. 
Removed MIDAS scale at the 4 and 8 Week 
Visits. 
Corrected inconsistencies, typographical errors 
throughout the protocol.
5-February-2021
Version 3.0
Switched the primary objective with a secondary 
objective.
Added an exploratory objective.
Updated LFTs to include CK at every visit. 
Corrected formatting in Exclusion criteria 6h-j.
Changed the central laboratory.
Corrected typographical errors and clarified 
wording throughout the document.
18-May-2021
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Version 4.0
Revised the target population of the study to 
subjects with chronic migraine.
Updated the introduction and study rationale to 
include background on chronic migraine.
Updated the primary objective to reference 
chronic migraine.
Revised the inclusion and exclusion criteria 
require subjects to have a history of chronic 
migraine prior to age 65.
Revised the inclusion and exclusion criteria to 
require subjects to have at least 8 migraine days
per month, at least 15 headache days per month, 
and at least 1 headache-free day per month, during 
the 3 months prior to the screening visit. Subjects 
must also have at least 15 headache days, at least 8 
migraine days, and at least one headache-free day 
during the Observation Phase.
Modified exclusion criterion to exclude subjects 
with chronic pain syndromes.
Removed history of use of analgesics (e.g., 
NSAIDs or acetaminophen on > 15 days per 
month during the 3 months (12 weeks) prior to the 
Screening Visit from list of prohibited 
concomitant medications. History of use of 
analgesics (e.g., nonsteroidal anti-inflammatory 
drugs [NSAIDs] or acetaminophen) on H 15 days 
per month during the 3 months (12 weeks) prior to 
the Screening Visit.
Modified use of devices, neuromodulation, 
neurostimulation, or injectable therapy (trigger 
point injections) for headache to prohibit acute 
treatment or prophylaxis 2 months prior to 
screening and during the study through week 
12/EOT.
Removed verapamil as an allowed prophylactic 
migraine treatment as it is a P-gp inhibitor.
Changed schedule of HbA1c collection to 
28-Jun-2021
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screening and EOT.
Corrected typographical errors and added 
clarification where needed.
Version 5.0
Added 52 week Open-Label Extension (OLE) 
phase to the protocol to allow subjects who 
completed the Double-blind Treatment (DBT) 
phase and have not entered the Follow-up phase to 
receive the same assigned zavegepant dose from 
the the DBT phase (either 100 mg or 200 mg) for 
up to 52 weeks in an OLE phase. All 
corresponding and relevant sections of the 
protocol were updated to reference this addition 
including the schedule of events and statistical 
sections. 
Reordered the 3 safety secondary objectives and 
endpoints to be last.
Added 2 exploratory objectives.
Corrected typographical errors and added 
clarification where needed. 
16-Nov-2021
Version 6.0
Added exploratory PK objective.
Corrected observation phase from screening or 
baseline.
Revised inclusion and exclusion criteria for clarity 
around use of CGRP monoclonal antibodies.
Added exclusion criterion 6l.
Removed St John’s Wort, as it is covered under 
CYP3A4 and P-gp inducers categories.
Corrected typographical errors and added 
clarification where needed.
16-May-2022
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BHV3500-302
A Phase 2/3, Randomized, Double-Blind, Placebo-Controlled Study to 
Evaluate the Efficacy and Safety of Zavegepant in Migraine Prevention
CONFIDENTIALITY AND INVESTIGATOR STATEMENT
The information contained in this protocol and all other information relevant to zavegepant 
(BHV-3500) are the confidential and proprietary information 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 zavegepant (BHV-3500) and the study.
______________________________
__________________________
Principal Investigator Name (printed)
Signature
___________ ___________
Date
Site Number
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Study Design:
All subjects will participate in a 28-day Observation Phase. During the 
Observation Phase, subjects will treat migraines with standard of care migraine 
medications. Subjects will report migraine occurrence, migraine pain features 
and associated symptoms (e.g., pain intensity, nausea, photophobia and 
phonophobia), and will document use of acute migraine medication in an 
electronic diary (eDiary). 
Eligible subjects will be randomized 2:2:1:1 across 4 treatment groups in the 
DBT Phase: zavegepant 100 mg (n = 480); zavegepant 200 mg (n = 480); 
placebo matching zavegepant 100 mg (n = 240); or placebo matching 
zavegepant 200 mg (n = 240). Subjects will take the assigned study drug every
day for 12 weeks. Subjects participating in PK draws will be required to dose 
in person at the study site to assess PK at the Week 4 and Week 8 Visits. 
Subjects will report migraine occurrence, migraine pain features and associated 
symptoms, and use of acute migraine medication in the eDiary during the DBT 
Phase. Upon completion of the DBT Phase, subjects may enter the 52-week 
OLE Phase and receive the assigned dose from the DBT Phase (either 
zavegepant 100 mg or 200 mg). If subjects do not enter the OLE Phase, they
will have visits in the Follow-up Phase at approximately 2 weeks and 8 weeks 
after the last visit in the DBT Phase. Subjects who complete the OLE Phase or 
who discontinue early during the OLE Phase will also have visits in the 
Follow-up Phase at approximately 2 weeks and 8 weeks after the last visit in 
the OLE Phase. 
Subjects will also report concomitant medication, including standard of care 
migraine medication (both prophylactic and acute), taken throughout the entire 
study in the concomitant medication paper diary.
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STUDY SCHEMATIC
Observation, DBT, and Follow-up Phases
OLE and Follow-up Phases
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TABLE OF CONTENTS
SUMMARY OF CHANGES.....................................................................................................2
CONFIDENTIALITY AND INVESTIGATOR STATEMENT .............................................5
STUDY SUMMARY (SYNOPSIS)...........................................................................................6
STUDY SCHEMATIC..............................................................................................................8
TABLE OF CONTENTS..........................................................................................................9
LIST OF TABLES ..................................................................................................................12
LIST OF FIGURES ................................................................................................................12
LIST OF ABBREVIATIONS .................................................................................................13
1
INTRODUCTION AND RATIONALE ..........................................................................15
1.1
Background..................................................................................................................15
1.2
CGRP’s Role in Migraine............................................................................................16
1.3
Product Development Background.............................................................................16
1.3.1
Clinical Experience................................................................................................16
1.3.1.1
Single Ascending Dose (SAD) BHV3500-101..................................................16
1.3.1.2
Multiple Ascending Dose Study (MAD) BHV3500-102..................................16
1.3.1.3
Phase 2/3 Dose Ranging Study (BHV3500-201)..............................................17
1.3.1.4
BHV3500-103 ...................................................................................................17
1.3.1.5
BHV3500-107 ...................................................................................................17
1.3.2
Summary of Animal Data with Oral and Sublingual Zavegepant.......................17
1.4
Study Rationale............................................................................................................18
1.4.1
Study Design Rationale..........................................................................................18
1.4.2
Dose Selection Rationale........................................................................................19
1.4.3
Other Rationale Related to the Compound / Study..............................................19
1.4.4
Research Hypothesis..............................................................................................19
2
STUDY OBJECTIVES ....................................................................................................20
2.1
Primary Objective(s) ...................................................................................................20
2.2
Secondary Objective(s)................................................................................................20
2.3
Exploratory Objective(s).............................................................................................21
3
STUDY ENDPOINTS ......................................................................................................23
3.1
Primary Endpoint(s)....................................................................................................23
3.2
Secondary Endpoint(s) ................................................................................................23
3.3
Definition of Migraine Days........................................................................................24
3.4
Definition of Headache Days.......................................................................................24
4
STUDY PLAN ..................................................................................................................25
4.1
Study Design and Duration .........................................................................................25
4.2
Study Schematic ..........................................................................................................27
4.3
Schedule of Assessments..............................................................................................29
4.3.1
Observation Phase .................................................................................................38
4.3.1.1
Screening Visit .................................................................................................38
4.3.1.2
Pre-randomization Laboratory Visit...............................................................38
4.3.2
Double-blind Treatment (DBT) Phase..................................................................39
4.3.2.1
Baseline (Randomization) Visit .......................................................................40
4.3.2.2
Week 12 or EOT Visit......................................................................................40
4.3.3
Open-label Extension (OLE) Phase.......................................................................40
4.3.3.1
Week 64 or EOT Visit......................................................................................41
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4.3.4
Follow-up Phase.....................................................................................................41
4.3.4.1
Follow-up Week 2 Visit....................................................................................42
4.3.4.2
Follow-up Week 8 Visit....................................................................................42
4.4
Post Study Access to Therapy (if applicable) .............................................................42
5
POPULATION.................................................................................................................43
5.1
Number of Subjects .....................................................................................................43
5.2
Inclusion Criteria.........................................................................................................43
5.3
Exclusion Criteria........................................................................................................44
5.4
Prohibited and Restricted Concomitant Medications and Devices............................48
5.5
Standard of Care Migraine Medications....................................................................50
5.5.1
Prophylactic Migraine Medications......................................................................50
5.5.2
Acute Migraine Medications .................................................................................51
5.6
Women of Childbearing Potential and Contraception...............................................51
5.7
Other Restrictions and Precautions (if applicable) ....................................................53
5.8
Deviation from Inclusion/Exclusion Criteria..............................................................53
6
STUDY CONDUCT AND DESCRIPTION OF STUDY PROCEDURES ....................54
6.1
Study Materials............................................................................................................54
6.2
Safety Assessments ......................................................................................................55
6.2.1
Vital Signs and Physical Measurements (Height and Weight).............................55
6.2.2
Electrocardiogram (ECG) .....................................................................................55
6.2.3
Physical Exam........................................................................................................55
6.2.4
Laboratory Tests....................................................................................................56
6.2.4.1
Safety Laboratory Testing...............................................................................56
6.2.4.2
PK Testing........................................................................................................56
6.2.4.3
Pregnancy Testing............................................................................................57
6.2.5
Columbia-Suicide Severity Rating Scale (C-SSRS)..............................................57
6.3
Efficacy Assessments ...................................................................................................57
6.4
Other Assessments.......................................................................................................57
6.4.1
Migraine-Specific Quality of Life Questionnaire v 2.1.........................................57
6.4.2
Migraine Disability Assessment ............................................................................58
6.4.3
Preference of Medication Scale .............................................................................58
6.4.4
Satisfaction with Medication Scale........................................................................58
6.4.5
Clinical Global Impression – Change (CGI-c) Scale ............................................58
6.5
Early Discontinuation from the Study........................................................................58
6.5.1
Lost to Follow-up ...................................................................................................59
6.6
Clinical Trial Subject Database (CTSdatabase).........................................................59
7
STUDY DRUG MANAGEMENT ...................................................................................61
7.1
Description of Study Drug...........................................................................................61
7.1.1
Investigational Product..........................................................................................61
7.1.2
Non-Investigational Product .................................................................................61
7.1.3
Formulation ...........................................................................................................61
7.1.4
Packaging, Shipment and Storage.........................................................................61
7.2
Dose and Administration.............................................................................................61
7.2.1
Method of Assigning Subject Identification..........................................................61
7.2.2
Selection and Timing of Dose and Administration...............................................62
7.2.3
Dose Modifications.................................................................................................63
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7.3
Blinding and Unblinding.............................................................................................63
7.4
Treatment Compliance................................................................................................63
7.5
Destruction and Return of Study Drug.......................................................................64
8
ADVERSE EVENTS........................................................................................................65
8.1
Serious Adverse Events ...............................................................................................66
8.1.1
Definition of Serious Adverse Event (SAE) ..........................................................66
8.1.2
Collection and Reporting Serious Adverse Events...............................................67
8.1.3
Pregnancy...............................................................................................................69
8.2
Non-Serious Adverse Events .......................................................................................69
8.2.1
Collection and Reporting of Non-serious Adverse Events ...................................70
8.2.2
Laboratory Test Abnormalities.............................................................................70
8.3
Overdose ......................................................................................................................70
8.4
Potential Drug Induced Liver Injury (DILI)..............................................................70
8.5
Adverse Events of Special Interest..............................................................................71
9
STATISTICS....................................................................................................................72
9.1
Sample Size ..................................................................................................................72
9.2
Analysis Sets ................................................................................................................72
9.3
Statistical Methods ......................................................................................................73
9.3.1
Efficacy Analyses ...................................................................................................73
9.3.1.1
Primary Efficacy Endpoint..............................................................................73
9.3.1.2
Secondary Efficacy Endpoints.........................................................................73
9.3.1.3
Adjustment for Multiplicity.............................................................................74
9.3.2
Safety Analyses ......................................................................................................74
9.4
Schedule of Analyses....................................................................................................75
10 ETHICS AND RESPONSIBILITIES..............................................................................76
10.1
Good Clinical Practice.................................................................................................76
10.2
Data and Safety Monitoring Committee.....................................................................76
10.3
Steering Committee .....................................................................................................76
10.4
Institutional Review Board/Independent Ethics Committee .....................................77
10.5
Informed Consent........................................................................................................77
10.6
Case Report Forms......................................................................................................78
11 RECORDS MANAGEMENT..........................................................................................79
11.1
Source Documentation ................................................................................................79
11.2
Study Files and Record Retention...............................................................................80
12 AMENDMENTS ..............................................................................................................81
13 STUDY REPORT AND PUBLICATIONS.....................................................................82
14 STUDY DISCONTINUATION .......................................................................................83
15 CONFIDENTIALITY......................................................................................................84
16 CLINICAL PROTOCOL APPROVAL FORM .............................................................85
17 APPENDICES..................................................................................................................86
17.1
APPENDIX 1 – Names of Study Personnel ................................................................86
17.2
Appendix 2 – Inhibitors and Inducers of CYP3A4 and Inhibitors of P-
glycoprotein (not all inclusive) ....................................................................................87
17.3
Appendix 3 – Definition of Migraine Days .................................................................89
17.4
Appendix 4 – Categories of Migraine Prevention Medications .................................91
18 REFERENCES.................................................................................................................92
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LIST OF TABLES
Table 1:
DBT Phase Schedule of Assessments...............................................................29
Table 2:
OLE Phase Schedule of Assessments...............................................................34
LIST OF FIGURES
Figure 1: 
Study Schematic: Observation, DBT, and Follow-up Phases.........................27
Figure 2: 
Study Schematic: OLE and Follow-up Phases................................................28
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LIST OF ABBREVIATIONS
AE
Adverse event
ALT
Alanine aminotransferase
AST
Aspartate aminotransferase
AUC
Area under the curve
bid
Twice daily
BP
Blood pressure
BUN
Blood urea nitrogen
CGRP
Calcitonin gene-related peptide
CI
Confidence interval
CK
Creatine kinase
Cmax
Maximum plasma concentration
CNO
Certificate of Non-Objection
CONMED
Concomitant medication
CRF
Case report form
C-SSRS
Columbia-Suicide Severity Rating Scale
CTCAE
Common Terminology Criteria for Adverse Events
CTSdatabase
Clinical Trial Subject Database
DAIDS
Division of AIDS
DBT
Double-blind Treatment
DSMC
Data and Safety Monitoring Committee
ECG
Electrocardiogram
eDiary
Electronic subject diary
GCP
Good Clinical Practice
GLMEM
Generalized linear mixed effect model
HR
Heart rate
ICF
Informed consent form
IB
Investigator’s Brochure
ICH
International Conference on Harmonization
IEC
Independent Ethics Committee
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IN
Intranasal
INR
International normalized ratio
IRB
Institutional Review Board
iv
Intravenous
kg
Kilogram
L
MBS
Liter
Most bothersome symptom
MedDRA
Medical Dictionary for Regulatory Activities
MIDAS
Migraine Disability Assessment
mg
Milligram
min
Minute
mmHg
Millimeters mercury
NOEL
No Observed Effect Level
NOAEL
No Observed Adverse Event Level
NO
ODT
Nitric oxide
Orally disintegrating tablet
OLE
PBO
Open-label Extension
Placebo
PK
Pharmacokinetic
P-gp
P-glycoprotein
po
By mouth, orally
qd
Once daily
SAE
Serious adverse event
SGC
Soft gelatin capsule
ULN
Upper limit of normal
WHO
World Health Organization
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1
INTRODUCTION AND RATIONALE
1.1
Background
Migraine is a common and debilitating neurological disorder that affects approximately 15% of 
the adult population. It is characterized by moderate-to-severe episodic unilateral pulsating 
headaches that last for 4 to 72 hours. Typical characteristics of the headache are unilateral 
location, pulsating quality, moderate or severe intensity, aggravation by routine physical activity, 
and association with nausea and/or photophobia and phonophobia.1 Roughly one third (38%) of 
migraine sufferers have more than 4 attacks per month or have a migraine attack that is 
incapacitating,2 and are candidates for preventive migraine therapy.
In the United States, as many as 38% of migraineurs of all types qualify for preventive therapy 
but fewer than 13% utilize such therapy. Similar and even lower utilization is noted in other 
countries that suffer comparable migraine burden.2 Chronic migraine affects about 1-3% of the 
world’s population, but the burden to these patients is high.3 Both direct and indirect costs 
(healthcare, lost productivity, disability, related comorbidities) for the chronic migraine patient 
are often 3 to 4 times higher than those of the episodic migraine patient.3,4 Reduction of migraine 
burden with preventative therapy for the patient with chronic migraine can be acheived by 
decreasing either attack frequency or level of impairment when migraines occur.2 The role of 
CGRP in migraine has been well-documented,5 and CGRP antagonists have been shown to be 
effective and well-tolerated acute treatment for migraine attacks as well as preventive treatment; 
including in patients with chronic migraine.6 CGRP antagonists have been shown to be effective 
for acute and preventative treatments for migraine as well as for chronic migraine.7 Increasing 
the number of preventive options for patients with chronic migraine will help reduce the personal 
and public health burden of this disease.
Zavegepant is a selective, competitive CGRP receptor antagonist being developed for the 
treatment of migraine. Zavegepant is being developed for intranasal (IN), oral, and sublingual 
administration. The CGRP receptor is located within pain-signaling pathways, intracranial 
arteries and the trigeminal ganglion, and its activation is thought to play a causal role in migraine 
pathophysiology. For example, research and clinical studies have shown that serum levels of 
CGRP are elevated during migraine attacks, infusion of intravenous CGRP produces persistent 
pain in migraine sufferers and non-migraine sufferers, and treatment with anti-migraine drugs 
normalizes CGRP levels. Additionally, multiple clinical studies show that small molecule CGRP 
receptor antagonists, which inhibit the binding of endogenous CGRP to CGRP receptors, are 
effective in aborting migraine attacks.
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1.2
CGRP’s Role in Migraine
CGRP receptor antagonists have been shown to be effective for both the acute and preventive 
treatment of migraine.5,8,9 The efficacy of CGRP receptor antagonists against migraine is 
believed to be effected through the following mechanisms:
!
Blocking Neurogenic Inflammation: Binding of CGRP receptor antagonists to CGRP 
receptors located on satellite glial cells would inhibit inflammation caused by trigeminal 
nerve release of CGRP onto satellite glial cells and cell bodies of a-delta fibers in the 
trigeminal ganglion.
!
Decreasing Artery Dilation: By blocking the CGRP receptors located in smooth muscle 
cells within vessel walls in the meninges, CGRP receptor antagonists would inhibit the 
pathologic dilation of intracranial arteries without the unwanted effect of active 
vasoconstriction.
!
Inhibiting Pain Transmission: Binding of CGRP receptor antagonists to CGRP 
receptors located on post-synaptic cells would inhibit the transmission of exaggerated 
pain signals in the brainstem.
1.3
Product Development Background
Details of the clinical and preclinical studies are provided in the most current Investigator 
Brochure. A summary of the relevant data to the study is presented below. 
1.3.1
Clinical Experience 
1.3.1.1
Single Ascending Dose (SAD) BHV3500-101 
Administration of IN zavegepant in the Phase 1, double-blind, placebo-controlled SAD study
ranging from 0.1 mg to 40 mg was safe and well tolerated in healthy adult subjects. A total of 72 
subjects were randomized and received a single dose of zavegepant or matching placebo as a
single intranasal dose of 0.1 mg to 40 mg and completed the study. Dose escalation to the highest
planned dose of 40 mg was completed and no dose limiting toxicity was observed. A Maximum
Tolerated Dose (MTD) was not identified. Intranasal administration of zavegepant in this study 
produced plasma levels predicted to be within the therapeutic range based on preclinical models
predictive for compounds of this class1,10.
Additional details can be found in the Investigator’s Brochure. 
1.3.1.2
Multiple Ascending Dose Study (MAD) BHV3500-102
The Phase 1, multiple ascending dose (MAD) study evaluating the safety, tolerability, and PK of 
zavegepant following IN administration of MADs (placebo, 5 mg, 10 mg, or 20 mg) in normal 
healthy subjects has concluded. In this study, a total of 36 healthy subjects (3 cohorts) were 
administered multiple ascending doses of IN zavegepant (planned doses of 5 mg, 10 mg or 
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20mg; N = 12 per treatment group [3:1 zavegepant:PBO]) with the first 3 cohorts receiving a 
once daily dose for 14 days. Cohort 4 received two sequential 20 mg zavegepant doses (n=9) or 
placebo (n=3) separated by 2 hours (40 mg total daily) for 8 consecutive days. Two additional 
alternate dosing cohorts received 2 repeated IN administrations of zavegepant 20 mg or placebo 
on a single day. Safety data from BHV3500-102 indicated that zavegepant was well tolerated at 
all dose levels and a maximum tolerated dose was not identified. No deaths or serious adverse 
events (SAEs) were reported in this study. Additional details can be found in the Investigator’s 
brochure.
1.3.1.3
Phase 2/3 Dose Ranging Study (BHV3500-201)
The pivotal Phase 2/3 dose-ranging study evaluating the safety and efficacy of 3 different IN 
dose levels (5 mg, 10 mg, 20 mg) of zavegepant, relative to placebo, in the acute treatment of 
migraine with moderate to severe pain intensity has concluded. Data from BHV3500-201 
indicate that zavegepant as a single IN spray containing 5mg, 10mg, or 20 mg was well tolerated 
in adult subjects with moderate to severe migraine attacks and demonstrated a favorable safety 
profile comparable with placebo. The study met the primary endpoint, and the 10 mg dose was 
identified as the lowest efficacious dose demonstrating statistically significant efficacy. 
No deaths were reported in the study. SAEs were reported in 2 subjects on-treatment including:
thrombosis reported in 1 subject from the 10 mg group; and vestibular migraine reported in 1 
subject in the placebo group. Both events were moderate in intensity and judged by the 
investigator as not related to study therapy. The SAE of thrombosis was reported 13 days after 
the single dose of zavegepant as post trauma from an automobile accident.  Additional details 
can be found in the Investigator’s Brochure.
1.3.1.4
BHV3500-103
This was a Phase 1 single dose of 50 mg in 3 different oral formulations of zavegepant in healthy 
subjects to evaluate the safety and tolerability and characterize the PK.  Additional details can be 
found in the Investigator’s Brochure. 
1.3.1.5
BHV3500-107
This is a recently concluded Phase 1, placebo-controlled, multiple ascending dose (MAD) study 
that evaluated the safety, tolerability, and PK of single and multiple ascending doses of oral 
zavegepant using 50 mg to 300 mg for up to 14 days. Preliminary blinded data from the
BHV3500-107 trial has shown to date that multiple dose administrations of 50 mg, 100 mg, 200 
mg or 300 mg daily for 14 days have been well tolerated. No deaths or SAEs were reported in 
the study. Thus far, the adverse events (AEs) reported have been predominantly mild in intensity, 
and there have been no clinically significant findings on ECG, lab assessments or vital signs.
1.3.2
Summary of Animal Data with Oral and Sublingual Zavegepant 
Oral (capsule) administration of 50 mg zavegepant to dogs for 14 days was well tolerated with 
no effects on clinical or physical examination findings, body weights, food consumption, 
ophthalmic and electrocardiograph (ECG) assessments, clinical pathology parameters 
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(hematology, clinical chemistry, coagulation, and urinalysis), organ weights, or macroscopic 
findings.
Summary of animal safety and PK data with oral and sublingual formulations can be found in the 
Investigator’s brochure.10
1.4
Study Rationale
Biohaven Pharmaceuticals is developing a new oral soft gelatin capsule (SGC) of zavegepant 
(BHV-3500) as a preventive treatment in subjects with chronic migraine.  
The goal of this study is to assess the efficacy and safety of daily (qd) dosing of zavegepant.
This study is being conducted to evaluate the efficacy, safety, and tolerability of zavegepant for 
the preventive treatment of chronic migraine. It will also further define the safety profile of 
zavegepant administration for as long as 64 weeks (12 weeks of double-blind and 52 weeks of 
open-label). Approximately 1440 subjects will dose with double-blind study drug every day for a 
period of approximately 12 weeks.  Randomization will be stratified by stable prophylactic 
migraine medication use through randomization (yes or no; see Section 7.2.1). Subjects who 
complete the 12-week DBT Phase may continue to the 52-week OLE Phase. In the OLE Phase, 
subjects will continue to take the dosing regimen they were randomized to during the DBT Phase 
(i.e., zavegepant 100 mg or 200 mg daily).
1.4.1
Study Design Rationale
This is a 12-week multicenter, randomized, double-blind, placebo-controlled evaluation of the 
efficacy and safety of zavegepant tablet taken every day for the prevention of migraine in 
subjects with a history of chronic migraine. Eligible subjects who complete the 12-week DBT 
Phase may continue to the 52-week OLE Phase.
Approximately 1440 subjects will be randomized and assigned treatment in the DBT Phase.  
Subjects will be randomized in a 2:2:1:1 ratio across 4 treatment groups: zavegepant 100 mg (n = 
480); zavegepant 200 mg (n = 480); placebo matching zavegepant 100 mg (n = 240); or placebo 
matching zavegepant 200 mg (n = 240). Randomization will be stratified by use of stable 
prophylactic migraine medication through randomization (yes or no; see Section 7.2). Upon 
completion of the 12-week DBT Phase, eligible subjects may continue to the 52-week OLE 
Phase. In the OLE Phase, subjects will continue to take the dosing regimen they were 
randomized to during the DBT Phase (i.e., zavegepant 100 mg or 200 mg daily).
During the DBT Phase, subjects will be instructed to follow one of the following 2 dosing 
regimens:
!
Take four (4) 25 mg soft gelatin capsules of blinded study drug every calendar day, if 
randomized to the zavegepant 100 mg or placebo matching zavegepant 100 mg treatment 
group
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!
Take eight (8) 25 mg soft gelatin capsules of blinded study drug every calendar day, if 
randomized to the zavegepant 200 mg or placebo matching zavegepant 200 mg treatment 
group. 
If subjects have a migraine, they may treat the migraine with permitted acute migraine 
medication (see Section 5.5.2) and continue to take study drug on their regular schedule.  
Subjects who enter the OLE Phase will continue to take the dosing regimen they were 
randomized to during the DBT Phase (i.e., 100 mg zavegepant daily or 200 mg zavegepant 
daily). 
1.4.2
Dose Selection Rationale
The oral soft gelatin formulation of zavegepant was selected based on safety and PK data from 
the single dose BHV3500-103 study and the multiple dose study, BHV3500-107. The 
preliminary exposures at steady state from the soft gelatin 100 mg oral dose (4 x 25 mg capsules) 
administered QD are a geometric mean (GM) Cmax of 9.0 ng/mL and AUC of 36.6 ng*hr/mL, 
similar to slightly higher than the AUC, and 30% lower than the Cmax following 10 mg QD by 
the IN route; 10 mg is the IN dose progressed into pivotal studies in treatment of acute migraine 
headache. 
Preliminary results from the soft gelatin 200 mg oral dose (8 x 25 mg capsules) administered QD 
produced a GM Cmaxof 23.6 ng/mL and AUC of 91.2 ng*hr/mL, 1.8- and 2.8-fold higher in 
Cmax and AUC, respectively, than that produced by the 10 mg IN dose. Relative to the multiple-
dose PK from the highest dose studied in Phase 2/3 acute migraine treatment study BHV3500-
201, 20 mg IN, the 200 mg oral soft gelatin dose yielded a Cmax that was 42% lower, and a 
comparable AUC.
1.4.3
Other Rationale Related to the Compound / Study
Not applicable. 
1.4.4
Research Hypothesis
Zavegepant 100 mg or zavegepant 200 mg soft gelatin capsule (SGC) oral dose taken daily is 
safe and effective for the prevention of migraine. 
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2
STUDY OBJECTIVES
A month is defined as 4 weeks (28 days) for the purpose of this protocol.
2.1
Primary Objective(s)
To compare the efficacy of zavegepant to placebo as a preventive treatment for chronic migraine, 
as measured by the mean reduction from the Observation Phase in the number of migraine days 
per month over the entire DBT Phase.  
2.2
Secondary Objective(s)
1. To compare the efficacy of zavegepant to placebo on the proportion of subjects with  50% 
reduction from the Observation Phase in the number of moderate to severe migraine days per 
month over the entire DBT Phase.
2. To compare the efficacy of zavegepant to placebo on the mean reduction from the 
Observation Phase in the number of migraine days per month in the last 4 weeks of the DBT
Phase.
3. To compare the efficacy of zavegepant to placebo on the mean reduction from the
Observation Phase in the number of migraine days per month in the first 4 weeks of the DBT
Phase.
4. To compare the efficacy of zavegepant to placebo on the mean number of acute migraine-
specific medication days per month over the entire DBT Phase.
5. To compare the mean change from baseline in the Migraine-Specific Quality-of-Life 
Questionnaire v 2.1 (MSQ) restrictive role function domain score at Week 12 of the DBT
Phase between zavegepant and placebo.
6. To compare the mean change from baseline in the Migraine Disability Assessment (MIDAS) 
total score at Week 12 of the DBT Phase between zavegepant and placebo.
7. To evaluate the safety and tolerability of zavegepant during the DBT and OLE Phases.
8. To evaluate the frequency of ALT or AST > 3x upper limit of normal (ULN) concurrent with 
total bilirubin > 2x ULN in subjects treated with zavegepant during the DBT and OLE 
Phases.
9. To evaluate the frequencies of hepatic-related adverse events and hepatic-related adverse 
events leading to study drug discontinuation in subjects treated with zavegepant during the 
DBT and OLE Phases.
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2.3
Exploratory Objective(s)
1. To compare the efficacy of zavegepant to placebo on the mean reduction from the 
Observation Phase in the number of migraine days per month and number of headache days 
per month by pain intensity (total; moderate or severe) in each month and over the entire 
DBT Phase.
2. To compare the efficacy of zavegepant to placebo on the proportions of subjects with  50% 
reduction,  75% reduction, and 100% reduction from the Observation Phase in the number 
of migraine days per month and number of headache days per month by pain intensity (total;
moderate or severe) in each month and over the entire DBT Phase.
3. To compare the efficacy of zavegepant to placebo on the mean reduction from the 
Observation Phase in the number of migraine days per week and number of headache days 
per week by pain intensity (total; moderate or severe) in each week of the first 4 weeks of the 
DBT Phase.
4. To compare the efficacy of zavegepant to placebo on the proportions of subjects with  50% 
reduction from the Observation Phase in the number of migraine days per week and number 
of headache days per week by pain intensity (total; moderate or severe) in each week of the 
first 4 weeks of the DBT Phase.
5. To compare the efficacy of zavegepant to placebo on the proportions of subjects with a 
migraine day and headache day by pain intensity (total; moderate or severe) on each day of 
the first week of the DBT Phase.
6. To compare the efficacy of zavegepant to placebo on the mean number of acute migraine-
specific medication days per month in each month and over the entire DBT Phase.
7. To compare the efficacy of zavegepant to placebo on the mean number of acute migraine 
medication days per month in each month and over the entire DBT Phase.
8. To evaluate the frequency of liver function test (LFT) elevations (AST, ALT, or total 
bilirubin) based on fold changes above ULN in subjects treated with zavegepant during the 
DBT and OLE Phases.
9. To evaluate the frequency of ALT or AST > 3x ULN in temporal association with nausea, 
vomiting, anorexia, abdominal pain or fatigue in subjects treated with zavegepant during the 
DBT and OLE Phases.
10. To compare the mean changes from baseline in the MSQ preventive role function and 
emotional function domain scores at Week 12 of the DBT Phase between zavegepant and 
placebo.
11. To compare the mean changes from baseline in the MIDAS absenteeism and presenteeism 
scores at Week 12 of the DBT Phase between zavegepant and placebo.
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12. To evaluate the mean changes from baseline in MSQ domain scores and MIDAS scores 
during the OLE Phase.
13. To evaluate the Preference of Medication (PoM) scale during the DBT and OLE Phases.
14. To evaluate the Satisfaction with Medication (SM) scale during the DBT and OLE Phases.
15. To evaluate the Clinical Global Impression – change (CGI-c) scale during the DBT and OLE 
Phases.
16. To evaluate the pharmacokinetics of zavegepant 100 mg and 200 mg.
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3
STUDY ENDPOINTS 
Migraine days per month and acute migraine-specific medication days per month are derived 
from eDiary data.
Adverse events (AEs) are determined from case report forms (CRFs).
MSQ domain scores and MIDAS total score are derived from CRFs.
Grade 3 to 4 laboratory test abnormalities are determined from laboratory test values graded 
using standardized criteria. Laboratory tests are identified from CRFs and central laboratory data.
3.1
Primary Endpoint(s)
Mean change from the Observation Phase in the number of migraine days per month over the 
entire DBT Phase (Weeks 1 to 12).
3.2
Secondary Endpoint(s)
1. Proportion of subjects with  50% reduction from the Observation Phase in the number of 
moderate to severe migraine days per month over the entire DBT Phase (Weeks 1 to 12).
2. Mean change from the Observation Phase in the number of migraine days per month in the 
last 4 weeks (Weeks 9 to 12) of the DBT Phase.
3. Mean change from the Observation Phase in the number of migraine days per month in the 
first 4 weeks (Weeks 1 to 4) of the DBT Phase.
4. Mean number of acute migraine-specific medication days per month over the entire DBT
Phase (Weeks 1 to 12). Acute migraine-specific medications are triptans and ergotamine (see 
Section 3.3).
5. Mean change from baseline in the MSQ restrictive role function domain score at Week 12 of 
the DBT Phase.
6. Mean change from baseline in the MIDAS total score at Week 12 of the DBT Phase.
7. Number and percentage of subjects with AEs by intensity, SAEs, AEs leading to study drug 
discontinuation, and grade 3 to 4 laboratory test abnormalities during the DBT and OLE 
Phases.
8. Number and percentage of subjects with AST or ALT elevations > 3x ULN concurrent (i.e., 
on the same laboratory collection date) with total bilirubin > 2x ULN during the DBT and 
OLE Phases. 
9. Number and percentage of subjects with hepatic-related AEs by intensity, and hepatic-related 
AEs leading to study drug discontinuation during the DBT and OLE Phases.
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3.3
Definition of Migraine Days 
A Migraine Day is defined as any calendar day which the subject experiences a qualified
migraine headache (onset, continuation or recurrence of the migraine headache). A qualified 
migraine headache is defined as a migraine with or without aura, lasting for H 30 minutes, and 
meeting at least one of the following criteria (A and/or B):
A. H 2 of the following pain features:
a.
Unilateral location,
b. Pulsating quality (throbbing),
c.
Moderate or severe pain intensity,
d. Aggravation by or causing avoidance of routine physical activity (e.g. walking or 
climbing stairs)
B.
H 1 of the following associated symptoms:
a.
Nausea and/or vomiting
b. Photophobia and phonophobia
During the DBT Phase, if the subject takes an acute migraine-specific medication (i.e., e.g., 
triptan or ergotamine) during aura or to treat a headache, then it will be counted as a migraine 
day regardless of the duration and pain features/associated symptoms. 
For the full definition of Migraine Days, please refer to Section 17.3 Appendix #3.
3.4
Definition of Headache Days 
A Headache Day is any calendar day in which the subject experiences a qualified headache 
(initial onset, continuation, or recurrence of the headache). A qualified headache is defined as:
!
A qualified migraine headache (including an aura-only event that is treated with acute
migraine-specific medication), or
!
A qualified non-migraine headache, which is a headache that lasts H 30 minutes and is not a 
qualified migraine headache, or
!
A headache of any duration for which acute headache treatment is administered (see Section 
5.5.2).
!
For the full definition of Headache Days, please refer to Section 17.3 Appendix #3.
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4
STUDY PLAN
4.1
Study Design and Duration
This is a multicenter, randomized, double-blind, placebo-controlled study to assess the efficacy 
and safety of zavegepant in migraine prevention with a 52-week OLE Phase.
The 28-day (+3 days) Observation Phase includes a Screening Visit and a Pre-randomization 
Laboratory Visit. Note that the +3 days should only be used for scheduling in cases of holidays 
or weekends. For subjects to be eligible for the study, they must have a one-year history of 
chronic migraine according to International Classification of Headache Disorders, 3rd Edition,11
as well as a history of one headache-free day per month during the last 3 months before 
Screening. Additionally, the subjects must have at least 15 headache days, at least 8 migraine 
days, and at least 1 headache-free day during 28 days in the Observation Phase which will be
documented in the eDiary.
Upon the completion of the Screening Visit, subjects will be provided an electronic diary 
(eDiary) to document the following on each day of the Observation Phase: migraine occurrence; 
migraine pain features and associated symptoms (see Section 3.3); and use of acute migraine
medication (e.g., triptans; see Section 5.5.2). In addition, subjects will record all concomitant 
medications, including standard of care migraine medications (both prophylactic and acute), 
taken in the concomitant medication paper diary (see Sections 5.5.1 and 5.5.2). After completing 
the Observation Phase, the subject will return to the clinic with the eDiary and concomitant 
medication paper diary for the Baseline (Randomization) Visit.
Subjects will have blood drawn for baseline laboratory profiles at the Pre-randomization 
Laboratory Visit; this visit must occur within 96 hours (4 days +2 days) of the Baseline Visit. 
Note that the +2 days should only be used for scheduling in cases of holidays or weekends. 
Subjects will then return for the Baseline Visit but cannot be randomized until the pre-
randomization laboratory results are reviewed and determined to meet eligibility.
At the Baseline Visit, eligibility for continued participation in the study will be assessed before
randomization occurs and study drug will be dispensed. Subjects will be instructed that they 
must take 4 or 8 soft gelatin capsules (SGC) of blinded study drug every calendar day. If subjects 
have a migraine during the DBT Phase, they may, if needed, treat the migraine with their 
standard of care medication and must continue to take study drug. 
During the DBT Phase, subjects will record their migraine occurrence, migraine pain features 
and associated symptoms, and use of acute migraine medication on each day in the eDiary. 
Subjects will also use the eDiary only during the DBT Phase to complete the Preference of
Medication (PoM) questionnaire and the Satisfaction with Medication (SM) questionnaire.
Subjects will also record all concomitant medications, including standard of care migraine 
medications (both prophylactic and acute), taken during the DBT, OLE, and Follow-up Phases in 
the concomitant medication paper diary.
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At select study visits, subjects will complete or will be administered the Migraine-Specific 
Quality-of-Life Questionnaire v 2.1 (MSQ v 2.1), the Migraine Disability Assessment (MIDAS), 
Clinical Global Impression – change (CGI-c) scale, PoM (OLE Phase only), SM (OLE Phase 
only), and the Columbia-Suicide Severity Rating Scale (C-SSRS) on paper forms.
At the DBT Week 4 and Week 8 Visits, subjects participating in PK draws will be required to 
dose in person at the study site to assess PK (predose and at least 1 hour after dose; exact time of 
PK collection relative to the dose will be documented). Additional assessments and visit 
schedule are outlined in Table 1. Procedures include study personnel review of the eDiary data
and concomitant medication paper diary data with the subject, assessment of study drug
compliance, and monitoring of tolerability and safety (including collection of adverse events, 
physical exam, vital signs, laboratory tests, and electrocardiography).
During the Observation Phase, study visits will occur at Screening (Enrollment) and Pre-
randomization Laboratory.
During the DBT Phase, study visits will occur at Baseline, Week 2, Week 4, Week 8, and Week 
12. Subjects who are not eligible to enter the OLE Phase should continue to the Follow-up Phase. 
Upon completion of the 12-week DBT Phase, eligible subjects may continue the same dosing 
regimen (zavegepant 100 mg or 200 mg daily) in the OLE Phase for up to 52 weeks (64 total 
weeks between DBT Phase and OLE Phase). During the OLE Phase, study visits will occur at 
Week 14, Week 16, and every 4 weeks thereafter until Week 64. If subjects have a migraine 
during the OLE Phase, they may, if needed, treat the migraine with their standard of care 
medication and must continue to take study drug.
During the Follow-up Phase, study visits will occur at Follow-up Week 2 and Follow-up Week 8 
for assessment of AEs and laboratory assessments.  All randomized subjects should complete the 
Follow-up Week 2 and Follow-up Week 8 Visits, regardless of completing either treatment 
phase.
To closely monitor for potential drug induced liver injury, guidance on reporting potential drug-
induced liver injury (DILI) events is provided in the protocol. Lab results that meet predefined 
LFT abnormality criteria as DILI should be reported as an SAE. See Section 8.4, Potential Drug 
Induced Liver Injury (DILI).
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4.2
Study Schematic
Figure 1:
Study Schematic: Observation, DBT, and Follow-up Phases
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Figure 2: 
Study Schematic: OLE and Follow-up Phases
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4.3
Schedule of Assessments
Table 1:
DBT Phase Schedule of Assessments
Observation Phase                  
(28 days, +3 days)
DBT Phase (12 weeks)1,2
Follow-up 
Phase
Procedure
Screening 
Visit
Pre-
randomization 
Laboratory 
Visit:3 must 
occur within 96 
hours before
Baseline 
(Randomization) 
Visit4
Baseline 
(Randomization) 
Visit5 (Day 1 of DBT 
Phase)
Week 2
Visit (Day 
15 +/- 2 
days) 
Week 4
Visit (Day 
29), Week 8
Visit (Day 
57)
(both visits 
+/- 2 days)
Week 12 (Day 
86 + 3 days) or 
EOT Visit for 
early 
discontinuation
Follow-up 
Week 2 Visit,
Follow-up 
Week 8 Visit
(both visits 
+/- 2 days)6
Informed Consent 
X
Duplicate subject check (in 
CTSdatabase)
X
Inclusion/ Exclusion Criteria 
X
X
X
Medical History 
X
                                               
1 Subjects who do not complete the DBT Phase should complete the EOT, Follow-up Week 2, and Follow-up Week 8 Visits.
2 While on-study, all visit windows are used for scheduling purposes and all efforts should be made to return subjects to the 28-day schedule if scheduling changes are made 
at any previous visit(s).
3 If the laboratory results are not acceptable per protocol, the subject is determined to be a screen failure and must return to the study site to return the eDiary. Repeat testing 
of liver function test (LFT) abnormalities will not be permitted at this visit.
4 The duration between the Pre-randomization Laboratory Visit and the Baseline Visit is 4 days.  The “+2” days window is included for scheduling purposes only. Every 
effort should be made to collect the Pre-randomization Laboratory Visit samples as close to, and within, the 4 days prior to the Baseline Visit as possible. However, for 
scheduling convenience, this window may be up to 6 days between the Pre-randomization Laboratory Visit and the Baseline Visit.
5 Subjects should take their first dose of study drug the day after the Baseline Visit to ensure the subject is fasting appropriately (dose 4 hours after a meal and 1 hour before a 
meal). Review section 4.3 where phases and visits are described.
6 Follow-up visits are based off the DBT Week 12/EOT Visit, for subjects who do not enter the OLE Phase.
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Observation Phase                  
(28 days, +3 days)
DBT Phase (12 weeks)1,2
Follow-up 
Phase
Procedure
Screening 
Visit
Pre-
randomization 
Laboratory 
Visit:3 must 
occur within 96 
hours before
Baseline 
(Randomization) 
Visit4
Baseline 
(Randomization) 
Visit5 (Day 1 of DBT 
Phase)
Week 2
Visit (Day 
15 +/- 2 
days) 
Week 4
Visit (Day 
29), Week 8
Visit (Day 
57)
(both visits 
+/- 2 days)
Week 12 (Day 
86 + 3 days) or 
EOT Visit for 
early 
discontinuation
Follow-up 
Week 2 Visit,
Follow-up 
Week 8 Visit
(both visits 
+/- 2 days)6
Migraine History 
(signs/symptoms/prior
treatment/frequency/intensity/MBS)
X
Concomitant medication paper 
diary 7
X
X
X
X
X
X
X
Randomize subject in IWRS
X8
Physical Examination9
X
X
X
X
X
Vital Signs / Physical 
Measurements
X
X
X
X
X
X
PK Sample Collection 10
X
                                               
7 Concomitant medications, including standard of care migraine medications (both prophylactic and acute), taken throughout the study should be recorded by subjects in the 
concomitant medication paper diary and reviewed by study personnel at each visit.
8 The actual Baseline Visit date should be used for IWRS enrollment date and eligibility date.
9 Height measured at Screening Visit only. Weight, body temperature, respiratory rate, blood pressure, and heart rate will be collected at all timepoints where indicated.  
Sitting arterial systolic and diastolic blood pressure and radial artery pulse rate will be measured. Recommend that subjects sit at rest for 5-10 minutes prior to measurement 
of blood pressure and pulse. Full physical exam required at the screening, Week 12/EOT, and Follow-up Week 2 visits. Targeted physical exam of heart, lungs, and abdomen; 
plus other systems based on signs and symptoms is required at the Baseline, Week 4, Week 8, and Follow-up Week 8 visits.
10 PK will be collected only at the DBT Week 4 and Week 8 Visits. Subjects will be instructed to not take study drug until they are at the study site.  Subjects will have PK 
drawn predose and at least 1 hour postdose; exact time of PK collection relative to the dose will be documented. Subjects should fast for duration of PK assessments.  
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Observation Phase                  
(28 days, +3 days)
DBT Phase (12 weeks)1,2
Follow-up 
Phase
Procedure
Screening 
Visit
Pre-
randomization 
Laboratory 
Visit:3 must 
occur within 96 
hours before
Baseline 
(Randomization) 
Visit4
Baseline 
(Randomization) 
Visit5 (Day 1 of DBT 
Phase)
Week 2
Visit (Day 
15 +/- 2 
days) 
Week 4
Visit (Day 
29), Week 8
Visit (Day 
57)
(both visits 
+/- 2 days)
Week 12 (Day 
86 + 3 days) or 
EOT Visit for 
early 
discontinuation
Follow-up 
Week 2 Visit,
Follow-up 
Week 8 Visit
(both visits 
+/- 2 days)6
Clinical Safety Laboratory Testing
X
X
X (Week 4 
only)
X
Liver Function Tests
X
X11
X
X
X
X
HbA1c
X
X
Lipid Panel
X
X
ECG
X
X (Week 4 
only)
X
Urinalysis
X
X
Urine Drug Screen for drugs of 
abuse
X
FSH, if applicable, to determine 
WOCBP status
X
Pregnancy Test
X (serum)
X (serum) 
X (urine)
X (urine)
X (urine)
X
(urine – FU 
week 2, serum 
– FU week 8)
                                               
11 Repeat testing of liver function test (LFT) abnormalities will not be permitted at this visit.
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Observation Phase                  
(28 days, +3 days)
DBT Phase (12 weeks)1,2
Follow-up 
Phase
Procedure
Screening 
Visit
Pre-
randomization 
Laboratory 
Visit:3 must 
occur within 96 
hours before
Baseline 
(Randomization) 
Visit4
Baseline 
(Randomization) 
Visit5 (Day 1 of DBT 
Phase)
Week 2
Visit (Day 
15 +/- 2 
days) 
Week 4
Visit (Day 
29), Week 8
Visit (Day 
57)
(both visits 
+/- 2 days)
Week 12 (Day 
86 + 3 days) or 
EOT Visit for 
early 
discontinuation
Follow-up 
Week 2 Visit,
Follow-up 
Week 8 Visit
(both visits 
+/- 2 days)6
AE, SAE and Concomitant 
Procedure assessment12
X
X
X
X
X
X
X
Columbia-Suicide Severity Rating 
Scale
X
X
X
X
X
X
Dispense Study Drug13
X
X
X
Administer Study Drug14
X
X
Dispense Electronic Diary (eDiary)
X 
Return used and unused study drug 
to site for compliance check15
X
X
X
                                               
12 SAEs, AEs, and Concomitant Procedures must be reported after subject signs informed consent.  SAEs should be reported from signing of consent through the Follow-up 
Week 8 Visit.  Non-serious AEs should be reported from signing of consent through the Follow-up Week 2 Visit.
13 Subjects randomized to zavegepant 100 mg or matching placebo will be assigned 2 wallets at the Baseline Visit and Week 2 Visit.  These subjects will then be assigned 4 
wallets at Week 4 and Week 8 Visits.  Subjects randomized to zavegepant 200 mg or matching placebo will be assigned 4 wallets at the Baseline Visit and Week 2 Visit.  
These subjects will then be assigned 8 wallets at Week 4 and Week 8 Visits.
14Subjects must take their study drug every day, regardless of whether they have a migraine. Doses are not required to be taken in the office on days of a study visit (with the 
exception of PK visits), however dosing requirements and compliance should be discussed with subjects at all visits. Zavegepant oral soft gel capsules should be taken 
fasting, at least 1 hour before breakfast/first meal of the day (and at least 4 hours after the previous meal). 
15 The Observation Phase to determine eligibility is 28 days +3 days. The “+3” days window is included for scheduling purposes only. Subjects in the DBT Phase who 
demonstrate poor compliance will be discussed with the Sponsor and corrective training will be completed by the site with the subject.  
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Observation Phase                  
(28 days, +3 days)
DBT Phase (12 weeks)1,2
Follow-up 
Phase
Procedure
Screening 
Visit
Pre-
randomization 
Laboratory 
Visit:3 must 
occur within 96 
hours before
Baseline 
(Randomization) 
Visit4
Baseline 
(Randomization) 
Visit5 (Day 1 of DBT 
Phase)
Week 2
Visit (Day 
15 +/- 2 
days) 
Week 4
Visit (Day 
29), Week 8
Visit (Day 
57)
(both visits 
+/- 2 days)
Week 12 (Day 
86 + 3 days) or 
EOT Visit for 
early 
discontinuation
Follow-up 
Week 2 Visit,
Follow-up 
Week 8 Visit
(both visits 
+/- 2 days)6
eDiary reviewed for completeness / 
returned 
X
X
X
X
X
Daily Report of migraine 
occurrence, migraine pain feature 
and associated symptoms, and use 
reported by subject in eDiary16
X
X
X
X
X
X
Migraine-Specific Quality of Life 
Questionnaire (MSQ) v 2.1
X
X
Preference of Medication (PoM) 
reported by subject in eDiary
X
Satisfaction with Medication (SM) 
reported by subject in eDiary
X
Satisfaction with Medication/ 
Clinical Global Impression Change 
(CGI-c) 
X
Migraine Disability Assessment 
(MIDAS)
X
X
                                               
16 The eDiary will be dispensed at the Screening Visit, after all screening procedures are completed.  The subject will use the eDiary every day during the Observation Phase
and DBT Phase to report migraine occurrence, migraine pain features and associated symptoms, and use of acute migraine medication.
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Table 2:
OLE Phase Schedule of Assessments 
OLE Phase (up to 52 Weeks)
Follow-up Phase
Procedure
Phone call with 
subject to 
confirm 
eligibility for 
OLE17
Week 14 Visit 
(Day 99 +/- 2 
days)
Week 16 (Day
113) Visit,
Week 20 (Day 
141) Visit, and 
every 4 weeks 
until Week 60
(Day 421)
(all visits +/- 2
days)
Week 64 (Day 449 +/- 2 days)
or EOT Visit for early 
discontinution
Follow-up Week 2
Visit, Follow-up 
Week 8 Visit 
(both visits +/- 2 
days)22
Inclusion/ Exclusion Criteria 
X
Concomitant medication paper 
diary 18
X
X
X
X
Physical Examination
X19
X19
X19
X19
Vital Signs / Physical 
Measurements
X
X
X
X
Clinical Safety Laboratory Testing
X (Weeks 16,
24, and 48 only)
X
                                               
17 Subject eligibility for the OLE Phase will be assessed based on the DBT Week 12 laboratory results (repeats not permitted) prior to taking the first dose of open-label study 
drug, which is dispensed at the DBT Week 12 Visit. Once the DBT Week 12 laboratory results are received and eligibility is confirmed, the subject should be contacted by 
telephone and instructed to start taking open-label study drug. Subjects who (1) discontinue early from the DBT Phase or (2) have already entered the Follow-up Phase are 
not eligible to enter the OLE Phase. If the subject is not eligible, subject must be instructed to not take study drug and return to site for the Follow-up Week 2 Visit with 
unused study drug. 
18 Concomitant medications, including standard of care migraine medications (both prophylactic and acute), taken throughout the study should be recorded by subjects in the 
concomitant medication paper diary and reviewed by study personnel at each visit.
19 Full physical exam required at Week 14, Week 64/EOT, and Follow-up Week 2. Targeted physical exam of heart, lungs, and abdomen; plus other systems based on signs 
and symptoms at Weeks 16, 20 and every 4 weeks until Week 60, and at Follow-up Week 8. 
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OLE Phase (up to 52 Weeks)
Follow-up Phase
Procedure
Phone call with 
subject to 
confirm 
eligibility for 
OLE17
Week 14 Visit 
(Day 99 +/- 2 
days)
Week 16 (Day
113) Visit,
Week 20 (Day 
141) Visit, and 
every 4 weeks 
until Week 60
(Day 421)
(all visits +/- 2
days)
Week 64 (Day 449 +/- 2 days)
or EOT Visit for early 
discontinution
Follow-up Week 2
Visit, Follow-up 
Week 8 Visit 
(both visits +/- 2 
days)22
Liver Function Tests
X
X
X
X
HbA1c
X
Lipid Panel
X
ECG
X (Weeks 16, 24 
and 48 only)
X
Urinalysis
X
Pregnancy Test
X (urine)
X (urine)
X
(urine – FU Week 
2, serum – FU 
Week 8)
AE, SAE and Concomitant 
Procedure assessment
X
X
X
X
Columbia-Suicide Severity Rating 
Scale
X 
X
X
X
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OLE Phase (up to 52 Weeks)
Follow-up Phase
Procedure
Phone call with 
subject to 
confirm 
eligibility for 
OLE17
Week 14 Visit 
(Day 99 +/- 2 
days)
Week 16 (Day
113) Visit,
Week 20 (Day 
141) Visit, and 
every 4 weeks 
until Week 60
(Day 421)
(all visits +/- 2
days)
Week 64 (Day 449 +/- 2 days)
or EOT Visit for early 
discontinution
Follow-up Week 2
Visit, Follow-up 
Week 8 Visit 
(both visits +/- 2 
days)22
Dispense Study Drug20
X
X
X
Administer Study Drug21
X17
X
X
Return used and unused study drug 
to site for compliance check
X
X
X
Migraine-Specific Quality of Life 
Questionnaire (MSQ) v 2.1
X (Week 24 
only)
X
Preference of Medication (PoM) 
reported by subject on paper  
X
Satisfaction with Medication (SM) 
reported by subject on paper
X
                                               
20 Subjects randomized to zavegepant 100 mg or matching placebo in the DBT Phase will receive open-label zavegepant 100 mg in the OLE Phase.  Subjects randomized to 
zavegepant 200 mg or matching placebo in the DBT Phase will receive open-label zavegepant 200 mg in the OLE Phase.  Subjects will be assigned sufficient study drug to 
last until the next dispensing visit.
21Subjects must take their study drug every day, regardless of whether they have a migraine. Doses are not required to be taken in the office on days of a study visit, however 
dosing requirements and compliance should be discussed with subjects at all visits. Zavegepant oral soft gel capsules should be taken fasting, at least 1 hour before 
breakfast/first meal of the day (and at least 4 hours after the previous meal). 
22 Follow-up visits are based off the Week 64/EOT Visit, for subjects who enter the OLE Phase.
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OLE Phase (up to 52 Weeks)
Follow-up Phase
Procedure
Phone call with 
subject to 
confirm 
eligibility for 
OLE17
Week 14 Visit 
(Day 99 +/- 2 
days)
Week 16 (Day
113) Visit,
Week 20 (Day 
141) Visit, and 
every 4 weeks 
until Week 60
(Day 421)
(all visits +/- 2
days)
Week 64 (Day 449 +/- 2 days)
or EOT Visit for early 
discontinution
Follow-up Week 2
Visit, Follow-up 
Week 8 Visit 
(both visits +/- 2 
days)22
Satisfaction with Medication/ 
Clinical Global Impression Change 
(CGI-c) 
X
Migraine Disability Assessment 
(MIDAS)
X (Week 24 
only)
X
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4.3.1
Observation Phase
The Observation Phase will be 28 days + 3 days. Note that the “+ 3 days” window is included 
for scheduling purposes only in cases of holidays or weekends. 
The Observation Phase will have 2 scheduled visits, Screening and Pre-randomization 
Laboratory, which should be completed in person.  
Subjects will report migraine occurrence, migraine pain features and associated symptoms, 
and use of acute migraine medication in the eDiary every day during the Observation Phase. 
All subjects will continue to use their standard of care migraine medications (both 
prophylactic and acute) during the Observation Phase. Subjects will record all concomitant 
medications, including standard of care migraine medications (both prophylactic and acute, 
prescribed and OTC), taken during the entire Observation Phase in a concomitant medication 
paper diary. 
After completing the Observation Phase, subjects will return to the study site for the Baseline 
(Randomization) Visit, and both their eDiary and paper diary will be reviewed for 
completeness.
4.3.1.1
Screening Visit
Before any study procedures are performed, subjects must sign informed consent. After
informed consent is obtained, 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 undergo all screening procedures as detailed in Table 1.  After the screening 
procedures are completed, subjects will be provided an eDiary to document occurrence, pain 
intensity, and characteristics of migraines each day during the Observation Phase.  The 
Screening Visit starts at day 1 of the Observation Phase.  Subjects with fewer than 24 
completed eDiary reports during 28 days in the Observation Phase will not be considered for 
participation due to non-compliance with the eDiary. This will be assessed at the Baseline
(Randomization) Visit. 
During this period, and within 96 hours (4 days + 2 days; note that the +2 days should only 
be used for scheduling in cases of holidays or weekends) of the Baseline Visit, subjects must
return to the study site for the Pre-randomization Laboratory Visit. See Table 1 for laboratory 
tests performed. Subjects then return to the site for the Baseline Visit; if the subject is not 
eligible, the subject will be considered a screen failure and should be recorded as such in 
IWRS.
If the subject meets inclusion/exclusion criteria, the subject may enter the DBT Phase. 
4.3.1.2
Pre-randomization Laboratory Visit
Within 96 hours (4 days + 2 days; note that the +2 days should only be used for scheduling in 
cases of holidays or weekends) of the Baseline Visit, subjects must return to the study site for
the Pre-randomization Laboratory Visit. 
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LFTs, CK and a serum pregnancy test for WOCBP will be obtained and compliance with the
eDiary will be assessed. If the subject continues to meet study entry criteria and laboratory 
test results are acceptable per protocol, the subject will be randomized at the Baseline Visit 
into the DBT Phase. 
If the laboratory results are not acceptable per protocol, the subject is determined to be a 
screen failure and must return to the study site to return the eDiary. 
Repeat testing of LFT abnormalities will not be permitted at this visit.
4.3.2
Double-blind Treatment (DBT) Phase 
The DBT Phase will be up to 12 weeks from the Baseline (Randomization) Visit through the 
Week 12 or End of Treatment (EOT) Visit. 
Zavegepant oral soft gel capsules should be taken fasting, at least 1 hour before 
breakfast/first meal of the day (and at least 4 hours after the previous meal). 
Subjects should take their first dose of study drug the day after the Baseline Visit to ensure 
the subject is fasting appropriately.
Subjects will be instructed that they must take four (4) or eight (8) capsules of study drug 
(depending on randomized treatment group assignment) every calendar day, regardless 
of whether they have a migraine on that day. If subjects have a migraine during the DBT
Phase, they may treat the migraine with their standard of care medication.
The electronic subject diary will be completed by subjects to capture frequency and severity 
of migraines during the DBT Phase. Subjects will also use the eDiary to complete the 
Preference of Medication (PoM) and Satisfaction with Medication (SM) questionnaire. The 
Migraine-Specified Quality-of-Life Questionnaire v 2.1 (MSQ), the Columbia-Suicide 
Severity Rating Scale (C-SSRS), Migraine Disability Assessment (MIDAS), and Clinical 
Global Impression (CGI-c) will be completed, or administered by the investigator, on paper 
at specified study visits (Table 1).
Study visits will be approximately every 2 weeks during the first month and then every 4
weeks, through Week 12 (Table 1). At each visit, the eDiary will be reviewed by site staff for
completeness and compliance; study drug wallet will be reviewed for compliance at each 
visit and concomitant medication use will be reviewed (and compared to the eDiary and 
concomitant medication paper diary entries, where applicable). Subjects will be dispensed 
additional study drug as needed. Additional safety assessments (including laboratory tests and 
ECGs) will be performed per the schedule outlined in Table 1.
Due to the COVID-19 Pandemic, visits may be conducted remotely (ex: telephone, 
telemedicine) and must be documented within the source records as being conducted 
remotely. All procedures not able to be completed due to a visit being conducted remotely 
must be reported as a protocol deviation and can be performed at the next visit, where 
appropriate to do so based on subject presentation.
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4.3.2.1
Baseline (Randomization) Visit
After completing the Pre-randomization Laboratory Visit in the Observation Phase, subjects 
will return to the study site for the Baseline (Randomization) Visit (i.e., Day 1 of the DBT 
Phase, approximately Day 29 of Observation Phase), which should be completed in person.  
Subjects who continue to meet all inclusion/exclusion criteria and have been compliant with 
the eDiary may enter the DBT Phase, pending review of additional laboratory test results; see
Section 4.3.1.2. Subjects with fewer than 24 completed eDiary reports during 28 days in the 
Observation Phase will not be considered for participation due to non-compliance with the 
eDiary. 
At the Baseline Visit, eligible subjects will be randomized randomized 2:2:1:1 across 4 
treatment groups in the DBT Phase: zavegepant 100 mg (n = 480); zavegepant 200 mg (n = 
480); placebo matching zavegepant 100 mg (n = 240); or placebo matching zavegepant 200 
mg (n = 240).   
4.3.2.2
Week 12 or EOT Visit
Subjects will return to the study site at the Week 12 Visit (Day 86 + 3 days) or at the EOT 
Visit for early discontinuation, for review of the electronic diary, assessment of medication 
compliance, assessment of tolerability and safety (including physical exam, vital signs, 
laboratory tests, and ECGs) (Table 1).  Subjects will return the unused blinded study drug and 
eDiary to the study site. 
All randomized subjects who discontinue early from the DBT Phase should complete the 
EOT Visit. Otherwise, subjects should complete the Week 12 Visit.
If the Week 12 or EOT Visit occurs remotely in order to be completed during the protocol 
required window and due to the COVID-19 Pandemic, the subject should return to the site for 
the Follow-up Week 2 Visit to complete all procedures that could not be completed remotely.
Procedures completed at the Week 12 or EOT Visit occurring remotely do not need to be 
repeated.
After the DBT Phase, subjects should enter the OLE or Follow-up Phase. Subjects who 
discontinue early from the DBT Phase or are otherwise not eligible for the OLE Phase should 
enter the Follow-up Phase.
Open-label zavegepant will be dispensed at the Week 12 Visit to be taken in the OLE Phase. 
Subjects should be instructed to NOT take open-label zavegepant until they have 
received a phone call from the site confirming their eligibility for the OLE Phase (see 
Section 4.3.3).
4.3.3
Open-label Extension (OLE) Phase 
The OLE Phase will be up to 52 weeks through the Week 64 or EOT Visit. 
Note that the OLE Phase was added to the study design after some subjects already entered 
the Follow-up Phase after the DBT Phase. Subjects who complete 12 weeks of the DBT
Phase and have not entered the Follow-up Phase may be offered to enter the OLE Phase. 
Subjects must meet the same laboratory eligiblilty criteria assessed prior to randomization in 
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the DBT Phase in order to be eligible for the OLE Phase. Repeat labs will not be allowed at 
the week 12 visit to determine OLE eligibility. The DBT Week 12 laboratory results will be 
used to assess eligibility for the OLE Phase. Once the Week 12 laboratory results are received 
and eligibility is confirmed, the subject should be contacted by telephone and instructed to 
start taking open-label study drug. 
Subjects who (1) discontinue early from the DBT Phase or (2) have already entered the 
Follow-up Phase are not eligibile to enter the OLE Phase.
Eligible subjects will have study visits approximately every 2 weeks during the first month of 
the OLE Phase and then every 4 weeks, through Week 64. See Table 2 for schedule of 
procedures. 
Subjects randomized to zavegepant 100 mg or matching placebo in the DBT Phase will 
receive open-label zavegepant 100 mg in the OLE Phase. Subjects randomized to zavegepant 
200 mg or matching placebo in the DBT Phase will receive open-label zavegepant 200 mg in 
the OLE Phase.  
At each visit, the study drug wallet will be reviewed for compliance and concomitant 
medication use will be reviewed (and compared to concomitant medication paper diary
entries, where applicable). Subjects will be dispensed additional study drug as needed. 
Additional safety assessments (including laboratory tests and ECGs) will be performed per 
the schedule outlined in Table 2.
Subjects will not use the eDiary in the OLE Phase.
Subjects must continue to record use of concomitant medications in the concomitant 
medication paper diary through the entire OLE Phase. 
4.3.3.1
Week 64 or EOT Visit
Subjects will return to the study site at the Week 64 Visit (Day 449 +/- 2 days), or at the EOT 
Visit for early discontinuation, for assessment of medication compliance and assessment of 
tolerability and safety (including vital signs, laboratory tests, and ECG) (Table 2).  Subjects 
must return the unused study drug to the study site. 
All randomized subjects who discontinue early from the OLE Phase should complete the 
EOT Visit. Otherwise, subjects should complete the Week 64 Visit.
If the Week 64 or EOT Visit occurs remotely in order to be completed during the protocol 
required window and due to the COVID-19 pandemic, the subject should return to the site for 
the Follow-up Week 2 Visit to complete all procedures that were not able to be completed 
remotely.  Procedures completed at the Week 64 or EOT Visit occurring remotely do not 
need to be repeated.
4.3.4
Follow-up Phase
The Follow-up Phase will have 2 scheduled visits, Follow-up Week 2 and Follow-up Week 8. 
These visits should occur approximately 2 weeks and 8 weeks, respectively, after the last visit 
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in the last treatment phase (i.e., Week 12/EOT Visit [+3 days] if the subject did not enter the 
OLE Phase; Week 64/EOT Visit [+/- 2 days] if the subject entered the OLE Phase). 
All randomized subjects should complete both follow-up visits, regardless of completing 
either treatment phase.  
Subjects will continue to record all concomitant medications, including standard of care
migraine medications (both prophylactic and acute, prescribed and OTC), taken during the 
entire Follow-up Phase in a concomitant medication paper diary.
4.3.4.1
Follow-up Week 2 Visit 
Subjects will return to the study site approximately 2 weeks (14 days +/- 2 days) after the last 
visit in the last treatment phase to collect LFTs, CK, vital signs, electrocardiography, and 
assessment of AEs/ SAEs. Subjects will return the concomitant medication paper diary which 
should be reviewed one final time by study staff. 
Investigators should assess subjects for AEs consistent with study drug dependency or 
withdrawal effects and report as appropriate (see Section 7.4).
4.3.4.2
Follow-up Week 8 Visit 
Subjects will return to the study site approximately 8 weeks (56 days +/- 2 days) after the last 
visit in the last treatment phase to collect LFTs, CK, vital signs, assessment of SAEs, and to 
have a serum pregnancy test performed (WOCBP). Subjects will return the concomitant 
medication paper diary for documenting concomitant medications.
4.4
Post Study Access to Therapy (if applicable)
At the conclusion of this study, subjects or investigators will not have access to the study 
drug.  The investigator should ensure that the subject receives appropriate standard of care to 
treat the condition under study.
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5
POPULATION
5.1
Number of Subjects
It is anticipated that up to approximately 2900 subjects may be screened in order to 
randomize up to approximately 1440 subjects to study drug (zavegepant 100 mg, zavegepant 
200 mg, placebo matching zavegepant 100 mg, or placebo matching zavegepant 200 mg) in 
the DBT Phase. It is estimated that approximately 1200 subjects will enter the OLE Phase.
5.2
Inclusion Criteria
1. Signed Written Informed Consent
a.
Written informed consent must be obtained from the subject in accordance with 
requirements of the study center’s institutional review board (IRB) or ethics 
committee, prior to the initiation of any protocol-required procedures.
2. Subjects must agree to provide all requested demographic information (i.e., gender, race).
3. Subjects must be able to read and understand English or Spanish.
4. Target Population:  
Subject has at least 1 year history of chronic migraine (with or without aura) consistent 
with a diagnosis according to the International Classification of Headache Disorders, 3rd
Edition11, including the following:
a.
Age of onset of migraines prior to 50 years of age
b. Age of onset of chronic migraine prior to 65 years of age
c.
Migraine attacks, on average, lasting 4 – 72 hours if untreated
d. Per subject report, the occurrence of at least 15 headache days per month, at least 8 
migraine days per month, and at least 1 headache-free day per month during the last 3 
months prior to the Screening Visit (month is defined as 4 weeks for the purpose of 
this protocol)
e.
8 or more migraine days (as defined in Appendix 3) during 28 days in the 
Observation Phase
f.
15 or more headache days (as defined in Appendix 3) during 28 days in the 
Observation Phase
g. 1 or more non-headache day during 28 days in the Observation Phase
h. Ability to distinguish migraine attacks from tension/cluster headaches
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i.
Subjects on one prophylactic migraine medication are permitted to remain on therapy 
if the dose has been stable for at least 3 months (12 weeks) prior to the Screening 
Visit, and the dose is not expected to change during the course of the study.
i.
Subjects may remain on one (1) medication with migraine-prophylactic effects, 
excluding CGRP antagonists [monoclonal antibody or small molecule], during the 
DBT Phase.  
ii. Subjects who previously discontinued prophylactic migraine medication must 
have done so at least 90 days prior to the Screening Visit. Specifically CGRP 
monoclonal antibodies must be discontinued 6 months (24 weeks) prior to the 
Screening Visit and are prohibited during the study.
j.
Subjects with contraindications for use of triptans may be included provided they 
meet all other study entry criteria. 
5. Age and Reproductive Status
a.
Male and Female subjects H18 years of age.
b. All subjects must understand the contraception requirements for this study and agree 
to use 2 acceptable methods of contraception to avoid pregnancy throughout the study
in such a manner that the risk of pregnancy is minimized. See Section 5.6 for the 
definition of WOCBP. 
c.
Women must not be pregnant, lactating, or breastfeeding.
d. At the Baseline Visit, prior to dispensing investigational study drug, WOCBP must 
have a negative pregnancy test.
6. Other Inclusion Criteria
a.
No clinically significant abnormality identified on the medical or laboratory 
evaluation. A subject with a clinical abnormality or laboratory parameters outside the 
reference range may be included only if the investigator considers the finding not 
clinically significant, that it will not introduce additional risk factors, nor interfere 
with the study assessments of safety or efficacy (not including exclusion criteria listed 
in Section 5 below). 
5.3
Exclusion Criteria
1. Target Disease Exclusion
a.
Subjects with a history of basilar migraine or hemiplegic migraine. 
2. Medical History and Concurrent Diseases 
a.
Subjects with a history of HIV disease 
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b. Subjects with current evidence of uncontrolled, unstable or recently diagnosed 
cardiovascular disease, such as ischemic heart disease, coronary artery vasospasm, 
and cerebral ischemia during the 6 months (24 weeks) prior to the Screening Visit. 
Subjects with history of myocardial infarction (MI), Acute Coronary Syndrome 
(ACS), Percutaneous Coronary Intervention (PCI), cardiac surgery, stroke or transient 
ischemic attack (TIA) during the 6 months (24 weeks) prior to the Screening Visit.
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 (12 weeks) prior to the Screening Visit. Blood pressure measurement 
of greater than 150 mmHg systolic or 100 mmHg diastolic after 10 minutes of rest is 
exclusionary. This may be repeated once at screening once during visit to confirm 
reproducibility.
d. Subjects with major depressive (MDD) or any anxiety disorder (AD) which require 
more than 1 daily medication for each disorder or subjects with major depressive 
episode (MDE) within the last 12 months of the Screening Visit.  Medications to treat 
major depressive disorder or an anxiety disorder must have been at a stable dose for at 
least 3 months prior to the Screening visit. 
e.
Chronic pain syndromes (such as fibromyalgia, chronic pelvic pain, complex regional 
pain syndrome (CRPS)).
f.
Subjects with other pain syndromes (including trigeminal neuralgia), psychiatric 
conditions, dementia, or significant neurological disorders (other than migraine) that, 
in the Investigator’s opinion, interfere with study assessments of safety or efficacy. 
g. History of gallstones or cholecystectomy. 
h. 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.
i.
Patient has a history or diagnosis of Gilbert’s Syndrome or any other active hepatic or 
biliary disorder.
j.
The subject has a history of 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 thetrial.
k. History of, treatment for, or evidence of, alcohol or drug abuse within the past 12 
months (48 weeks) or subjects who have met DSM-V criteria12 for any significant
substance use disorder within the past 12 months (48 weeks) from the date of the 
Screening Visit according to PI assessment.
l.
History of use of opioid- or barbiturate- (e.g., butalbital) containing medication for 4 
or more days per month during the 3 months (12 weeks) prior to Screening Visit.
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m. 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. Inaddition:
i.
Detectable levels of cocaine, amphetamine, and phencyclidine (PCP) in the drug 
screen are exclusionary. Retesting is not allowed.
ii. 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 (12 weeks) prior to the Baseline 
Visit until the EOT Visit occurs.   
iii. 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 criteria12
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. Subject must agree to refrain from marijuana use during the trial.
n. Malignancy diagnosis within 5 years prior to the Screening Visit, with the exception 
of a history of localized basal cell or squamous cell skin cancer. Subjects are eligible 
for the study if they are cancer-free prior to the Screening Visit in this study.  
o. Subject has current diagnosis of schizophrenia, bipolar disorder, borderline 
personality disorder, or subject has major depressive disorder requiring treatment with 
atypical antipsychotics. 
p. Body mass index > 33.0 kg/m2
3. History of anaphylaxis to any substance or a clinically important reaction to any drug.
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. See Section 5.6 for acceptable contraception methods.
b. Women who are pregnant, lactating, or breastfeeding. 
c.
Women with a positive pregnancy test. 
5. ECG and Laboratory Test Findings 
a.
Estimated glomerular filtration rate (eGFR) according to the re-expressed abbreviated 
(4-variable) Modification of Diet in Renal Disease (MDRD) Study equation X 40
ml/min/1.73m2.
b. Corrected QT interval > 470 msec (QTc by method of Frederica), at Screening.
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c.
Left Bundle Branch block.
d. Right Bundle Branch Block with a QRS duration H 150 msec.
e.
Intraventricular Conduction Defect with a QRS duration H 150 msec.
f.
Serum bilirubin (Total, Direct or Indirect) > 1x ULN.
(Only abnormal values between 1-1.5x ULN obtained at the Screening Visit may be 
repeated once for assessment of eligibility during the Observation Phase. Abnormal 
bilirubin results obtained at the Pre-randomization Laboratory Visit may not be 
repeated and will result in the subject being a screen failure.)
g. AST (SGOT) or ALT (SGPT) > 1x ULN.
(Only abnormal values between 1-1.5x ULN obtained at the Screening Visit may be 
repeated once for assessment of eligibility during the Observation Phase.  Abnormal
AST or ALT results obtained at the Pre-Randomization Laboratory Visit may not be 
repeated and will result in the subject being a screen failure.)
h. Neutrophil count X 1000/YL (or equivalent).
i.
HbA1c > 6.5%
6. Other Exclusion Criteria
a.
Prisoners or subjects who are involuntarily incarcerated.
b. Subjects who are compulsorily detained for treatment of either a psychiatric or 
physical (e.g., infectious disease) illness.
c.
Non-compliance with or inability to complete eDiary during Observation Phase. 
Subjects with fewer than 24 completed eDiary reports during 28 days in the 
Observation Phase will not be considered for participation due to non-compliance 
with the eDiary.  
d. Exposure to non-biological investigational agents (other than zavegepant) within 30 
days prior to the Screening Visit.
e.
Exposure to biological investigational agents such as monoclonal antibodies within 6 
months (24 weeks) prior to the Screening Visit.
f.
Subjects who meet criteria for C-SSRS Suicidal Ideation Items 4 or 5 within the last 
12 months prior to the Screening Visit, OR subjects who endorse any of the 5 C-SSRS 
Suicidal Behavior Items (actual attempt, interrupted attempt, aborted attempt, 
preparatory acts, or behavior) within the last 10 years prior to the Screening Visit, OR 
subjects who, in the opinion of the investigator, present a serious risk of suicide (See 
Section 6.2.5).
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g. Previous enrollment in any multi-dose BHV-3500 (zavegepant) study. Note that 
subjects who were considered screen failures in a past BHV-3500 study may be 
considered after discussion with the Sponsor and written approval isreceived.
h. No therapeutic response with > 2 of the 8 medication categories for prophylactic 
treatment of migraine listed in Appendix 4 after an adequate therapeutic trial. 
Additional details can be found in Section 17.4 (Appendix 4). 
i.
Past participation in a clinical trial within 30 days prior to the Screening Visit. Note
that subjects who were considered screen failures within the last 30 days should not 
be considered as excluded.
j.
Participation in any other investigational clinical trial while participating in this 
clinical trial. Participation in a COVID-19 mRNA vaccine study (vaccine must be 
authorized under FDA emergency use authorization or approval) who are at least 30 
days post last dose of the vaccine are permitted to be screened for this study.
k. Subjects with an exclusionary match found in the CTSdatabase.
l.
Any reason which, in the opinion of the Investigator, would prevent the subject from 
participating in the study.
7. Prohibited Medications
Please see Section 5.4 for prohibited medications and devices and Section 5.5 for allowable 
prophylactic and standard of care medications. 
a.
Use of ergotamine on  10 days per month on a regular basis for  3 months ( 12 
weeks) in the year prior to the Screening Visit.
b. Use of CGRP monoclonal antibodies (e.g., Emgality® [galcanezumab], Aimovig®
[erenumab], Ajovy® [fremanezumab], Vyepti® [eptinezumab]) within 6 months (24 
weeks) prior to the Screening Visit. 
c.
Use of FDA-approved gepants (e.g. Nurtec ODT® [rimegepant], Ubrelvy®
[ubrogepant]) within 2 weeks prior to the Screening Visit.
d. Use of a prohibited medication or device during the Observation Phase (refer to
Section 5.4).
5.4
Prohibited and Restricted Concomitant Medications and Devices
All medications taken by subjects after screening until the last study day will be documented 
as concomitant medications including vaccinations. 
The medications and devices listed below are prohibited starting at the Baseline Visit and 
during the course of this study or as specified. 
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1. The use of CGRP monoclonal antibodies (e.g., Emgality® [galcanezumab), Aimovig®
[erenumab], Ajovy® [fremanezumab], Vyepti® [eptinezumab]) is prohibited during the 
study from the Screening Visit through the Follow-up Week 8 Visit.  
2. The use of FDA-approved gepants (e.g., Nurtec ODT® [rimegepant], Ubrelvy®
[ubrogepant]) is prohibited during the study from the Screening Visit through the Follow-
up Week 8 Visit.
3.
Butterbur root or extracts should not be taken 14 days prior to the Baseline Visit and 
throughout the study, including the Follow-up Week 8 Visit.
4. Use of ergotamine is prohibited from the Screening Visit through the Follow-up Week 8 
Visit.
5. Use of narcotic medication, such as opioids (e.g., morphine, codeine, oxycodone, and
hydrocodone) or barbiturates, is prohibited starting from 2 days prior to the Baseline Visit 
and throughout the study, including the Follow-up Week 8 Visit. 
6. Use of acetaminophen or acetaminophen containing products for non-migraine
indications after the Baseline Visit is prohibited. Any use of acetaminophen or
acetaminophen containing products for non-migraine indications during the Observation 
Phase must be stopped at least 2 days prior to the Baseline Visit. 
7. Use of marijuana and all forms of ingested or inhaled cannabidiol (CBD) and THC-
containing products are prohibited during the study from the Screening Visit through the 
Follow-up Week 8 Visit. 
8. Use of strong CYP3A4 inhibitors is prohibited during the study from the Screening Visit 
through the Follow-up Week 8 Visit. If use of a strong CYP3A4 inhibitor is required,
dosing should be stopped and should not start again until 14 days after the last dose of the 
strong CYP3A4 inhibitor. Refer to Section 17.2, Appendix #2.
9. Use of strong CYP3A4 inducers is prohibited during the study from the Screening Visit 
through the Follow-up Week 8 Visit. If use of a strong CYP3A4 inducer is required,
dosing should be stopped and should not start again until 14 days after the last dose of the 
strong CYP3A4 inducer. Refer to Section 17.2 Appendix #2.
10. Use of potent P-glycoprotein (P-gp) inhibitors from the Screening Visit through the 
Follow-up Week 8 Visit. If use of a P-gp inhibitor is required, dosing should be stopped 
and should not start again until 14 days after the last dose of the P-gp inhibitor. Refer to 
Section 17.2 Appendix #2.
11. Use of potent P-glycoprotein (P-gp) inducers from the Screening Visit through the 
Follow-up Week 8 Visit. If use of a P-gp inducer is required, dosing should be stopped 
and should not start again until 14 days after the last dose of the P-gp inducer. Refer to 
Section 17.2 Appendix #2.
12. Use of atypical antipsychotics such as Abilify (aripiprazole), Zyprexa (olanzapine), 
Seroquel (quetiapine), Geodon (ziprasidone), or Risperdal (risperidone) or 
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Depakote/Depakene (divalproex/valproic acid/valproate) is prohibited during the study
from the Screening Visit through the Follow-up Week 8 Visit.
13. Use of LAMICTAL (lamotrigine) is prohibited during the study from the Screening Visit 
through the Follow-up Week 8 Visit.
14. Use of acetaminophen or acetaminophen-containing products for the treatment of 
migraine on >2 consecutive days per month or use of more than 1000 mg/day of 
acetaminophen are both prohibited for duration of the trial.
15. Devices, neuromodulation, neurostimulation, or injectable therapy (trigger point 
injections) for headache acute treatment or prophylaxis are prohibited 2 months prior to 
the Screening Visit and during the study through Week 64/EOT.
16. Use of any investigational agent other than zavegepant from the Screening Visit through 
the Follow-up Week 8 Visit.
17. Low dose aspirin (e.g. 81 mg daily) for documented cardiovascular prophylaxis is 
allowed.
5.5
Standard of Care Migraine Medications
Use of standard of care migraine medication during the Observation Phase and through the 
Follow-up Week 8 Visit will be recorded by the subject on the concomitant medication paper 
diary and reported to the site. Migraine medications include both prophylactic and acute 
migraine medications.
5.5.1
Prophylactic Migraine Medications
Subjects may use no more than 1 of the following medications with possible migraine-
prophylactic effects, regardless of indication, if not otherwise prohibited by the protocol.  
Doses must be stable within 3 months (12 weeks) prior to the Screening Visit and 
throughout the study.  Use of more than 1 of the following medications is prohibited within 3 
months (12 weeks) prior to the Screening Visit and throughout the study.
Prophylactic migraine medications that are permitted during the study include:
!
Topiramate, gabapentin
!
Beta blockers (such as: atenolol, bisoprolol, metoprolol, nadolol, nebivolol, pindolol, 
propranolol, timolol)
!
Tricyclic antidepressants (such as: amitriptyline, nortriptyline, protriptyline)
!
Venlafaxine, desvenlafaxine, duloxetine, milnacipran
!
Flunarizine, lomerizine
!
Lisinopril, candesartan
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!
Clonidine, guanfacine
!
Cyprohepatdine
!
Methysergide
!
Pizotifen
!
Feverfew, magnesium (H 600 mg/day), riboflavin (H 100 mg/day)
!
Botox® 
The above listed medications are the only prophylactic migraine medications allowed.
5.5.2
Acute Migraine Medications
Subjects may use their permitted standard of care medication if needed for acute treatment of 
a migraine throughout the study. 
Acute migraine medications that are permitted during the study include the following: 
!
Triptans (e.g., almotriptan, eletriptan, frovatriptan, naratriptan, rizatriptan, sumatriptan, 
zolmitriptan)
!
Aspirin
!
Ibuprofen
!
Baclofen
!
Acetaminophen up to 1000 mg/day for a maximum of 2 consecutive days at a time (this 
includes Excedrin Migraine and any other acetaminophen-containing products)
!
Naprosyn (or any other type of non-steroidal anti-inflammatory (NSAID))
!
Antiemetics (e.g., metoclopramide or promethazine) 
!
Muscle relaxants.
The above listed medications are the only acute migraine medications allowed.
If a subject experiences a migraine after dosing with study drug for the day during the DBT
or OLE Phase, the subject may take their acute migraine medication as described above in 
this section of the protocol.  
5.6
Women of Childbearing Potential and Contraception
Women of childbearing potential (WOCBP) includes any female who has experienced 
menarche and who has not undergone successful surgical sterilization (hysterectomy, 
bilateral salpingectomy, or bilateral oophorectomy) or is not postmenopausal. Tubal ligation 
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is considered one form of contraception; therefore, one additional form of contraception must 
be used to fulfill contraception requirements for the study. Essure, tubal occlusion and 
endometrial ablation are not acceptable methods of contraception.  Menopause is defined as:
!
Amenorrhea greater than or equal to 12 consecutive months without another cause and a
documented serum follicle stimulating hormone (FSH) level > 35mIU/mL
!
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 1 year
OR
!
Woman on hormone replacement therapy (HRT) who no longer menstruate.
Women of childbearing potential (WOCBP) and all men must understand the following
requirements and use an acceptable method 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. 
The requisite drug interaction studies to determine the interaction of zavegepant with oral 
contraceptives have not been performed to date. It is, therefore, not possible to determine the 
efficacy of oral contraceptives as an effective method of contraception for WOCBP or men 
with partners who are WOCBP who are participating this study. Oral estrogen and progestin 
hormonal contraceptives as a sole method of contraception are therefore prohibited. 
It is required that all WOCBP use 2 methods of contraception to prevent pregnancy, for the 
duration of the study (i.e., this study begins with signed consent form through 90 days after 
dosing with study drug). The 2 methods should include 1 barrier method (ex. Condom with 
spermicidal gel, non-hormonal intrauterine devices, cervical cap etc.) and 1 other method. 
The other method could include another barrier method or hormonal contraceptives (e.g., oral 
contraceptives, injectable contraceptives, patch, or contraceptive implant [e.g., hormonal 
intrauterine device]) used since at least 4 weeks prior to sexual intercourse.  
WOCBP and all male subjects must be counseled on the requirements to avoid pregnancy 
throughout the study and for 90 days after the last dose of study drug, as well as acceptable 
methods of contraception to use during the study.  Subjects who report abstinence, or who 
report exclusively being in same-sex relationships are still required to understand the 
contraception requirements in this study to prevent pregnancy. If subjects who report 
abstinence, or who report exclusively being in a same-sex relationship engage in heterosexual 
activity, then the contraception requirements must be followed.  
Males with vasectomy are considered surgically sterile provided the procedure occurred 
greater than 6 months (24) weeks prior to the screening visit. Vasectomy is considered one 
form of contraception; therefore, one additional form of contraception must be used to fulfill 
the contraception requirements for the study.  Male subjects must not donate sperm until 90 
days following the last study drug administration.
All WOCBP must complete the pregnancy test schedule in Table 1.
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5.7
Other Restrictions and Precautions (if applicable)
Not applicable. 
5.8
Deviation from Inclusion/Exclusion Criteria
Any significant event that does not comply with the inclusion/exclusion criteria, study
conduct, or study procedures will be documented as a deviation. Deviations will be 
documented and reported through the clinical monitoring of the trial. Deviations will be 
reported to the IRB/IEC at the frequency required by your IRB/IEC. Prospective approval of 
protocol deviations to recruitment and enrollment criteria, also known as protocol waivers or 
exemptions, is not permitted.
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6
STUDY CONDUCT AND DESCRIPTION OF STUDY 
PROCEDURES
6.1
Study Materials
The following study materials will be provided at the study start:
!
Investigator File/Study Binder
!
Pharmacy Binder
!
Drug Accountability Logs
!
Sample source documents, where applicable 
!
Concomitant medication paper diary (take home for subject) 
!
Investigator Brochure
!
Interactive Web-based Response System (IWRS) manual
!
Electronic Case Report Forms (eCRF) instructions
o
Electronic Case Report Forms (eCRFs) will be prepared for all data collection fields 
o
All sites will use an Electronic Data Capture (EDC) tool to submit study data to the 
CRO. Electronic Case Report Forms (eCRFs) will be prepared for all data collection 
fields including Serious Adverse Events (SAE) Reporting. SAE data (including 
queries) will be submitted to the CRO using eCRFs. 
!
Electronic Clinical Outcome Assessment (eCOA) Handheld devices (eDiary)
o
The eDiary will be used daily during the Observation Phase and DBT Phase to record 
migraine occurrence, migraine pain features and associated symptoms, use of acute 
migraine medication (i.e., triptans, ergotamine, or other). The eDiary will be used 
during the DBT phase to record select subject-rated scales (PoM and SM). Any 
assessment completed by the subject in the eDiary will be transferred from the 
site/subject to the vendor and from the vendor to the CRO and Sponsor. No additional 
source documents are required for scales and assessments completed by the subject on 
the eDiary. In the OLE Phase, the PoM and SM will be reported on paper forms at the 
site. 
!
Laboratory kits and laboratory manual
o
Safety laboratory, plasma, urinalysis and serum instructions for all specimens 
collected will be provided by a designated central laboratory.
!
ECG Machine and instructions
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o
ECG equipment, supplies, instructions and training materials will be supplied by a 
centralized ECG vendor.
!
SAE forms and SAE Reporting instructions
!
Pregnancy surveillance forms
!
C-SSRS documents
!
MIDAS forms 
!
MSQ v 2.1 forms 
!
PoM forms (OLE Phase only)
!
SM forms (OLE Phase only)
!
CGI-c forms 
!
Study system access: 
o
Electronic Data Capture (EDC) tool to submit study data to Sponsor / CRO
o
IWRS
o
Central Laboratory
o
Central ECG Vendor
6.2
Safety Assessments
6.2.1
Vital Signs and Physical Measurements (Height and Weight)
Vital signs, body weight and height will be recorded at the scheduled visits as outlined in 
Table 1.
6.2.2
Electrocardiogram (ECG)
A standard 12-lead ECG will be recorded during the Observation Phase and at all scheduled 
visits as outlined in Table 1 and Table 2. A central ECG service will be utilized for all ECGs.
The over-read from the central ECG vendor should be used to determine eligibility for the 
study.  The investigator will determine whether any ECG abnormalities are clinically 
significant based on the overread from the central ECG vendor. 
6.2.3
Physical Exam 
Subjects will undergo a complete physical examination during the Observation Phase and 
brief and symptom-directed physical exam at all scheduled visits as outlined in Table 1 and 
Table 2. Targeted physical examinations to include examination of heart, abdomen, and 
lungs; plus review of any other system to be guided by signs and symptoms.
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6.2.4
Laboratory Tests 
The investigator must review the laboratory report, document this review, and record any 
clinically relevant changes occurring during the study in the AE section of the CRF. The 
laboratory reports must be filed with the source documents. Clinically significant abnormal 
laboratory test findings are those which are not associated with the underlying disease, unless 
judged by the investigator to be more severe than expected for the participant’s condition.
6.2.4.1
Safety Laboratory Testing
Blood and urine samples will be obtained as outlined in Table 1 and Table 2 for clinical 
laboratory evaluations. A central laboratory vendor will be utilized for this study and a 
laboratory manual will be provided to each site. If possible, subjects should be fasting for a 
minimum of 8 hours before laboratory tests. 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.
1. Clinical safety labs: 
Hematology: Hemoglobin, hematocrit, red blood cell count, white blood cell count with 
differential, and platelets; 
Chemistry: Sodium, potassium, chloride, bicarbonate, calcium; glucose, BUN (urea), 
serum creatinine, uric acid, LDH, total protein, albumin.
eGFR estimated using the MDRD formula (calculated at central lab).
2. LFTs: AST, ALT, Alkaline Phosphatase and Bilirubin (Total, Direct, Indirect), CK 
(fractionation will be ordered if CK result is > 5.0x ULN). 
3. HbA1c
4. Lipid panel: Cholesterol, LDL, HDL, triglycerides.
5. Urinalysis: pH, specific gravity, ketones, nitrites, urobilinogen, leukocyte esterase, 
protein, glucose, and blood. If blood, protein or leukocytes are positive, reflex to 
microscopic examination.
6. Urine Drug Screen: For drugs of abuse.
7. FSH: At screening in female subjects to confirm postmenopausal status, if applicable.
Additional tests may be required to evaluate laboratory abnormalities and/or adverse 
events; please refer to the Laboratory Manual.
6.2.4.2
PK Testing 
PK will be collected at the Week 4 and Week 8 Visits only. Subjects will be instructed to not 
take study drug until they are at the study site. Subjects will have PK drawn predose and at 
least 1 hour postdose. The time of dose administration in the clinic, time and date of last dose 
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and the exact time of PK sample collection will be documented at the clinic visit. Subjects 
should be fasting prior to dose administration (at least 4 hours after the last meal) and for 
duration of PK assessments.
6.2.4.3
Pregnancy Testing
WOCBP will complete pregnancy tests (serum and/or urine) at specified study visits, prior to 
taking study drug, and as outlined in Refer to Section 5.6.
6.2.5
Columbia-Suicide Severity Rating Scale (C-SSRS)
The Columbia-Suicide Severity Rating Scale (C-SSRS) is a questionnaire used for suicide
Assessment.13 The C-SSRS “Screening version” will be used at the Screening Visit and the
“Since Last Visit version”14 will be used at subsequent visits in this study.
The C-SSRS Assessment is intended to help establish a person’s immediate risk of suicide.
The C-SSRS is a clinician administered scale that should be administered by a certified rater. 
This scale will be collected on site with a paper form. The C-SSRS should be reviewed by 
the Investigator or designee before the subject is allowed to leave clinic.
At the Screening Visit, the recall period for completing is 12 months for suicidal ideation and 
10 years for suicidal behavior; at all other visits, the recall period for completing the C-SSRS 
is since the last visit (reference Table 1 and Table 2).
If the Investigator determines that a participant is at risk of suicide or self-harm, or reports a 
“Yes” response to any question during the course of the study, appropriate measures to 
ensure the participant’s safety and obtain mental health evaluation must be implemented. In 
such circumstances, the participant must immediately be discontinued from the study. The 
event should be recorded as either a non-serious AE or SAE through the Follow-up Week 8 
Visit as determined by the Investigator and reported within 24 hours to the Sponsor.
6.3
Efficacy Assessments
The eDiary will be used daily to record acute migraine medication dosing occurrences and 
migraine pain features and associated symptoms during the Observation Phase and DBT
Phase.
Efficacy assessments will be derived from eDiary data and will include the number of 
migraine days per month by pain intensity (total; moderate or severe), and number of acute
migraine-specific medication days per month, in each month by study period. 
6.4
Other Assessments
6.4.1
Migraine-Specific Quality of Life Questionnaire v 2.1
Impact of treatment on subject-reported quality of life will be assessed using the Migraine-
Specific Qualify-of-Life Questionnaire version 2.1 (MSQ v 2.1). The MSQ v 2.1 is a 14-item 
instrument that has been validated in 3 domains: role function – restrictive, role function –
preventive, and emotional function.15 The MSQ will be completed on a paper form at the site.
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6.4.2
Migraine Disability Assessment 
The Migraine Disability Assessment (MIDAS) is a retrospective, subject-reported, 5-item 
questionnaire that measures headache-related disability as lost days due to headache from 
paid work or school, household work and non-work activities over a 3-month period.16 The 
MIDAS will be completed on a paper form at the site.
6.4.3
Preference of Medication Scale 
The Preference of Medication Scale (PoM) is a subject-rated, 5-point scale that measures
preference of the study drug compared to the previous medications to treat migraine pain. 
The eDiary will be used to evaluate the PoM in the DBT Phase, and a paper form will be used 
at the site to evaluate the PoM in the OLE Phase.
6.4.4
Satisfaction with Medication Scale 
The Satisfaction with Medication (SM) scale is a subject-rated, 7-point scale that measures 
satisfaction with the study drug to treat migraine headaches. The eDiary will be used to 
evaluate the SM in the DBT Phase, and a paper form will be used at the site to evaluate the 
SM in the OLE Phase.
6.4.5
Clinical Global Impression – Change (CGI-c) Scale 
The Clinical Global Impression-change (CGI-c) scale is an observer-rated, 7-point scale that 
measures subject total improvement relative to the investigator’s past experience with other 
subjects with the same diagnosis, with or without collateral information.17 The CGI-c will be 
administered by the investigator or designee who has been trained on administration and will 
be completed on a paper form at the site.
6.5
Early Discontinuation from the Study
Subjects MUST discontinue investigational product (and non-investigational product at the 
discretion of the investigator) for any of the following reasons:
!
Withdrawal of informed consent (subject’s decision to withdraw for any reason)
!
Any clinical adverse event (AE), laboratory abnormality or intercurrent illness which, in 
the opinion of the investigator or sponsor, indicates that continued participation in the 
study is not in the best interest of the subject
!
Pregnancy
!
Termination of the study by Biohaven Pharmaceuticals
!
Loss of ability to freely provide consent through imprisonment or involuntary 
incarceration for treatment of either a psychiatric or physical (e.g., infectious disease) 
illness
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!
Poor compliance with study procedures and visits, including poor completion compliance 
with evening reports in eDiary; poor compliance with study drug – see Schedule of 
Assessments Table 1 and Table 2.
!
All subjects who discontinue in the DBT Phase early should comply with protocol 
specified DBT EOT procedures as outlined in Table 1. All subjects who discontinue in 
the OLE Phase early should comply with the protocol specified OLE EOT procedures as 
outlined in Table 2. The only exception to this requirement is when a subject withdraws 
consent for all study procedures or loses the ability to consent freely (i.e., is imprisoned or 
involuntarily incarcerated for the treatment of either a psychiatric or physical illness).
6.5.1
Lost to Follow-up
A participant will be considered lost to follow-up if he or she repeatedly fails to return for 
scheduled visits and is unable to be contacted by the study site.
The following actions must be taken if a participant fails to return to the clinic for a required 
study visit:
!
The site must attempt to contact the participant and reschedule the missed visit as soon as 
possible and counsel the participant on the importance of maintaining the assigned visit 
schedule and ascertain whether or not the participant wishes to and/or should continue in
the study.
!
Before a participant is deemed lost to follow-up, the investigator or designee must make 
every effort to regain contact with the participant (where possible, 3 telephone calls and, 
if necessary, a certified letter to the participant’s last known mailing address or local 
equivalent methods). These contact attempts should be documented in the participant’s 
medical record.
!
Should the participant continue to be unreachable, he/she will be considered to have 
withdrawn from the study.
6.6
Clinical Trial Subject Database (CTSdatabase) 
CTSdatabase is a clinical trial subject registry that maintains the privacy and security of 
research subjects while providing sponsors and investigators with crucial information about 
subjects’ current and/or previous study participation. 
CTSdatabase has been shown to reduce the number of duplicate and professional subjects 
entering clinical trials.
The use of this database must be presented to all subjects participating in this protocol.  If 
subjects refuse to provide authorization, the study team should be notified.  At the time of 
providing the Informed Consent for the study, the Investigator or designee will explain the 
IRB-approved Subject Database Authorization to the subject and witness the signature.
During screening, site staff that have received training and login information should access 
www.ctsdatabase.com and enter the last 7 digits of the subject study ID and authorized 
subject identifiers.  An immediate report detailing matches is generated and should be printed 
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for source documentation. The report will specify either (1) no matches found, (2) a match 
was found with a subject participating in another study within 30 days or (3) the subject 
matches with a subject who has pre-screened at another site.  
At the last subject contact, CTSdatabase staff will automatically close out subjects (SF, ET or 
Completer) based on IWRS information.
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7
STUDY DRUG MANAGEMENT
7.1
Description of Study Drug
7.1.1
Investigational Product
An investigational product, also known as investigational medicinal product in some regions, 
is defined as follows:
A pharmaceutical form of an active substance or placebo being tested or used as a reference 
in a clinical study, including products already with a marketing authorization but used or 
assembled (formulated or packaged) in a way different from the authorized form, or used for 
an unauthorized indication, or when used to gain further information about the authorized 
form.
The investigational product should be stored in a secure area according to local regulations. It 
is the responsibility of the investigator to ensure that investigational product is only dispensed 
to study subjects. The investigational product must be dispensed only from official study sites 
by authorized personnel according to local regulations.
In this protocol, investigational product (study drug) is zavegepant (BHV-3500) 25 mg soft 
gelatin capsule (SGC) or matching placebo.
7.1.2
Non-Investigational Product
In this protocol, there are no non-investigational products. 
7.1.3
Formulation
Zavegepant (BHV-3500) is formulated as a 25 mg soft gelatin capsule (SGC) taken as either 
4 soft gelatin capsules (SGC) for each 100 mg daily dose (25 mg x 4 = 100 mg) or 8 SCG for 
each 200 mg daily dose (25 mg x 8 = 200 mg).
7.1.4
Packaging, Shipment and Storage
The product storage manager should ensure that the study drug is stored in accordance with 
the environmental conditions (temperature, light, and humidity) as determined by the 
sponsor. Please see the Pharmacy Manual/Investigator Brochure for specific conditions. If 
concerns regarding the quality or appearance of the study drug arise, do not dispense the 
study drug and contact the sponsor/CRO immediately.
7.2
Dose and Administration
7.2.1
Method of Assigning Subject Identification
The Investigator or designee will need to access an Interactive Web-based Response System 
(IWRS) in order to register each subject. Initially, after informed consent is obtained at the 
Screening Visit, the Investigator or designee will enter the subject into the study and obtain a 
subject number assignment. At the Baseline Visit and subsequent visits in the DBT and OLE 
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Phases, container assignments will be obtained by the Investigator (or designee) via the 
IWRS system. This subject number must not be reused for any other participant in the study. 
Subjects will maintain their subject number assigned at screening, throughout the trial. 
At the Baseline Visit, eligible subjects will be randomized to a treatment group (see Section 
1.4.1). The randomization will be stratified by stable prophylactic migraine medication use 
through randomization (yes or no), as determined by site review of subjects’ concomitant
medication paper diary. Subjects should be categorized as “yes” if they took a specified 
prophylactic migraine medication > 3 months (12 weeks) before the Screening Visit and 
through randomization, i.e., (1) the medication start date is > 12 weeks before the Screening 
Visit date, and (2) either the medication stop date is on or after the randomization date or the 
medication is ongoing. Otherwise, subjects should be categorized as “no”.
Subjects may not be rescreened for this study.
Study drug will be assigned via IWRS; the system will assign specific container numbers for 
all study drug to be dispensed to the subject. Sites will be responsible for recording the 
container numbers dispensed to the subject on the Drug Accountability Form provided in the 
Study Binder, as well as ensure appropriate documentation of dispensation in the subject’s 
medical record. 
Once a subject completes the study, or if a subject is discontinued early from the study, the 
Investigator or designee must access the IWRS to document discontinuation of the subject 
from participation in the study.
7.2.2
Selection and Timing of Dose and Administration
Study drug (zavegepant or matching placebo) will be assigned via the IWRS system. There 
are no dose adjustments in this study and subjects will receive wallets as outlined in Table 1.
Subjects will be dispensed study drug at the Baseline (Randomization) Visit, and the subjects 
will be instructed that they must take 4 or 8 capsules of study drug (depending on 
randomized treatment group assignment) every calendar day, regardless of whether they 
have a migraine on that day. This is the scheduled dosing regimen for the 12-week DBT
Phase.
Zavegepant oral soft gelatin capsules should be taken fasting, at least 1 hour before 
breakfast/first meal of the day (and at least 4 hours after the previous meal). 
Scheduled visit for Week 4 and Week 8 – subjects should not dose until they arrive at the 
study site and will take study drug with site staff to assess PK outlined in Table 1.  PK will be 
drawn predose and at least 1 hour postdose; exact time of PK collection relative to the dose 
will be documented. At these visits, subjects should fast for the duration of PK assessments. 
Date and time of last meal will be collected (regardless of fasting status).
Subjects who complete 12 weeks of the DBT Phase may continue to take their assigned dose, 
either zavegepant 100 mg or 200 mg, in the OLE Phase for 52 weeks. 
During the DBT or OLE Phase, if the subject has a migraine when they have already taken
study drug for the day, the subject can take their acute migraine medication in accordance 
with protocol restrictions (see Section 5.5.2). Subjects must be instructed that they CANNOT 
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take more than what their randomization assignment allows (4 (four) capsules, or 8 (eight) 
capsules of study drug every day). 
7.2.3
Dose Modifications
There will be no dose adjustments in this study. 
7.3
Blinding and Unblinding
Blinding is critical to the integrity of this clinical study. However, in the event of a medical 
emergency or pregnancy in an individual subject, in which knowledge of the investigational 
product is critical to the subject’s management, the blind for that subject may be broken by 
the treating physician.
Before breaking the blind of an individual subject’s treatment, the Investigator should have 
determined that the information is necessary, (i.e., that it will alter the subject’s immediate 
management). In many cases, particularly when the emergency is clearly not investigational 
product related, the problem may be properly managed by assuming that the subject is 
receiving active product without the need for unblinding.
In cases of accidental unblinding, contact the Medical Monitor and ensure every attempt is 
made to preserve the blind for remaining site personnel.
7.4
Treatment Compliance
Responsible study personnel will dispense the study drug.  Subjects should finish a wallet
blister of study drug before starting a new wallet. Accountability and compliance verification 
should be documented in the subject’s study records.  
Subjects must be counseled on the importance of taking the study drug as directed (see 
Section 7.2.2). Treatment compliance should be completed by a thorough review of returned 
study drug.  Treatment compliance should be assessed by site staff at each study visit. 
Discrepancies, review of study drug and information provided by subject must be 
documented in the source record. Investigators should inform subjects that involuntary 
termination from the study will occur in cases where non-compliance is identified. Study staff 
should contact a subject in between the study visits if the subject demonstrates non-
compliance with the eDiary and document the contact in the source, to identify potential lost 
to follow-up subjects as early as possible. 
Investigators must monitor subjects for possible cases of abuse of study drug (subjects taking 
study drug for non-therapeutic purposes, e.g., for psychoactive effects such as high or 
euphoria). Investigators should also assess study drug accountability discrepancies (e.g.,
missing study drug, loss of drug, or non-compliance cases in which more study drug was 
used, as compared to expected). Investigators should obtain more information and 
explanation from subjects when there are study drug accountability discrepancies. See 
Section 8.1.1.
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Cases of potential study drug abuse or overdose (including cases of non-compliance with 
study drug dosing instructions or subjects who discontinue treatment without returning study 
drug) should be documented in the source record and reported as an AE or SAE as 
appropriate. Overdose is defined in Section 8.3. Dosing errors (e.g., accidentally taking over 
the assigned number of soft gelatin capsules in one calendar day) should be reported as 
deviations. 
7.5
Destruction and Return of Study Drug
All unused and/or partially used study drug can be sent back to the drug depot for destruction 
only after being inspected and reconciled by the responsible Study monitor or the sponsor’s
designee. If it is site policy to destroy study drug on site, it is the Investigator’s responsibility 
to ensure that arrangements have been made for the disposal, procedures for proper disposal 
have been established according to the applicable regulations, guidelines and institutional 
procedures, and appropriate records of the disposal have been documented. 
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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) or symptom, or any 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.
If a specific diagnosis or syndrome is identified by the Investigator, this should be recorded 
as the AE, rather than recording (as separate AEs) the individual signs/symptoms or clinically 
significant laboratory abnormalities known to be associated with and considered by the 
Investigator to be a component of, the disease/syndrome.
Definition of terms related to all Adverse Events (serious and non-serious):
Mild: Is usually transient and may require only minimal treatment or therapeutic 
intervention. The event does not generally interfere with usual activities of daily living.
Moderate: Is usually alleviated with additional specific therapeutic intervention. The event 
interferes with usual activities of daily living, causing discomfort, but poses no significant or 
permanent risk of harm to the subject.
Severe: Interrupts usual activities of daily living, significantly affects clinical status, or may 
require intensive therapeutic intervention.
Life threatening: An AE is life threatening if the subject was at immediate risk of death from 
the event as it occurred, i.e., it does not include a reaction that if it had occurred in a more 
serious form might have caused death. For example, drug-induced hepatitis that resolved 
without evidence of hepatic failure would not be considered life threatening even though 
drug-induced hepatitis can be fatal.
Hospitalization: AEs requiring hospitalization should be considered SAEs. Hospitalization 
for elective surgery or routine clinical procedures that are not the result of AE (e.g., elective 
surgery for a pre-existing condition that has not worsened) need not be considered AEs or 
SAEs. If anything untoward is reported during the procedure, that occurrence must be 
reported as an AE, either ‘serious’ or ‘non-serious’ according to the usual criteria.
Assessment for Determining Relationship of AE to Study Drug:
The relatedness of each AE to study drug must be classified based on medical judgement and 
according to the following categories. The definitions are as follows:
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Related: This category applies to AEs that are considered, with a high degree of certainty, to 
be related to the study drug. An AE may be considered related when it follows a temporal 
sequence from the administration of study drug, it cannot reasonably be explained by the 
known characteristics of the subject’s clinical state, environment, or toxic factors, or other 
modes of therapy administered to the subject. An AE may be considered related when it 
follows a known pattern of response to the study drug, or if the AE reappears upon re-
challenge.
Possibly related (non-serious AEs only): This category applies to AEs that are considered to 
have an unlikely connection to study drug, but a relationship cannot be ruled out with 
certainty.
Unlikely related (non-serious AEs only): This category applies to AEs that do not follow a 
reasonable temporal sequence from the administration of the study drug. The AE may readily 
have been produced by the subject’s clinical state, environmental or toxic factors, or other 
modes of therapy administered to the subject.
Unrelated: This category applies to AEs that are considered with a high degree of certainty to 
be due only to extraneous causes (e.g., subject’s clinical state, environment, toxic factors, 
disease under study, etc.) and does not meet the criteria of other categories above.
There are two types of adverse events, Serious Adverse Events (SAE) and Non-Serious 
Adverse Events (AEs).
8.1
Serious Adverse Events
8.1.1
Definition of Serious Adverse Event (SAE)
An SAE is any event that meets any of the following criteria at any dose:
!
Death
!
Life-threatening
!
Inpatient hospitalization or prolongation of existing hospitalization
!
Persistent or significant disability/incapacity
!
Congenital anomaly/birth defect in the offspring of a subject who received zavegepant
!
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
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o
Development of drug dependency or drug abuse
o
Potential drug induced liver injury (see Section 8.4)
o
Abuse or Overdose of medication

Potential study drug abuse (including cases of excessive non-compliance 
with study drug dosing instructions or subjects who discontinue treatment 
without returning study drug) should be documented in the source record 
and reported as an AE or SAE as appropriate. Investigators must monitor 
subjects for possible cases of abuse of study drug (subjects taking study 
drug for non-therapeutic purposes, e.g., for psychoactive effects such as 
high or euphoria). Investigators should obtain more information and 
explanation from subjects when there are study drug accountability 
discrepancies

Potential study drug overdose is defined in Section 8.3
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 Biohaven clinical studies (but may 
be considered non-serious AEs):
!
A visit to the emergency room or other hospital department <24 hours that does not result 
in an admission (unless considered “important medical event” or event that is life 
threatening);
!
Elective surgery planned prior to signing consent;
!
Admissions as per protocol for a planned medical/surgical procedure;
!
Routine health assessment requiring admission (i.e., routine colonoscopy);
!
Admission encountered for another life circumstance that carries no bearing on health and 
requires no medical intervention (i.e., lack of housing, care-giver respite, family 
circumstances).
Disability/incapacitating: An AE is incapacitating or disabling if the experience results in a 
substantial and/or permanent disruption of the subject’s ability to carry out normal life 
functions.
8.1.2
Collection and Reporting Serious Adverse Events
Following the subject’s written consent to participate in the study, all SAEs, whether related 
or not related to study drug, must be collected, including those thought to be associated with 
protocol-specific procedures.  All SAEs must be collected that occur during the Observation 
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Phase and throughout the course of the study, up to and including the End of Treatment Visit 
and through the Follow-up Week 8 Visit. The investigator should report any SAE occurring 
after this time period that is believed to be related to study drug or protocol-specific 
procedures.  
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 8.3), potential drug 
induced liver injury (see Section 8.4) and pregnancies (see Section 8.1.3) must be reported 
within 24 hours of the Investigator becoming aware 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 into the Case Report 
Form (CRF) and/or system (i.e., event term, start/stop dates, causality, and severity).
Any serious adverse event must be reported immediately or no later than 24 hours after 
awareness of the event to PPD Pharmacovigilance (PVG).  A written description of any 
serious adverse event, using the PPD SAE report form, must be sent to PPD PVG by 
facsimile (fax), which is the preferred method of submission, within 24 hours after awareness 
of the event: 
!
North America Fax – 1-888-488-9697
If a form is unable to be submitted within 24 hours, the SAE may be reported by telephone 
via the Safety Hotline Number:
!
North America Telephone – 1-800-201-8725
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.
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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
Pregnancy
If, following the Baseline Visit, it is subsequently discovered that a 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 safety).  Protocol-required procedures for study discontinuation and 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 patients to contact the Investigator if they become pregnant during the 
course of the study. The investigator must immediately notify the Biohaven (or designee) 
Medical Monitor and PPD of the event and complete the Pregnancy Form in accordance with 
SAE reporting procedures as described in Section 8.1.2. The pregnancy should be reported
using paper forms, which should be faxed to PPD PVG by facsimile (fax), which is the 
preferred method of submission, within 24 hours after Investigator/site awareness of the 
event: 
!
North America Fax – 1-888-488-9697
!
Or if the form cannot be faxed or emailed (wilsafety@ppdi.com; subject line must include 
“Biohaven Protocol BHV3500-302”), reported via phone to the PPD Safety Hotline at 
North America: 1-800-201-8725 or EU EMEA: +44 1223 374 240.  
!
Once the paper form is available, the data must be reported per standard procedures.
Follow-up information regarding the course of the pregnancy, including perinatal and 
neonatal outcome and, where applicable offspring information must also be reported on a 
Pregnancy Report Form.
Any pregnancy that occurs in a female partner of a male study participant should be reported 
to the sponsor/PPD.  Information on this pregnancy will be collected on the Pregnancy 
Report Form, as appropriate.   
8.2
Non-Serious Adverse Events
A non-serious adverse event is an AE not classified as serious. 
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8.2.1
Collection and Reporting of Non-serious Adverse Events
Non-serious AE information should be collected from the start of the Observation Phase
intended to establish a baseline status for a subject and should be captured through the 
Follow-up Week 2 Visit except for non-serious suicidality AEs which should be captured 
through the Follow-up Week 8 Visit (see Section 6.2.5).
Non-serious adverse events should be followed until conclusion or stabilization or reported as 
SAEs if they become serious.  Follow-up is also required for non-serious AEs that cause 
interruption or discontinuation of study drug or those that are present at the end of study 
treatment. 
8.2.2
Laboratory Test Abnormalities
The following laboratory test abnormalities should be captured on the non-serious AE CRF 
page or SAE Report Form (paper or electronic) as appropriate:
1. Any laboratory test result that is clinically significant or meets the definition of an SAE;
2. Any laboratory abnormality that required the subject to have the study drug discontinued 
or interrupted;
3. Any laboratory abnormality that required the subject to receive specific corrective 
therapy.
8.3
Overdose
An overdose is defined as the accidental or intentional administration of any dose of a
product that is considered both excessive and medically important.  
All occurrences of medically significant overdose (suspected or confirmed and irrespective of 
whether it involved study drug) 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 treatments administered.
Asymptomatic dosing errors (e.g., accidentally taking more than 4 capsules instead of 
prescribed dose of 4 capsules in one calendar day) should be reported as deviations.
8.4
Potential Drug Induced Liver Injury (DILI)
Wherever possible, timely confirmation of the initial liver-related laboratory abnormalities 
should occur prior to the reporting of a potential DILI event.  All occurrences of potential 
DILIs, meeting the defined criteria, must be reported as SAEs as per Section 8.1.2. 
Potential drug induced liver injury is defined as: 
1. ALT or AST elevation > 3x ULN
AND
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2. Total bilirubin > 2x ULN, without initial findings of cholestasis (elevated serum 
alkaline phosphatase)
AND
3. No other immediately apparent possible causes of ALT or AST elevation and 
hyperbilirubinemia, including but not limited to, viral hepatitis, pre-existing chronic 
or acute liver disease, or the administration of other drug(s) known to be hepatotoxic. 
If any potential DILI is identified and meets the criteria above, the Biohaven Medical 
Monitor (or designee) should immediately be contacted for further instruction and whether 
the subject must discontinue from the trial and appropriate follow-up requirements. 
8.5
Adverse Events of Special Interest
Not applicable. 
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9
STATISTICS
Complete details on the statistical methods for this study may be found the Statistical 
Analysis Plan (SAP).
9.1
Sample Size
With a sample size of approximately 480 randomized subjects per zavegepant treatment 
group and 240 randomized subjects per placebo treatment group, we expect approximately
440 subjects per zavegepant treatment group and 220 subjects per placebo treatment group in 
the migraine analysis set. Assuming zavegepant provides a 1-day advantage over placebo 
pooled on the mean change in migraine days per month over the entire DBT Phase (Weeks 1 
to 12), and a common standard deviation of 4.2 days, then the study will have  90% power 
for the primary endpoint with an alpha level of 0.025. The estimates for the migraine analysis 
set sample size, mean change in migraine days per month, and standard deviation are based 
on observed pooled data from rimegepant study BHV3000-305.
9.2
Analysis Sets
The following analysis sets will be used in this study:
!
Enrolled: Subjects who sign informed consent and are assigned a subject identification
number
!
Randomized: Subjects in the enrolled analysis set who receive a randomized treatment 
group assignment (zavegepant or placebo)
!
DBT safety: Subjects in the enrolled analysis set who take  1 dose of double-blind study 
drug (zavegepant or placebo)
!
Open-label zavegepant safety: Subjects in the enrolled analysis set who take  1 dose of 
open-label zavegepant
!
Double-blind or open-label zavegepant safety: Subjects in the enrolled analysis set who 
take  1 dose of double-blind or open-label zavegepant
!
PK: Subjects in the DBT safety analysis set who take  1 dose of double-blind 
zavegepant and have  1 PK sample collected
!
DBT efficacy: Subjects in the randomized analysis set who are randomized only once, 
and take  1 dose of double-blind study drug
!
Migraine: Subjects in the DBT efficacy analysis set with  14 days (not necessarily 
consecutive) of eDiary efficacy data in both the Observation Phase and  1 month (4-
week interval) in the DBT Phase.
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9.3
Statistical Methods
Results will be summarized by treatment group and the 2 matching placebo groups pooled, 
where applicable.
9.3.1
Efficacy Analyses
9.3.1.1
Primary Efficacy Endpoint
The primary endpoint will be assessed for the migraine analysis set using a generalized linear 
mixed effect model (GLMEM) with repeated measures that will use the identity link function 
and include the following variables: change from the Observation Phase in the number of 
migraine days per month as the dependent variable; subject as a random effect; number of
migraine days per month in the Observation Phase as a covariate; and fixed effects for
treatment group, randomization stratum (i.e., stable prophylactic migraine medication use 
through randomization), month, and month-by-treatment group interaction. Migraine days are 
of any pain intensity. Months are defined using 4-week intervals as Month 1 (Weeks 1 to 4), 
Month 2 (Weeks 5 to 8), and Month 3 (Weeks 9 to 12). The number of migraine days per 
month is prorated to 28 days account for days with missing migraine data. The difference 
estimate (zavegepant – placebo), standard error (SE), 97.5% confidence interval (CI), and p-
value will be reported for the entire DBT Phase (Weeks 1 to 12) for each dose of zavegepant 
versus placebo pooled.
The repeated measures error structure is assumed to be constant across treatment groups, and 
will be initially specified as unstructured. If the model fails to converge or cannot be fit with 
an unstructured error structure, then a heterogeneous Toeplitz error structure will be 
attempted. If the Toeplitz fails, then an autoregressive order 1 error structure will be
attempted. 
The Kenward-Roger method will be used to approximate denominator degrees of freedom.
9.3.1.2
Secondary Efficacy Endpoints
The proportion of subjects with  50% reduction from the Observation Phase in the number 
of moderate or severe migraine days per month over the entire DBT Phase (Weeks 1 to 12) 
will be analyzed using a Cochran-Mantel-Haenszel test stratified by randomization stratum 
for the migraine analysis set. Missing data are imputed as non-response (i.e., failure). The 
difference estimate (zavegepant – placebo), SE, 97.5% CI, and p-value will be reported for 
each dose of zavegepant versus placebo pooled.
The mean change from the Observation Phase in the number of migraine days per month in
the last 4 weeks (Weeks 9 to 12) of the DBT Phase will be assessed for the migraine analysis 
set from the same GLMEM used for the primary efficacy endpoint.  
The mean change from the Observation Phase in the number of migraine days per month in 
the first 4 weeks (Weeks 1 to 4) of the DBT Phase will be assessed for the migraine analysis 
set from the same GLMEM used for the primary efficacy endpoint.
The mean number of acute migraine-specific medication days per month over the entire DBT
Phase (Weeks 1 to 12) will be assessed for the migraine analysis set using a GLMEM that is 
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similar in structure to that used for the primary efficacy endpoint, except that the number of 
acute migraine-specific medication days per month is the dependent variable and there is no 
covariate. Acute migraine-specific medications are triptans and ergotamine.
The mean changes from baseline in MSQ restrictive role function domain score and MIDAS
total score at Week 12 will be analyzed for the DBT efficacy analysis set using GLMEMs 
that will use the identity link function and include the following variables: Week 12 change 
from baseline in the score as the dependent variable; baseline score as a covariate; and fixed 
effects for treatment group and randomization stratum. The Week 12 difference estimate
(zavegepant – placebo), SE, 97.5% CI, and p-value will be reported for each endpoint and 
each dose of zavegepant versus placebo pooled.
9.3.1.3
Adjustment for Multiplicity
Type 1 error is controlled through the use of hierarchical testing. The significance of the
primary endpoint is evaluated at the 0.025 level for each dose of zavegepant versus placebo. 
If the primary endpoint is significant for a dose, then the following secondary efficacy and 
outcomes research endpoints will be tested hierarchically in the following order, each at the 
0.025 level:
!
Proportion of subjects with  50% reduction from the Observation Phase in the number of 
moderate or severe migraine days per month over the entire DBT Phase
!
Mean change from the Observation Phase in the number of migraine days per month in
the last 4 weeks of the DBT Phase
!
Mean change from the Observation Phase in the number of migraine days per month in 
the first 4 weeks of the DBT Phase
!
Mean number of acute migraine-specific medication days per month over the entire DBT
Phase
!
Mean change from baseline in MSQ restrictive role function domain score at Week 12 of 
the DBT Phase
!
Mean change from baseline in MIDAS total score at Week 12 of the DBT Phase.
9.3.2
Safety Analyses
Deaths will be listed regardless of onset for the enrolled analysis set.
The frequencies of safety endpoints will be assessed descriptively as the number and 
percentage of subjects with events/findings separately for the 3 safety analysis sets.
The frequencies of the following safety endpoints will be tabulated on treatment: AEs by 
intensity (mild, moderate, severe, total); AEs by relationship to study drug (related, possibly 
related, unlikely related, not related); SAEs; AEs leading to study drug discontinuation; 
hepatic-related AEs by intensity; hepatic-related AEs leading to study drug discontinuation; 
clinically significant laboratory test abnormalities; and LFT elevations based on fold changes 
above ULN, including ALT or AST > 3x ULN concurrent (on the same laboratory test
collection date) with total bilirubin > 2x ULN.
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The investigators will determine the intensity of AEs and the relationship of AEs to study
drug. The investigators’ terms will be coded using the latest version of the Medical
Dictionary for Regulatory Activities (MedDRA) available at the start of the study. AEs will 
be tabulated by system organ class and preferred term. In tables by intensity, if a subject has
an AE with different intensities over time, then only the greatest intensity will be reported. In 
tables by relationship to study drug, if a subject has an AE with different relationships over 
time, then the highest degree of relatedness to study drug will be reported.
Clinically significant laboratory test abnormalities will be identified as grade 3 to 4 
laboratory test results graded according to numeric laboratory test criteria in Common 
Terminology Criteria for Adverse Events (CTCAE) Version 5.0 (2017), if available. 
Otherwise, if CTCAE grades are not available, then results will be graded according to 
numeric laboratory test criteria in Division of AIDS (DAIDS) Table for Grading the Severity 
of Adult and Pediatric Adverse Events Corrected Version 2.1 (2017). If a subject has a 
laboratory test abnormality with different toxicity grades over time, then only the highest 
toxicity grade will be reported.
9.4
Schedule of Analyses
A clinical study report will be produced after the last subject completes the last visit in the 
DBT Phase in order to assess the primary and secondary efficacy endpoints.
An addendum study report will be produced after the last subject completes the last visit in 
the study. 
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10 ETHICS AND RESPONSIBILITIES
10.1
Good Clinical Practice
This study will be conducted in compliance with the protocol, Good Clinical Practice (GCP), 
Good Laboratory Practice (GLP), International Conference on Harmonization guidelines, and 
all applicable regulations, including the Federal Food, Drug and Cosmetic Act, U.S. 
applicable Code of Federal Regulations (title 21), any Independent Ethics Committee (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 study 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).
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.
10.2
Data and Safety Monitoring Committee
This study will not make use of a Data Safety Monitoring Committee (DSMC). The study 
drug, zavegepant, has been tested and found to be well-tolerated.  Safety will be closely 
monitored via oversight by the investigators, Sponsor and CRO/designee and an Institutional 
Review Board/Independent Ethics Committee.
10.3
Steering Committee
Not applicable. 
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10.4
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 (if 
any) 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. 
In the event that the protocol is amended, the revised protocol must be approved by the 
IRB/IEC prior to its implementation, unless the changes involve only logistical or 
administrative aspects of the trial. 
10.5
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, sign and date an 
IRB/IEC approved written informed consent form for study participation and CTSdatabase 
participation. The signed and dated ICF will be retained at the Investigator’s site, with a copy 
provided to the study subject and date will be entered in his or her CRF or appropriate 
system. The IRB/IEC must review and approve all protocol versions and informed consent 
form versions and a copy of each version of the IRB/IEC approved protocol and informed 
consent form is to be retained in the Study Master file. Any revisions to the protocol or ICF 
will be reviewed and approved by the IRB/IEC and subjects will be informed of ICF changes 
and document continuing consent by signing and dating the revised version of the ICF.
If a revised ICF is introduced during the study, each subject’s further consent must be 
obtained. The new version of the ICF must be approved by the IRB/IEC, prior to 
subsequently obtaining each subject’s consent. 
If informed consent is initially given by a subject’s legal guardian or legally acceptable 
representative, and the subject subsequently becomes capable of making and communicating 
their informed consent during the study, then the consent must additionally be obtained from 
the subject. 
The informed consent form must also include a statement that Biohaven and its 
representatives and regulatory authorities may have direct access to subject records.  
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10.6
Case Report Forms
An investigator is required to prepare and maintain adequate and accurate case histories 
designed to record all observations and other data pertinent to the investigation of each study 
patient. Data reported on the CRF that are derived from source documents must be consistent 
with the source documents or the discrepancies must be explained.
Electronic CRFs will be prepared for all data collection fields when EDC is being used.   
The confidentiality of records that could identify patients must be protected, respecting the 
privacy and confidentiality rules in accordance with the applicable regulatory requirement(s). 
The investigator must retain a copy of the CRFs including records of changes and 
corrections.   If EDC is being used, signatures will be obtained electronically and a copy of 
the electronic CRFs will be provided (or the data from the CRFs) for future reference.
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11 RECORDS MANAGEMENT
In accordance with the principles of GCP and GLP, the study may be inspected by regulatory 
authorities, the Sponsor and CRO. The Sponsor is entitled to access information about the 
status of the study and to review the original documents of the study.
The investigator must retain all study records and source documents for the maximum time 
period required by the applicable regulations and guidelines, or institution procedures or for 
the period of time specified by the sponsor, whichever is longer.  The investigator 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 (may be supplied by the sponsor) is maintained at each study site 
where the study drug is inventoried and dispensed.  Records or logs must comply with 
applicable regulations and guidelines and should include:
!
amount of study drug received and placed in storage area
!
label ID number or batch number or Kit number as specified for the protocol
!
amount dispensed to and returned from each patient
!
amount transferred to another area or site for dispensing or storage if applicable
!
amount of drug lost or wasted
!
amount destroyed at the site if applicable
!
amount returned to sponsor, if applicable
!
retain samples for bioavailability/bioequivalence, if applicable
!
record of dates and initials of personnel responsible for IM dispensing and accountability  
11.1
Source Documentation
An Investigator is required to prepare and maintain adequate and accurate case histories 
designed to record all observations and other data pertinent for all subjects on study.  
If source documents are created to support the collection of study information, this must be 
retained with the other pertinent medical records for each subject for verification of data 
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points, unless otherwise instructed by the Sponsor or designee to enter data directly on the 
eCRF.
Study monitors will perform ongoing source data verification to confirm that data entered 
into the CRF by authorized site personnel are accurate, complete, and verifiable from source 
documents; that the safety and rights of participants are being protected; and that the study is 
being conducted in accordance with the currently approved protocol and any other study 
agreements, ICH GCP, and all applicable regulatory requirements.
The investigator must permit study-related monitoring, audits, IRB/IEC review, and 
regulatory agency inspections and provide direct access to source data documents.
11.2
Study Files and Record Retention
The Sponsor does not require original documents that have already been scanned and entered 
into the eTMF system to be forwarded to the Sponsor. Any original documents (i.e. 1572, 
signed financial disclosure, signed ICF, etc.) will be retained in the regulatory binder at the 
study site. The CRO will conduct a final TMF reconciliation to ensure all study files and 
regulatory documents have been correctly uploaded to the TMF prior to the close or 
termination of the study. Any materials or documents to support the clinical trial outside of 
the eTMF (i.e. rater training tapes) should be maintained by the CRO. The Sponsor will be 
contacted to determine whether the study documents/materials that are retained outside of the 
TMF will be forwarded to the Sponsor, destroyed or kept at the CRO or at another facility for 
a longer period of time at the Sponsor’s expense.
The CRO will maintain adequate study records after completion or termination of study. 
After that period, the Sponsor will be contacted to determine whether the study records will 
be forwarded to the Sponsor, destroyed or kept at CRO or at another facility for a longer
period of time at the Sponsor’s expense.
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12 AMENDMENTS
Protocol modifications, except those intended to reduce immediate risk to study subjects, may 
be made only by Biohaven (or specified designee). 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 or specified designee will submit protocol 
amendments to the appropriate regulatory authorities for approval.
If in the judgment of the IRB/IEC, the investigator, and/or Biohaven, the amendment to the 
protocol substantially changes the study design and/or increases the potential risk to the 
subject and/or has an impact on the subject’s involvement as a study participant, the currently 
approved written informed consent form will require similar modification. In such cases, 
informed consent will be renewed for subjects enrolled in the study before continued 
participation.
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13 STUDY REPORT AND PUBLICATIONS
Biohaven (or specified designee) is responsible for preparing and providing the appropriate 
regulatory authorities with clinical study reports according to the applicable regulatory 
requirements.
The publication policy of Biohaven is discussed in the investigator’s Clinical Research 
Agreement.
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14 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 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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15 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 CRFs shall be by initials (when allowed), screening and 
treatment numbers only. If required, the subject’s full name may be made known to an 
authorized regulatory agency or other authorized official.
The Sponsor may approve the sharing of de-identified data from this study to be made 
available to researchers for the purpose of advancing the understanding of neurologic or 
psychiatric illness, rating scales, or trial methodology for the affected population. In any 
publication of this data, confidentiality of individual subjects will be protected.
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17 APPENDICES
17.1
APPENDIX 1 – Names of Study Personnel
Sponsor:
Biohaven Pharmaceuticals
Refer to contact list in study binder for contact information 
Medical Monitor:
, MD
Clinical Research 
Organizations:
Synteract
Refer to contact list in study binder for contact information
Central Laboratory:
ACM Global Laboratories
Refer to contact list in study binder for contact information
Central ECG:
Clario (formerly known as Bioclinica)
Refer to contact list in study binder for contact information
eCOA:  
Yprime
Refer to contact list in study binder for contact information
Pharmacovigilance:
PPD
Refer to SAE, Pregnancy Surveillance Forms and study binder 
for contact information.
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17.2
Appendix 2 – Inhibitors and Inducers of CYP3A4 and Inhibitors of P-
glycoprotein (not all inclusive)
The following tables present some of the inhibitors and inducers of CYP3A4 and P-
glycoprotein (P-gp). This list should not be considered all-inclusive. Individual drug labels 
should be reviewed for specific information on propensity to inhibit or induce CYP450 or to 
inhibit P-gp enzymes for a specific compound.
As described in the study protocol, concomitant use of strong CYP3A4 inhibitors or inducers 
is prohibited.
Strong CYP3A4 Inhibitors 
Clarithromycin, cobicistat, conivaptan, danoprevir and ritonavir, elvitegravir and ritonavir,
indinavir and ritonavir, itraconazole, ketoconazole, lopinavir and ritonavir, nefazodone, 
nelfinavir, paritaprevir and ritonavir and (ombitasvir and/or dasabuvir), posaconazole, 
ritonavir, saquinavir and ritonavir, tipranavir and ritonavir, troleandomycin, voriconazole
Strong CYP3A4 Inducers
Apalutamide, carbamazepine, phenobarbital, phenytoin, rifampin, rifapentine, St. John’s 
Wort
As described in the study protocol, concomitant use of P-gp inhibitors or inducers is 
prohibited. 
P-gp Inhibitors
Amiodarone, clarithromycin, cyclosporine, dronedarone, itraconazole, lapatinib, propafenone, 
quinidine, ritonavir, verapamil
P-gp Inducers
Carbamazepine, phenobarbital, phenytoin, rifampin, St. John’s Wort
Resources:
https://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/DrugInter
acti onsLabeling/ucm093664.htm#table3-2
https://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/DrugInter
actionsLabeling/ucm093664.htm#table3-3
https://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/DrugInter
actionsLabeling/ucm093664.htm#table5-2
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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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17.3
Appendix 3 – Definition of Migraine Days 
Migraine Day: Any calendar day in which the subject experiences a qualified migraine 
headache (onset, continuation, or recurrence of the migraine headache). A qualified migraine 
headache is defined as a migraine with or without aura, lasting for H 30 minutes, and meeting 
the conditions specified in at least one of the two sets of criteria specified below criteria (A
and/or B)
A. H 2 of the following pain features:
a.
Unilateral location,
b. Pulsating quality (throbbing),
c.
Moderate or severe pain intensity,
d. Aggravation by or causing avoidance of routine physical activity (e.g. walking 
or climbing stairs)
B.
H 1 of the following associated symptoms:
a.
Nausea and/or vomiting
b. Photophobia and phonophobia
If the subject took a migraine-specific medication (i.e., e.g., triptan or ergotamine) during 
aura or to treat headache, then it will be counted as a migraine day regardless of the duration 
and pain features/associated symptoms.
A moderate to severe migraine day is a migraine day with a migraine reported with moderate 
or severe pain intensity.
Headache Day: Any calendar day on which the subject experiences a qualified headache 
(initial onset, continuation, or recurrence of the headache). A qualified headache is defined 
as:
!
a qualified migraine headache (including an aura-only event that is treated with 
acute migraine-specific medication), or
!
a qualified non-migraine headache, which is a headache that lasts H 30 minutes 
and is not a qualified migraine headache, or
!
a headache of any duration for which acute headache treatment is administered.
Acute Migraine-specific Medication Day: Any calendar day on which the subject took an 
acute migraine-specific medication (i.e., triptan or ergotamine). 
Monthly eDiary Data: Data collected by the eDiary based on the subject’s monthly study 
drug dosing schedule when at least 14 days of eDiary data are collected within that interval. 
Monthly frequency measurements will be prorated to 28-day equivalents.
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Migraine Attack: An episode of any qualified migraine headache. The following rules will 
be used to distinguish an attack of long duration from two attacks, or to distinguish between 
attacks and relapses:
a) A migraine attack that is interrupted by sleep, or temporarily remits, and then 
recurs within 48 hours (i.e., X 48 hours between the start of the migraine attack to 
the time of the recurrence) will be considered as one attack and not two.
b) An attack treated successfully with medication but with relapse within 48 hours 
(i.e., X 48 hours between the start of the migraine attack to the time of the 
recurrence) will be considered as one attack.
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17.4
Appendix 4 – Categories of Migraine Prevention Medications 
No therapeutic response with > 2 of the following 8 medication categories for prophylactic 
treatment of migraine after an adequate therapeutic trial. These medication categories are:
o
Category 1: Divalproex sodium, sodium valproate
o
Category 2: Topiramate, carbamazepine, gabapentin
o
Category 3: Beta blockers (for example: atenolol, bisoprolol, metoprolol, nadolol, 
nebivolol, pindolol, propranolol, timolol)
o
Category 4: Tricyclic antidepressants (for example: amitriptyline, nortriptyline, 
protriptyline)
o
Category 5: Serotonin-norepinephrine reuptake inhibitors (for example: 
venlafaxine, desvenlafaxine, duloxetine, milnacipran)
o
Category 6: Flunarizine, verapamil (verapamil use is prohibited during the study)
o
Category 7: Lisinopril, candesartan
o
Category 8: Botox®
No therapeutic response is defined as no reduction in headache frequency, duration, or 
intensity after administration of the medication for at least 6 weeks at the generally accepted
therapeutic dose(s) based on the investigator’s assessment.
The following scenarios do not constitute lack of therapeutic response:
o
Lack of sustained response to a medication
o
Failure to tolerate a therapeutic dose
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18 REFERENCES
1.
Marcus R, Goadsby PJ, Dodick D, Stock D, Manos G, Fischer TZ. BMS-927711 for 
the acute treatment of migraine: a double-blind, randomized, placebo controlled, dose-
ranging trial. Cephalalgia 2014;34:114-25.
2.
Lipton RB, Bigal ME, Diamond M, et al. Migraine prevalence, disease burden, and 
the need for preventive therapy. Neurology 2007;68:343-9.
3.
Messali A, Sanderson JC, Blumenfeld AM, et al. Direct and Indirect Costs of Chronic 
and Episodic Migraine in the United States: A Web-Based Survey. Headache 2016;56:306-
22.
4.
Adams AM, Serrano D, Buse DC, et al. The impact of chronic migraine: The Chronic 
Migraine Epidemiology and Outcomes (CaMEO) Study methods and baseline results. 
Cephalalgia 2015;35:563-78.
5.
Dodick DW. CGRP ligand and receptor monoclonal antibodies for migraine 
prevention: Evidence review and clinical implications. Cephalalgia 2019;39:445-58.
6.
Croop R, Lipton RB, Kudrow D, et al. Oral rimegepant for preventive treatment of 
migraine: a phase 2/3, randomised, double-blind, placebo-controlled trial. Lancet 
2021;397:51-60.
7.
Lipton RB, Goadsby PJ, Smith J, et al. Efficacy and safety of eptinezumab in patients 
with chronic migraine: PROMISE-2. Neurology 2020;94:e1365-e77.
8.
Dubowchik GM, Conway CM, Xin AW. Blocking the CGRP Pathway for Acute and 
Preventive Treatment of Migraine: The Evolution of Success. J Med Chem 2020;63:6600-23.
9.
Steiner TJ, Jensen R, Katsarava Z, et al. Aids to management of headache disorders in 
primary care (2nd edition) : on behalf of the European Headache Federation and Lifting The 
Burden: the Global Campaign against Headache. The journal of headache and pain 
2019;20:57.
10.
BHV-3500. Calcitonin Gene-Related Peptide Receptor Antagonist, Investigator 
Brochure V2.0September 2019.
11.
Headache Classification Committee of the International Headache Society (IHS) The 
International Classification of Headache Disorders, 3rd edition. Cephalalgia 2018;38:1-211.
12.
APA. Diagnostic and Statistical Manual of Mental Disorders, 5th Edition: DSM-5 5th 
Edition. 5th ed: American Psychiatric Publishing; 2013.
13.
Posner K, Brown GK, Stanley B, et al. The Columbia-Suicide Severity Rating Scale: 
initial validity and internal consistency findings from three multisite studies with adolescents 
and adults. Am J Psychiatry 2011;168:1266-77.
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14.
Posner K, Brent D, Lucas C, et al. Columbia-Suicide Severity Rating Scale. The 
Research Foundation for Mental Hygiene, inc 2008;Version 1/14/09.
15.
Wagner TH, Patrick DL, Galer BS, Berzon RA. A new instrument to assess the long-
term quality of life effects from migraine: development and psychometric testing of the 
MSQOL. Headache 1996;36:484-92.
16.
Lipton RB, Stewart WF, Sawyer J, Edmeads JG. Clinical utility of an instrument 
assessing migraine disability: the Migraine Disability Assessment (MIDAS) questionnaire. 
Headache 2001;41:854-61.
17.
Guy W. ECDEU Assessment Manual for psychopharmacology. Rockville, Md. : U.S. 
Dept. of Health, Education, and Welfare, Public Health Service, Alcohol, Drug Abuse, and 
Mental Health Administration, National Institute of Mental Health, Psychopharmacology 
Research Branch, Division of Extramural Research Programs; 1976.
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SAP_001.pdf: 
 
Statistical Analysis Plan 
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Protocol BHV3500-302 (C5301006) 
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Pfizer Confidential 
Protocol BHV3500-302 (C5301006) 
 
A Phase 2/3 Randomized, Double-Blind, Placebo-Controlled Study to 
Evaluate the Efficacy and Safety of Oral Zavegepant in Migraine Prevention 
Statistical Analysis Plan 
 
 
Version 9 
Date: 30-May-2024  


 
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SIGNATURE PAGE
Protocol Title:
BHV3500-302: A Phase 2/3 Randomized, Double-
Blind, Placebo-Controlled Study to Evaluate the 
Efficacy and Safety of Oral Zavegepant in Migraine 
Prevention 
Document Version:
9
Date:
30-May-2024
Author:
 
 
Signature: _
__ 
Date: _____
___ 
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).
 
 
 
 
Signature: _
Date: _____
PPD
PPD
PPD
PPD


 
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TABLE OF CONTENTS 
SIGNATURE PAGE ......................................................................................................................2
LIST OF TABLES .........................................................................................................................5
LIST OF FIGURES .......................................................................................................................5
ABBREVIATIONS ........................................................................................................................6
REVISION HISTORY ..................................................................................................................8
1
INTRODUCTION AND OBJECTIVES OF ANALYSIS.................................................23
1.1
Research Hypothesis ........................................................................................................23
1.2
Schedule of Analyses ........................................................................................................23
2
STUDY DESCRIPTION ......................................................................................................23
2.1
Study Design .....................................................................................................................23
2.2
Treatment Assignment ....................................................................................................25
2.3
Blinding and Unblinding .................................................................................................26
2.4
Protocol and Protocol Amendments...............................................................................26
3
STUDY OBJECTIVES AND ESTIMANDS ......................................................................26
3.1
Objectives..........................................................................................................................26
3.1.1
Primary Objective ......................................................................................................26
3.1.2
Secondary Objectives.................................................................................................26
3.1.3
Exploratory Objectives ..............................................................................................27
3.2
Estimands..........................................................................................................................28
3.2.1
Primary Objective Estimand ....................................................................................30
3.2.2
Secondary Objective Estimands ...............................................................................30
3.2.3
Exploratory Objective Estimands ............................................................................33
4
ANALYSIS SETS, TREATMENT GROUPS, AND SUBGROUPS ................................35
4.1
Analysis Sets .....................................................................................................................35
4.2
Treatment Groups ...........................................................................................................36
4.3
Subgroups .........................................................................................................................37
5
SAMPLE SIZE, POWER, AND TYPE 1 ERROR ............................................................37
6
STATISTICAL ANALYSES ...............................................................................................37
6.1
General ..............................................................................................................................37
6.1.1
Programmed Output .................................................................................................37
6.1.1.1 
Tables ....................................................................................................................37
6.1.1.2 
Listings ..................................................................................................................38
6.1.2
Statistical Methods .....................................................................................................39
6.1.3
Missing Data ...............................................................................................................39
6.2
Study Population ..............................................................................................................39
6.2.1
Analysis Sets ...............................................................................................................39
6.2.2
Enrollment ..................................................................................................................39
6.2.3
Subject Disposition.....................................................................................................39
6.2.3.1 
Subject Disposition from Enrollment to Randomization .................................40
6.2.3.2 
Subject Disposition from Randomization to Treatment ..................................40
6.2.3.3 
Subject Disposition during the DBT Phase .......................................................40
6.2.3.4 
Subject Disposition during the OLE Phase .......................................................41
6.2.3.5 
Subject Disposition during the Follow-up Phase ..............................................42
6.2.4
Protocol Deviations ....................................................................................................43


 
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6.2.4.1 
Relevant Protocol Deviations ..............................................................................43
6.2.4.2 
Significant Protocol Deviations ...........................................................................43
6.2.5
Baseline Characteristics ............................................................................................43
6.2.5.1 
Demographics and Other Relevant Baseline Characteristics ..........................44
6.2.5.2 
Baseline Disease Characteristics .........................................................................44
6.2.5.3 
Medical History ....................................................................................................45
6.2.5.4 
Non-study Prior Medications ..............................................................................45
6.2.6
Exposure .....................................................................................................................45
6.2.6.1 
Study Medication .................................................................................................45
6.2.6.2 
Measurements of Treatment Compliance .........................................................48
6.2.6.3 
Nonstudy Concomitant Medications ..................................................................50
6.3
Efficacy..............................................................................................................................50
6.3.1
Primary Efficacy Endpoint .......................................................................................51
6.3.1.1 
Missing Efficacy Data ..........................................................................................52
6.3.1.2 
Descriptive Analyses ............................................................................................52
6.3.1.3 
Treatment Group Comparisons .........................................................................52
6.3.2
Secondary Efficacy Endpoints ..................................................................................53
6.3.2.1 
Percentages of Subjects with Reduction in Number of Migraine Days 
per Month .............................................................................................................53
6.3.2.2 
Acute Migraine-specific Medication Days per Month in the DBT 
Phase......................................................................................................................55
6.3.2.3 
Overall Summary of Primary and Secondary Endpoints in 
Hierarchical Testing ............................................................................................56
6.3.3
Exploratory Efficacy Endpoints ...............................................................................57
6.3.3.1 
Acute Migraine Medication Days per Month in the DBT Phase .....................57
6.3.4
Pharmacokinetics .......................................................................................................57
6.4
Safety .................................................................................................................................58
6.4.1
Adverse Events ...........................................................................................................58
6.4.1.1 
Deaths ....................................................................................................................59
6.4.1.2 
AE Overviews .......................................................................................................59
6.4.1.3 
On-DBT AEs.........................................................................................................59
6.4.1.4 
On-OL Zavegepant AEs ......................................................................................60
6.4.1.5 
Follow-up AEs ......................................................................................................60
6.4.2
Laboratory Tests ........................................................................................................60
6.4.2.1 
Laboratory Test Abnormalities ..........................................................................61
6.4.2.2 
LFT Elevations .....................................................................................................61
6.4.2.3 
Laboratory Test Changes from Baseline over Time .........................................62
6.4.3
Vital Signs and Physical Measurements ..................................................................62
6.4.3.1 
Vital Sign and Physical Measurement Changes from Baseline over 
Time .......................................................................................................................62
6.4.3.2 
Vital Sign and Physical Measurement Abnormalities ......................................62
6.4.4
Electrocardiograms....................................................................................................63
6.4.4.1 
ECG Changes from Baseline over Time ............................................................63
6.4.4.2 
ECG Abnormalities .............................................................................................63
6.4.5
C-SSRS........................................................................................................................64
6.4.6
Safety Narrative Subject Identifiers.........................................................................64


 
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6.5
Outcomes Research ..........................................................................................................64
6.5.1
MSQoL ........................................................................................................................65
6.5.2
MIDAS ........................................................................................................................66
7
CONVENTIONS...................................................................................................................67
7.1
Derived Dates ...................................................................................................................67
7.2
Analysis Periods ...............................................................................................................69
7.3
Analysis Visit Windows ...................................................................................................70
8
CONTENTS OF REPORTS ................................................................................................71
9
APPENDICES .......................................................................................................................72
9.1
Relevant Protocol Deviations ..........................................................................................72
9.2
eDiary Efficacy .................................................................................................................75
9.2.1
Efficacy Parameters ...................................................................................................75
9.2.2
eDiary Efficacy Data Day ..........................................................................................76
9.2.3
Acute Migraine Medication Day...............................................................................76
9.2.4
Acute Migraine-specific Medication Day.................................................................77
9.2.5
Migraine Day ..............................................................................................................77
9.2.6
Headache Day .............................................................................................................77
9.3
SAS Code ..........................................................................................................................78
9.3.1
Linear Mixed Effects Model with Repeated Measures ..........................................78
9.3.2
Linear Regression Model ..........................................................................................79
9.4
Study Drug Dosing Day ...................................................................................................79
10 REFERENCES .....................................................................................................................81
 
LIST OF TABLES 
Table 1
Primary Objective Estimands .............................................................................30
Table 2 
Secondary Objective Estimands .........................................................................30
Table 3
Exploratory Objective Estimands ......................................................................33
Table 4
Treatment Group Presentation in Tables by Analysis Set ...............................38
Table 5
Analysis Visit Windows .......................................................................................70
 
LIST OF FIGURES 
Figure 1 
Study Schematic: Observation, DBT, and Follow-up Phases ..........................25
Figure 2 
Study Schematic: OLE and Follow-up Phases ..................................................25
 
 
 


 
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ABBREVIATIONS 
Abbreviation 
Definition 
AE 
Adverse event 
ALP 
Alkaline phosphatase  
ALT 
Alanine aminotransferase  
ASE 
Asymptotic standard error 
AST 
Aspartate aminotransferase  
BLQ 
Below the limit of quantification 
BMI 
Body mass index 
CGI-c 
Clinical Global Impression - change
CGRP 
Calcitonin gene-related peptide 
CI 
Confidence interval 
CRF 
Case report form 
CSR 
Clinical study report 
C-SSRS 
Columbia-Suicide Severity Rating Scale 
DB 
Double-blind 
DBT 
Double-blind treatment 
ECG 
Electrocardiogram 
eDiary 
Electronic diary 
eGFR 
Estimated glomerular filtration rate
EOFU 
End of follow-up
EOT 
End of treatment 
HDL 
High-density lipoprotein  
IWRS 
Interactive web response system 
LDL 
Low-density lipoprotein 
LFT 
Liver function test  
LLOQ 
Lower limit of quantification 
LSLV 
Last subject last visit 
LSM 
Least-squares mean 
MDRD 
Modification of diet in renal disease 
MIDAS 
Migraine Disability Assessment  
MSQoL 
Migraine Specific Quality of Life 
OP 
Observation Phase
PoM 
Preference of medication
PT 
Preferred term


 
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Abbreviation 
Definition 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SD 
Standard deviation 
SE 
Standard error 
SGC 
Soft gelatin capsule 
SI 
Systeme Internationale 
SOC 
System organ class 
SM 
Satisfaction with medication  
TBL 
Total bilirubin 
TLF 
Table, listing, and figure 
ULOQ 
Upper limit of quantification 
ULN 
Upper limit of normal  
 


 
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REVISION HISTORY 
Version 
Description of Change 
1 
Original version (08-Sep-2021) based on Protocol Version 4 
2 
Amended version (29-Sep-2021) based on Protocol Version 4 
Section 2.1: Specified that subjects are randomized 2:2:1:1 to a treatment group and that 
randomization is stratified. 
Section 2.2: Specified that the IWRS randomizes subjects to a treatment group at the Baseline Visit 
and that randomization is stratified. 
Section 2.4: Specified that SAP Version 2 is based on Protocol Version 4. 
Section 6.2.3: Moved text about by-subject listings to Sections 6.2.3.1, 6.2.3.3, and 6.2.3.4. 
Section 6.2.3.6: Specified identification of treatment in previous studies. Added a listing of previous 
study participation. 
Section 6.5: Modified the handling of multiple questionnaires or rating scale values in analysis visit 
windows. 
Sections 6.5.1 and 6.5.2: Specified that results are based on completed questionnaires. Specified the 
handling of multiple questionnaires on the same assessment date. 
Sections 6.5.3, 6.5.4, and 6.5.5: Specified the handling of multiple questionnaires or rating scale 
values on the same assessment date or time. 
Section 6.6.2: Modified the definition of evaluable at an analysis visit during pretreatment or on-
treatment. 
Section 7.1: Modified the derivation of the eDiary reference date and study drug end date. 
Section 7.4: Removed. 
3 
Amended version (05-Jan-2022) based on Protocol Version 5.0 
General: Changed “non-missing” to “nonmissing”, “pre-treatment” to “pretreatment”, “on-treatment” 
to “on-DBT”, “efficacy analysis set” to “DBT efficacy analysis set”, “first week migraine analysis set” 
to “first month analysis set”, “follow-up analysis set” to “follow-up safety analysis set”, and “study 
drug” to “DB study drug”. Renumbered objectives and endpoints. Added the “zavegepant pooled” 
treatment group to select tables. 
Section 1.2: Modified the schedule of analyses to account for the addendum report. 
Section 2.1: Replaced Screening Phase with Observation Phase. Specified the Open-label Extension 
Phase and modified the timing of follow-up visits. Updated Figure 1 and added Figure 2. 
Section 2.2: Specified that the IWRS also dispenses study drug during visits in the OLE Phase. 
Section 2.3: Removed text about interim analyses. Specified that TLFs for the CSR and subsequent 
database locks are produced unblinded.
Section 2.4: Specified that SAP Version 3 is based on Protocol Version 5. 
Section 3.1.2: Moved the 3 safety objectives to the end. Added “during the DBT and OLE Phases” to 
the end of the 3 safety objectives.  
Section 3.1.3: Added 2 new objectives #5 and #12. Added “during the DBT and OLE Phases” to the 
end of objectives #8, 9, 13, 14, and 15.
Section 3.2: Specified the external source of the eDiary data.
Section 3.2.2: Modified Table 2 to align with changes in Section 3.1.2. 
Section 3.2.3: Modified Table 3 to align with changes in Section 3.1.3. 
Section 4.1: Modified the definition of the migraine analysis set. Defined the first month migraine, 
first week treated migraine, DBT safety, OL zavegepant safety, DB or OL zavegepant safety, interim 
safety, and PK analysis sets.


 
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Version 
Description of Change 
Section 4.2.: Specified OL zavegepant dose groups in the OLE Phase. 
Section 4.3.2.1: New section “On-DBT Safety Subgroups”. Moved existing text in Section 4.3.2 here. 
Section 4.3.2.2: New section “On-OL Zavegepant Safety Subgroups”. 
Section 4.3.2.3: New section “On-DB or OL Zavegepant Safety Subgroups”. 
Section 5: Changed “zavegepant study” to “rimegepant study” (typo). Specified that only secondary 
efficacy and outcomes research endpoints are tested hierarchically. 
Section 6.1.1.1: Added the table presentation of the OL zavegepant, DB or OL zavegepant, and 
interim safety analysis sets. Modified the table presentation of the follow-up safety analysis set. Added 
Table 4 “Treatment Group Presentation in Tables by Analysis Sets”. Defined “Zavegepant Pooled”. 
Section 6.1.1.2: Specified the treatment group abbreviation for subjects not in the randomized analysis 
set in listings. Added zavegepant study day to listings. Modified the abbreviated names of the analysis 
periods. 
Section 6.2.1: Changed “14” to “24” for the OP. Specified as-treated for all safety analysis sets. 
Sections 6.2.3.3 and 6.2.3.5: Modified categories based on the changes to the DB Subject Status CRF 
and addition of OLE Subject Status CRF. 
Section 6.2.3.4: New section “Subject Disposition during the OLE Phase” based on OLE Subject 
Status CRF. 
Section 6.2.5: Added tables and defined baseline for the OL zavegepant and DB or OL zavegepant 
safety analysis sets.  
Section 6.2.5.1: Added age and age category at reference baseline to tables for the OL zavegepant and 
DB or OL zavegepant safety analysis sets. 
Section 6.2.5.4: Renamed as “Non-study Prior Medications”. 
Section 6.2.6.1: Specified that OL zavegepant 100 or 200 mg is taken during the OLE Phase, and 
updated kit type identifiers. Defined valid DB and OL wallet IDs based on respective kit list files. 
Changed “study drug” to “DBT”. Moved current text under “DBT Exposure”. Added 2 subsections 
“OL Zavegepant Exposure” and “DB or OL Zavegepant Exposure”. 
Section 6.2.6.2: Changed “Treatment Compliance” to “DB Treatment Compliance”, “tablet” to 
“capsule” (typo), and “maxdate” to “DB maxdate”. Added new section “OL Zavegepant Treatment 
Compliance”. Removed “Last 28 days before DB study drug start” category. 
Section 6.2.6.3: Renamed as “Non-study Concomitant and Follow-up Medications”. Defined on-DBT, 
on-OL zavegepant, and on-DB or OL zavegepant concomitant medications. Added output for the OL 
zavegepant and DB or OL zavegepant safety analysis sets. 
Section 6.3: Changed “eDiary reference” to “eDiary efficacy” throughout. 
Section 6.3.1: Specified that pretreatment measurements that are not in the OP analysis period are 
labeled “PRETRT”, criterion (1) of the migraine analysis set definition aligns with protocol exclusion 
criterion 6c, and results are prorated only in the DBT Phase, not the OP. Modified the algorithm for 
calculating results in the OP. 
Section 6.3.1.1: Changed “14” to “24” for the OP. 
Section 6.3.2.3: Modified the section title.  
Section 6.3.3.1: Specified that results are prorated only in the DBT Phase, not the OP.  
Section 6.3.3.3: Modified the algorithm for calculating results in the OP and each week. 
Section 6.3.3.5: Specified that analyses are based on the first week treated migraine analysis set, and 
that results support exploratory objective #5. 
Section 6.3.4: Specified that results are tabulated by zavegepant treatment group. 
Section 6.4: Specified that treatment group is as-treated according to Section 6.1.1.1. Added the OL 
zavegepant, DB or OL zavegepant, and interim safety analysis sets. Modified the algorithm for 
measurement slotting. 


 
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Version 
Description of Change 
Section 6.4.1.1: Modified algorithm for identifying deaths. Added zavegepant study day to the listing. 
Section 6.4.1.2: Added tables for the OL zavegepant, DB or OL zavegepant, and interim safety 
analysis sets.
Section 6.4.1.5: New section “On-OL Zavegepant AEs”. Added tables for the OL zavegepant safety 
analysis set. 
Section 6.4.1.6: New section “On-DB or OL Zavegepant AEs”. Added tables for the DB or OL 
zavegepant safety analysis set. 
Section 6.4.1.7: New section “Post-DBT Pre-OL Zavegepant AEs”. Added tables for the interim 
safety analysis set. 
Section 6.4.2: Removed sentence about clinically significant laboratory abnormalities. Added output 
for the OL zavegepant, DB or OL zavegepant, and interim safety analysis sets. 
Sections 6.4.3 and 6.4.4: Added output for the OL zavegepant, DB or OL zavegepant, and interim 
safety analysis sets. 
Section 6.4.6: Modified events of interest. 
Sections 6.5.1 to 6.5.5: Added results at Weeks 24 and 64 to tables. Added tables for the OL 
zavegepant efficacy analysis set. 
Section 6.5.3: Specified that PoM is assessed for subjects with “yes” response to the lead question. 
Section 6.6.2: Modified the definition of evaluable subjects in the pretreatment analysis period. 
Specified which visits are tabulated. 
Section 6.6.3: Added zavegepant study day to the listing. 
Section 7.1: Modified the derivation of the eDiary reference date, study drug end, study drug last, last 
contact, OP start, and OP end dates. Added the derivation of the DB study drug start, DB study drug 
end, OL zavegepant start, OL zavegepant end, OL zavegepant last, DB or OL zavegepant start, DB or 
OL zavegepant end, and DB or OL zavegepant last dates. Changed “Study Drug Exposure” to “IP 
Dosing”. 
Section 7.2: Changed “follow-up efficacy” to “post-DBT efficacy”. Defined the pre-OL zavegepant, 
pre-DB or OL zavegepant, on-DBT safety, OL zavegepant safety, DB or OL zavegepant safety, and 
interim safety analysis periods. 
Section 7.3: Defined zavegepant study days. Specified how (1) study days and follow-up days are used 
to define analysis visit windows in safety analysis periods, and (2) display of zavegepant study days in 
select listings. Renumbered Table 4 as Table 5. Changed Week 12 target day from 84 to 85. Added 
study visits Week 14 though Week 64 to Table 5. 
Section 8: Specified the timing of the CSR database and final database locks and content of the 
reports.
Section 9.1.4: Modified study premature termination derivations. 
Section 9.2: Changed “Demographics CRF” to “Demographics/Informed Consent CRF”. Specified the 
full analysis set efficacy data issues during the OP. Added OL zavegepant dosing errors. 
4 
Amended version (02-Mar-2022) based on Protocol Version 5 
Section 6.1.1.1: Modified treatment group labels for results by OL zavegepant dose and overall in 
Table 4. 
Sections 6.2.3.3 and 6.2.3.4: Modified the derivations of the on-going, completed phase, and did not 
complete phase categories. 
Section 6.2.5.4: Removed prior medications. Changed “3 months” to “12 weeks” and “90” to “84”, 
Section 6.2.6.1: Modified the derivations of cumulative DB study drug exposure, cumulative OL 
zavegepant exposure, and cumulative DB or OL zavegepant exposure. 
Section 6.2.6.2: Modified the derivations of actual cumulative DB capsule count and actual cumulative 
OL zavegepant capsule count. 


 
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Version 
Description of Change 
Section 6.2.6.3: Modified the definitions of non-study concomitant medications to consider missing 
study drug last date. Defined prophylactic migraine and acute migraine medications. 
Section 6.4: Moved text about the procedures listing to Section 6.4.5. 
Section 6.4.5: New section “Procedures”. 
Section 7.1: Modified the derivation of the DB study drug last date. 
Section 9.2: Changed “3 months” to “12 weeks”, “90” to “84”, and “receptor antagonist” to 
“antagonist”. 
5 
Amended version (26-May-2022) based on Protocol Version 6 
General: Changed “Zavegepant Core SAP” to “Core SAP”. Removed references to former Section 9.1 
(“COVID-19 Visit Impact”) and its subsections, and instead referenced the Core SAP for COVID-19 
visit impact. Modified language to use phrases like “table of <specified endpoint> is provided” instead 
of “<specified endpoint> is tabulated”. Changed “stop date” to “end date”. 
Corrected hyperlink errors. 
Section 1: Specified that this SAP references the Rimegepant/Zavegepant Core SAP. 
Section 2.4: Specified that SAP Version 5 is based on Protocol Version 6. 
Sections 3.1, 3.2, and 3.3: Changed “baseline” to “the OP” in efficacy objectives and endpoints as per 
Protocol Version 6. 
Section 3.1.3: Added new objective #16 as per Protocol Version 6.
Section 3.2.3: Added new endpoint #16 to Table 3 as per Protocol Version 6.
Section 4.1: Changed the definition of the migraine analysis set back to SAP Version 2 definition 
based on FDA feedback on BHV3000-404. Modified the definition of the first week treated migraine 
analysis set to include DB study drug dosing days. 
Section 6.1.1.1: Modified last column of Table 3 to display abbreviated treatment group. 
Section 6.2.1: Specified that the COVID-19 impacted analysis set is excluded from the table. 
Section 6.2.3: Added a footnote to subject disposition listings about the last contact date. 
Section 6.2.3.3: Modified definitions of “continued to the next phase” and “did continue to the next 
phase” categories. 
Section 6.2.3.5: Modified definition of “did not formally enter the Follow-up Phase” category. 
Section 6.2.3.6: Moved text from Section 9.1.4 here. 
Section 6.2.5: Removed baseline derivations and instead referenced the Core SAP. Specified that 
tables of baseline characteristics are produced for the full analysis set excluded from the migraine 
analysis set only if > 5 subjects are in this analysis set.
Section 6.2.5.2: Removed migraine history parameters that are covered in the Core SAP.
Section 6.2.6.2: Added a by-subject listing of treatment compliance. Modified the definitions of the 
following compliance categories: more than the required number of DB capsules per day taken on any 
1 day; no DB study drug taken for  3 days (not necessarily consecutive) in any 1 week through Week 
12; more than the required number of OL zavegepant capsules per day taken on any 1 day; no OL 
zavegepant taken for 
3 days (not necessarily consecutive) in any 1 week after Week 12 through 
Week 64. Added category “DB study drug and OL zavegepant taken on same day”. 
Section 6.2.6.3: Removed the definitions of DB, OL zavegepant, and DB or OL zavegepant 
concomitant medications, and instead referenced the Core SAP. 
Section 6.3.1: Changed the definitions of the following back to SAP Version 2.0 definition: migraine 
analysis set; number of migraine days per month in the OP.
Section 6.3.1.1: Changed “24” to “14” for the OP. 
Section 6.3.1.2: Added a table of values and changes from the OP in the number of migraine days per 
month in the DBT Phase for the DBT efficacy analysis set. Removed scatter plots. 


 
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Section 6.3.2.1: Specified that results across all subgroups are displayed together in the same CMH 
table. 
Section 6.3.2.3: Added the number of subjects with data as a summary statistic. 
Section 6.3.3.5: Modified the definition of the first week treated migraine analysis set to include DB 
study drug dosing days. 
Section 6.4: Removed the algorithm for handling multiple measurements in the same analysis visit 
window, and instead referenced the Core SAP. 
Section 6.4.1: Added references to the Core SAP for AE end date imputation, death date derivation, 
and TLF contents. 
Section 6.4.1.1: Modifies the definition of deaths. 
Sections 6.4.1.2, 6.4.1.3, and 6.4.2.2: Changed “DBT safety analysis set” to “safety analysis set”. 
Sections 6.4.1.4, 6.4.15, and 6.4.1.6: Specified analysis period reference start and end dates for 
calculations of exposure-adjusted multiple occurrences of unique AEs. 
Section 6.4.2.2: Specified that tables of exposure-adjusted cumulative LFT elevations use the same 
analysis period reference start and end dates as corresponding exposure-adjusted AEs. Modified the 
definition of treated migraine days to include study drug dosing days. 
Sections 6.4.2.3 and 6.4.3.1: Added overall treatment group to the table of values and changes from 
baseline for the safety analysis set. Specified the time points at which results for zavegepant pooled, 
placebo pooled, and overall are displayed. Removed text about handling multiple values on the same 
date, and instead referenced the Core SAP for handling multiple values in an analysis visit window or 
on the same date, and deriving the EOT value in an on-treatment safety analysis period.  
Section 6.4.2.3: Specified that Cerba Research provides sample code (vial/tube identifier), whereas 
ACM Global Laboratories provide accession identifier. 
Section 6.4.4: Specified that (1) ECGs are analyzed using results from local tests reported on ECG 
CRFs and the external central vendor Bioclinica, and (2) the ECG CRF collects RR in sec, not msec. 
Section 6.4.4.1: Added overall treatment group to the table of values and changes from baseline for the 
safety analysis set. Specified the time points at which results for zavegepant pooled, placebo pooled, 
and overall are displayed. Modified text about handling multiple values on the same date. Referenced 
the Core SAP for handling multiple values in an analysis visit window and deriving the EOT value in 
an on-treatment safety analysis period. 
Section 6.5: Specified the slotting of measurements into analysis periods and analysis visits, and a 
confidence level of 97.5% is used for CIs. Removed text about handling multiple values on the same 
date. Added references to the Core SAP for handling multiple values in an analysis visit window or on 
the same date, and deriving the EOT value in an outcomes research analysis period. 
Sections 6.5.1 and 6.5.2: Added overall treatment group to the table of values and changes from 
baseline for the DBT efficacy analysis set. Specified the time points at which results for overall are 
displayed. 
Sections 6.5.3, 6.5.4, and 6.5.5: Added overall treatment group to the frequency table for the DBT 
efficacy analysis set. Specified the time points at which results for overall are displayed. 
Section 6.6: Removed subsections 6.6.1 though 6.6.3. Referenced the Core SAP. 
Section 7.1: Specified which derived dates are analysis period reference dates. Modified the derivation 
of the OP end date and last contact date. 
Section 7.2: Defined the 28-day OP analysis period. Removed the definitions of analysis periods for 
pretreatment characteristics, safety endpoints, and outcomes research endpoints, and instead 
referenced the Core SAP. 
Section 7.3: Removed the definitions of randomization day, study day, rimegepant study day, and 
follow-up day, and instead referenced the Core SAP. Modified contents of Table 5 and added 2 
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Section 9.1: Removed.  
Section 9.2: Renumbered as 9.1. Specified using the 28-day OP analysis period for assessing efficacy 
data issues during the OP. Specified that narcotic is barbiturate or opioid. Removed deviation category 
for St. John’s wort because it is covered under CYP3A4 and P-gp inducer categories.
Sections 9.3 and 9.4: Renumbered respectively as 9.2 and 9.3.
Section 9.4: New section “Study Drug Dosing Days”. 
6 
Amended version (11-Aug-2022) based on Protocol Version 6
Section 2.4: Specified that SAP Version 6.0 is based on Protocol Version 6. 
Section 3.2.2: Modified the efficacy endpoint for objective #2 in Table 2. 
Section 3.2.3: Modified the efficacy endpoint for objectives #1, 6, and 7 in Table 3. 
Section 6.1.1.1: Modified the treatment group layout of OL zavegepant safety and follow-up safety 
analysis sets by treatment group/OL zavegepant dose and overall in Table 4. 
Section 6.3.1: Specified that results are prorated to account for missing migraine reports. 
Section 6.3.2.1: Removed longitudinal plots. 
Section 6.3.4: Modified data sources, contents of the plasma zavegepant concentration listing, and 
merging of CRF and external PK data.
Section 6.4.2.1: Specified the main presentation only for shift tables.
7 
Amended version (11-May-2023) based on Protocol Version 6 
General: Removed “Biohaven Pharmaceuticals” throughout. Added “(C5301006)” next to BHV 
protocol number, and footer “Pfizer Confidential”. Removed statements throughout about displaying 
COVID-19 visit impact code for visits impacted by COVID-19 in listings. Added ‘, normal 
distribution’ throughout after ‘Identity link function’. Replaced the randomized analysis set with the 
full analysis set.   
Signature page: Removed all references to “sponsor”. Replaced 
 with 
, 
and 
 with 
, and removed 
.  
Abbreviations: Added CYP3A4, eDiary, and GLM. Removed CK, TEAE, and US. 
Section 1.2: Changed “CSR” to “first”, and specified that no interim analyses are planned (moved text 
from Section 8). Removed the last sentence. 
Section 2.3: Changed “CSR” to “first”, and removed “and subsequent database locks”. 
Section 2.4: Specified that SAP Version 7 is based on Protocol Version 6. 
Section 3.1: In Table 1, formatted text to bold for primary objective. 
Section 3.2: Specified treatment group comparisons for efficacy and outcomes research endpoints. In 
the “Intercurrent Events” section, specified (1) hypothetical or composite strategy for handling study 
drug discontinuation for efficacy objectives, (2) 7-day cutoff on study drug discontinuation for safety 
objectives, and (3) non-study prophylactic migraine medication use before the time point of interest 
defining the endpoint as an intercurrent event for all objectives. Changed “change” to “mean change” 
and “value” to “mean value” in the “Summary” rows for continuous endpoints in Tables 1 to 3. 
In the “Data Sources for Endpoints” section, removed the sentence “Deaths are determined from AE 
and subject disposition case report forms (CRFs).”.  
Section 3.2.1: In the first sentence, replaced “attributes” with “estimand” and removed “for this study 
are” after “endpoint”. Modified the “Summary” and “Intercurrent Events” rows in Table 1. 
Section 3.2.2: In Table 2, (1) modified “Summary” row for objectives #1 to 6, and (2) modified 
“Intercurrent Events” row for all objectives. 
Sections 3.2.3: In Table 3, (1) modified “Summary” row for objectives #1 to 7, 10, and 11, (2) 
modified “Intercurrent Events” row for all objectives, and (3) formatted text to bold in rows for 
“Objective 4 and “Objective 16”. 
PPD
PPD
PPD
PPD
PPD


 
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Section 4.1: Removed the previous definition of the full analysis set. 
Section 4.3: Specified that the efficacy subgroup of interest is stable prophylactic migraine medication 
use through randomization.
Section 4.3.1: Removed this section because all efficacy subgroups were removed except for 
randomization stratum, which was moved up to Section 4.3. 
Section 4.3.2: Removed this section because all safety subgroups were removed. 
Section 5: Specified 2-side alpha levels. 
Section 6.1.1.1: Removed references to safety subgroups. 
Section 6.1.1.2: Removed significant protocol deviations. Replaced ‘COVID-19 visit impact’ with 
‘visits impacted by COVID-19’.  
Section 6.1.3: Modified second sentence to reference Section 6.3 for statistical methods for handling 
missing data in efficacy analyses. 
Section 6.2.1: Removed the frequency table of inclusion and exclusion from the migraine analysis set 
and the listing of subjects excluded from efficacy analyses. Specified that the administrative listing of 
randomization scheme and codes is provided for the full analysis set. 
Section 6.2.2: Removed the frequency tables of enrollment by age group and accrual by randomization 
month and year.  
Section 6.2.3: Added the by-subject listing of subject discontinuation for the enrolled analysis set, and 
specified its contents. 
Section 6.2.3.1: Removed the by-subject listing of eligibility with inclusion/exclusion criteria. 
Section 6.2.3.3: Removed the frequency table of subject disposition for the migraine analysis set. 
Removed the by-subject listing of DBT subject disposition.  
Section 6.2.3.4: Removed the by-subject listing of OLE subject disposition. 
Section 6.2.3.5: Removed the frequency table of subject disposition for the as-treated treatment 
group/OL zavegepant dose and overall. Removed the by-subject listing of follow-up subject 
disposition. 
Section 6.2.3.6: Added reference to Section 6.2.3.1.
Section 6.2.3.7: Removed the by-subject listing of rescreen and previous study participation.
Section 6.2.4: Moved text from Section 6.2.4.1 here. 
Sections 6.2.4.1 and 6.2.4.2: Removed. 
Section 6.2.5: Removed tables of baseline characteristics for select analysis sets. Replaced ‘IWRS 
stable prophylactic migraine medication’ with ‘prior prophylactic migraine medication use’. Removed 
the by-subject listing of cardiac and other risk factors. 
Section 6.2.5.1: Replaced ‘IWRS stable prophylactic migraine medication’ with ‘prior prophylactic 
migraine medication use’. 
Section 6.2.5.2: Removed “Age at chronic migraine onset (years)” and “Number of headache-free 
days per month in the 3 months prior to screening” because the Core SAP was updated with these 
parameters. Specified that the frequency table of cardiac and other risk factors is provided only for the 
DBT safety analysis set. Changed “efficacy endpoint” to “migraine-related even day” and “Efficacy 
parameter” to “parameter”. 
Section 6.2.6.1: Modified the contents of the by-subject listing of study drug. Removed tables of DB 
study drug exposure by subgroups. Removed reference to subgroups and exposure table by subgroups. 
For the last time on DB or OL zavegepant milestone category, changed ‘18 months’ to ‘15 months’ 
(typo). 


 
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Section 6.2.6.2: Specified the required number of capsules per day by OL zavegepant dose group in 
the calculation of OL zavegepant capsule count compliance. Changed “< 80%” to “  80%” and 
removed the no study drug taken for 
3 days in any week category in the treatment compliance tables. 
Changed “
the table of eDiary usage compliance. 
Section 6.2.6.3: Renamed section as “Non-study Concomitant Medications”. Removed frequency 
tables of non-study DB or OL zavegepant concomitant and follow-up medications. Simplified the 
definition of migraine standard of care medications.
Section 6.3: Replaced IWRS stable prophylactic migraine mediation through randomization with use 
of prior prophylactic migraine medication. Removed by-subject listings of exploratory migraine and 
headache days per month endpoints. 
Section 6.3.1: Removed the by-subject listing of eDiary headache report. 
Section 6.3.1.1: Modified the contents of the frequency table of missing efficacy data in the OP and 
DBT Phase. 
Section 6.3.1.2: Removed the table of values and changes from the OP in the number of migraine days 
per month in the DBT Phase for the DBT efficacy analysis set. 
Section 6.3.1.3: Removed “n (i.e., number of subjects with data)” from the GLMEM table. Removed 
the longitudinal plot of LSM change from OP in the number of moderate or severe migraine days per 
month versus month of the DBT Phase. Removed “subject as a random effect” from the GLMEM. 
Specified that Protocol Versions 1 to 6 erroneously specify to include subject as a random effect in the 
GLMEM. Specified the J2R and tipping point sensitivity analyses to be on the DBT efficacy analysis 
set instead of the migraine analysis set. Removed the supplementary analysis of the DBT efficacy 
analysis set and subgroup analyses of the migraine analysis set. 
Section 6.3.2.1: Removed the frequency table of descriptive analyses, histogram, and CMH table of    
 50% reduction of moderate or severe pain intensity by subgroups. Specified that percentages are 
calculated against the number of subjects in the migraine analysis set. Removed reference to Non-
evaluable = Failure. Replaced ‘a Cochran-Mantel-Haenszel (CMH) test stratified’ with ’Mantel-
Haenszel risk estimation with stratification’ and replaced ‘CMH table’ with ‘table’. Added a note that 
the protocols specified that the stratified CMH test would be used for treatment groups comparisons, 
but that the Mantel-Haenszel risk estimation is the more appropriate test to use given the estimand is 
based on a difference in percentages between treatment groups.  
Section 6.3.2.2: Removed “change from OP in” from the description of the dependent variable and 
“subject as a random effect” from the GLMEM. Removed “n (i.e., number of subjects with data)” 
from the GLMEM table.  
Section 6.3.2.3: Described the hierarchical testing strategy for secondary endpoints. In last 2 main 
bullets, replaced ‘in the last month of the’ with ‘over the entire’. 
Section 6.3.3.1: Specified that the table of values and changes has the same format as the one 
described in Section 6.3.1.2. 
Sections 6.3.3.2, 6.3.3.4, and 6.3.3.5: Replaced ‘a CMH test stratified’ with ’Mantel-Haenszel risk 
estimation with stratification’ and replaced ‘CMH table’ with ‘table’. 
Section 6.3.3.2: Specified that the percentage of subjects with reduction in the number of headache 
days during the DBT Phase is defined and assessed analogously to the percentage of subjects with 
reduction in the number of migraine days during the DBT Phase. Removed the frequency table of 
descriptive analyses. Removed reference to Non-evaluable = Failure. 
Section 6.3.3.3: Modified the calculation of migraine days per week in the OP and each week of the 
on-DBT efficacy analysis period. Removed “subject as a random effect” from the GLMEM. Removed 
“n (i.e., number of subjects with data)” from the GLMEM table. 
Section 6.3.3.4: Specified that analyses of headache days per week are defined analogously to those 
for migraine days per week. Removed the frequency table of descriptive analyses. Specified that 
percentages are calculated against the number of subjects in the first month migraine analysis set. 


 
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Section 6.3.3.5: Specified that percentages are calculated against the number of subjects in the first 
week treated migraine analysis set. Added percentage of efficacy endpoint days in the OP to the table. 
Section 6.3.3.6: Specified that the table of the number of acute migraine medication days per month in 
the DBT Phase has the same format as the one in Section 6.3.2.2. Removed “The corresponding CMH 
table has the same format.”. 
Section 6.4: Removed tables during pretreatment for the enrolled analysis set by overall.  
Section 6.4.1: Specified the sorting order of AE tables, and that the by-subject listing of AEs for the 
enrolled analysis set includes all AEs (i.e., non-SAEs and SAEs). Removed by-subject listings of 
SAEs, AEs leading to study drug discontinuation, and AEs of special interest. 
Section 6.4.1.1: Removed the frequency table of deaths. 
Section 6.4.1.2: Removed AE overview frequency tables during pretreatment for the enrolled analysis 
set and by subgroups. 
Section 6.4.1.3: Removed AE frequency tables for the enrolled analysis set. 
Section 6.4.1.4: Removed frequency tables of AEs occurring with  5% frequency, TEAEs by 
intensity, TEAEs occurring with  2% frequency in any zavegepant treatment group and greater than 
placebo after rounding, exposure-adjusted multiple occurrences of unique SAEs, exposure-adjusted 
multiple occurrences of SAEs related to study drug, exposure-adjusted multiple occurrences of non-
SAEs with  5% frequency, and by subgroups. Clarified that AE frequency is presented in descending 
order of Zavegepant pooled within SOC and PT. 
Section 6.4.1.5: Renumbered as Section 6.4.1.6. Removed AEs of special interest, exposure-adjusted 
multiple occurrences of unique AEs (all variations), and by subgroups. 
Section 6.4.1.6: Renumbered as Section 6.4.1.7. Specified that frequency tables of on-DB or OL 
zavegepant AEs are provided for the same endpoints as in section 6.4.1.4. 
Section 6.4.1.7: Renumbered as Section 6.4.1.5. 
Section 6.4.2: Specified that TLFs display results in SI units, if applicable. Removed by-subject 
listings of laboratory tests by laboratory test group and pregnancy tests. Removed creatine kinase 
elevation questionnaire listing. 
Section 6.4.2.1: Removed frequency tables of laboratory test low/normal/high shift from baseline to 
any abnormal value for all analysis periods, laboratory test toxicity grade shift from baseline to the 
worst toxicity grade on OL zavegepant, and by subgroups.  
Section 6.4.2.2: Removed frequency tables of LFT elevations during pretreatment for the enrolled 
analysis set, LFT ULN shifts from baseline to the worst LFT elevation on OL zavegepant, exposure-
adjusted cumulative LFT elevations on OL zavegepant, and time to time to first LFT elevation on OL 
zavegepant. Removed eDISH plot on OL zavegepant. Replaced “treated migraine days” with “DB 
study drug and OL zavegepant dosing days” in the by-subject longitudinal LFT plot.
Section 6.4.2.3: Replaced the table of values and changes from OL zavegepant baseline with the 
corresponding one from DB or OL zavegepant baseline. 
Section 6.4.3: Added BMI definition. Removed the by-subject listing of vital signs and physical 
measurements. 
Section 6.4.3.1: Replaced the table of values and changes from OL zavegepant baseline with the 
corresponding one from DB or OL zavegepant baseline.
Section 6.4.3.2: Removed the frequency table on OL zavegepant.
Section 6.4.4: Removed the by-subject listing of ECG results. 
Section 6.4.4.1: Replaced the table of values and changes from OL zavegepant baseline with the 
corresponding one from DB or OL zavegepant baseline. 
Section 6.4.4.2: Removed. 
Section 6.4.4.3: Renumbered as Section 6.4.4.2. Removed the frequency table on OL zavegepant.


 
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Section 6.4.5: Removed. 
Section 6.4.6: Renumbered as Section 6.4.5. Removed the frequency table on OL zavegepant and the 
by-subject listing of C-SSRS. 
Section 6.4.7: Renumbered as Section 6.4.6. 
Section 6.5: Removed reference to the OL zavegepant efficacy analysis set. Removed by-subject 
listings of PoM, SM and CGI-c. Specified the contents of the by-subject listing of MSQoL and 
MIDAS. Referred to the Core SAP for calculating scores, imputing missing data, and deriving 
categories. 
Section 6.5.1: Removed 2 sentences above “Descriptive Analyses” because these methods were added 
to the Core SAP. Added a frequency table of MSQoL domain score increase from baseline categories 
for the DBT efficacy analysis set. Specified that treatment group comparisons were on subjects with 
paired data. Changed “GLMEM” to “GLM”. Removed the table of values and changes from OL 
zavegepant baseline in scores for the OL zavegepant efficacy analysis set.
Section 6.5.2: Removed 2 sentences above “Descriptive Analyses” because these methods were added 
to the Core SAP. Changed “GLMEM” to “GLM”. 
Section 6.5.3: Removed the frequency table of PoM for the OL zavegepant efficacy analysis set.
Section 6.5.4: Removed the frequency table of SM for the OL zavegepant efficacy analysis set. 
Section 6.5.5: Removed the frequency table of CGI-c for the OL zavegepant efficacy analysis set.
Section 6.6: Removed the by-subject listing of COVID-19 impact codes by visit. Renamed the by-
subject listing of COVID-19 visit impact to visits impacted by COVID-19. 
Section 7.1: Added the death date. 
Section 7.2: Removed the on-OL zavegepant efficacy, post-DBT pre-OL zavegepant efficacy and 
follow-up efficacy analysis periods. Removed references to the eDiary headache report listing. 
Section 7.3: Replaced 'rimegepant’ with ‘zavegepant’ (typo). Modified analysis visit windows for the 
Screening and Pre-randomization Visits in Table 5. Removed “Baseline #” row and corresponding 
footnote from Table 5. Specified how analysis visit windows are defined according to analysis period. 
Section 8: Specified the TLFs produced for the CSR and Addendum Report. 
Section 9.1: Modified deviation about major depressive disorder. Changed “P-gp” to “strong P-gp”. 
Section 9.3.1: Added “cl diff” to the lsmeans statement. 
Section 9.3.2: Renamed section as “GLM”. Added “cl diff” to the lsmeans statement. 
8 
Amended version (27-Feb-2024) based on Protocol Version 6 
Abbreviations: Removed FCS, GLM, GLMEM, J2R, MAR, MCMC, and MNAR. Added LSLV. 
General: Replaced 'GLMEM’ with ‘linear mixed effects model’ and ‘GLM’ with ‘linear regression 
model’ throughout. Used ‘model’ or ‘models’ in place of ‘GLMEM’ or ‘GLM’ to avoid redundant text 
on the type of model.
Section 1: Specified that the study was terminated prematurely for business reasons and not a safety 
concern, and the SAP was being amended to reduce the number of TLFs. 
Section 1.2: Revised study plans to have 1 final database lock after the last subject completes the 
follow-up week 8 visit and a final CSR. 
Section 2.3: Removed reference to an addendum report. Specified that dummy treatment groups are 
used for the draft TLFs for the final CSR prior to DBL, and TLFs for the final CSR are produced 
unblinded. 
Section 2.4: Specified that SAP Version 8 is based on Protocol Version 6. 
Section 3.2: In the data sources for endpoints sub-section, updated acute migraine medication days 
definition. Removed PoM, SM and CGI-c categories.


 
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Section 3.2.3: Specified that Table 3 only includes the endpoints to be assessed. In Table 3, updated 
sections for exploratory objectives: 1, 2, 6, 7, 10-12, and removed sections for exploratory objectives 
3-5 and 13-16. 
Section 4.1: Removed text on headache days for migraine analysis set. Removed first month migraine, 
PK, and OL zavegepant efficacy analysis sets. 
Section 4.3: Specified that the randomization strata are based on the actual data and not those assigned 
in IWRS. 
Section 5: Removed language about Type 1 error, testing hierarchy for the primary and secondary 
endpoints, and exploratory endpoints. Stated that type 1 error is not applicable, and significance of the 
primary and secondary endpoints will not be evaluated.
Section 6.1.1.1: In Table 4, removed OL zavegepant efficacy and PK by zavegepant treatment group. 
Section 6.1.1.2: Added listing of significant protocol deviations.
Section 6.2.1: Removed by-subject listing of subjects excluded from the efficacy analysis. 
Section 6.2.3.3: Replaced ‘CSR’ with ‘LSLV’. 
Section 6.2.3.4: Replaced ‘final’ with ‘LSLV’. Removed subject disposition table for as-treated 
treatment group/OL zavegepant dose and overall. 
Section 6.2.3.7: Removed Section (treatment in previous studies). 
Section 6.2.4: Moved Relevant Protocol Deviations section to new Section 6.2.4.1. 
Section 6.2.4.1: Changed analysis set to full in by-subject listing of relevant protocol deviations.
Section 6.2.4.2: Added new section for Significant Protocol Deviations. 
Section 6.2.5: Removed text for DB or OL zavegepant safety analysis set. Revised frequency table of 
randomization stratum to a frequency cross table of randomization stratum from IWRS vs actual data 
for the full analysis set by treatment group and overall. 
Section 6.2.5.1: Updated 2nd bullet to use randomization stratum based on actual data. Removed text 
for DB or OL zavegepant safety analysis set. 
Section 6.2.5.2: Removed table of migraine-related event days per week from OP for first migraine 
analysis set. Removed sentence on the percentage calculation. Removed reference to sections on 
headache days per month, migraine days per week and headache days per week. 
Section 6.2.5.4: Replaced ‘standard of care’ with ‘acute’.
Section 6.2.6.1: Removed administrative listing of investigational produce batch numbers. 
Section 6.2.6.2: Removed DB treatment compliance, OL zavegepant treatment compliance, and ediary 
usage compliance tables and by-subject listing of treatment compliance. Specified that DB treatment 
compliance, OL zavegepant treatment compliance, and ediary usage compliance categories are defined 
for relevant protocol deviations. In sub-sections for DB treatment compliance and OL zavegepant 
Section 6.2.6.3: Removed bullet on migraine standard of care medications. Replaced ‘standard of care’ 
with ‘acute’. 
Section 6.3: Specified that the randomization stratum used in analyses is based on actual data, not 
from IWRS, and provided the rationale. For the listing of primary and key secondary efficacy 
endpoints, specified the reasons for exclusion from the migraine analysis set and data methods for 
presenting endpoints. Removed p-values for all models. 
Section 6.3.1: Removed text about data from previous visit to current visit. 


 
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Section 6.3.1.3: Removed ‘Identity link function, normal distribution’. Removed “subject as a random 
effect’ from the model. Changed ‘Repeated measures error structure’ to ‘Covariance structure for 
repeated measures accounting for within-subject correlated errors’ and modified text describing 
specification of the covariance structure. Changed ‘degrees of freedom method: Kenward-Roger’ to 
Standard error (SE) estimation method: Huber-White “sandwich” (refer to the Core SAP)”. Removed 
the longitudinal plot. Removed sensitivity analyses: jump to reference and tipping point. 
Section 6.3.2.1: Replaced ‘efficacy dates’ with ‘efficacy data dates’. In treatment group sub-section, 
 
Section 6.3.2.2: Removed text about data from previous visit to current visit. Specified that acute 
migraine medication days are prorated. Replaced ‘reference time point’ with ‘efficacy data’.
Removed ‘Identity link function, normal distribution’. Changed ‘Denominator degrees of freedom 
method: Kenward-Roger’ to ‘Standard error (SE) estimation method: Huber-White “sandwich” (refer 
to the Core SAP)’. 
Section 6.3.2.3: Removed text about p-values and hierarchical testing. 
Section 6.3.3: Removed Sections 6.3.3.1, 6.3.3.2, 6.3.3.3, 6.3.3.4 and 6.3.3.5.  
Section 6.3.3.6: Renumbered to Section 6.3.3.1. 
Section 6.3.3.1: Replaced ‘reference time point’ with ‘efficacy data’. 
Section 6.3.4: Removed table of plasma zavegepant concentrations along with the text to support this 
table. Specified that the by-subject plasma zavegepant concentrations will be presented for the DBT 
efficacy analysis set. 
Section 6.4: For On-OL zavegepant for the OL zavegepant safety analysis set, specified to present by 
OL zavegepant dose and overall. Removed the following: ‘OL zavegepant dose and overall, i.e., main 
presentation’, ‘Treatment group/OL zavegepant dose and overall, i.e., supplemental presentation’. 
Removed ‘Both presentations are produced’. 
Section 6.4.1: Removed ‘exposure-adjusted multiple occurrences of unique AEs’. 
Section 6.4.1.2: For the AE overview frequency table, removed rows for 'Mild AEs’ and ‘Moderate 
AEs’, and changed row for ‘Severe AEs’ to ‘Moderate or Severe AEs’. 
Section 6.4.1.4: Removed table for exposure-adjusted multiple occurrences of unique AEs along with 
the calculations. 
Section 6.4.1.5: Removed section. 
Section 6.4.1.6: Renumbered to Section 6.4.1.5. 
New Section 6.4.1.5: Specified to produce the same tables as in Section 6.4.1.4.
Section 6.4.1.7: Removed section. 
Section 6.4.1.8: Renumbered to Section 6.4.1.6. 
Section 6.4.1.9: Removed section.  
Section 6.4.2.1: Removed ‘Post-DBT pre-OL zavegepant for the interim safety analysis set’ and ‘On-
DB or OL zavegepant for the DB or OL zavegepant safety analysis set’. Removed tables of laboratory 
test grade shifts from baseline. 
Section 6.4.2.2: Removed bullet: Post-DBT pre-OL zavegepant for the interim safety analysis set. 
Removed LFT ULN shifts from baseline to worst elevation, exposure-adjusted cumulative LFT 
elevations, and time to first LFT elevation. Removed LFT plots. 
Sections 6.4.2.3 and 6.4.3.1: Removed table of values and changes from DB or OL zavegepant 
baseline. 
Sections 6.4.3.2 and 6.4.4.2: Updated from: ’ On-DB or OL zavegepant for the DB or OL zavegepant 
safety analysis set using DB or OL zavegepant baseline’ to: On-OL zavegepant for the OL zavegepant 
safety analysis set using OL zavegepant baseline’. 
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Section 6.4.5: Updated from:’ On-DB or OL zavegepant for the DB or OL zavegepant safety analysis 
set’ to: On-OL zavegepant for the OL zavegepant safety analysis set’.
Section 6.4.6: Removed bullet: ‘Pre-DB or OL zavegepant for the enrolled analysis set treated 
previously with zavegepant in studies BHV3500-201/301’ 
Section 6.5: Removed redundant word ‘efficacy’.  Specified that the randomization stratum used in 
analyses is based on actual data. Removed the following outcomes research questionnaires and rating 
scales: PoM, SM, and CGI-c. Removed text about deriving EOT value. Removed p-values for all 
models. 
Section 6.5.1: Removed EOT. Under treatment group comparisons, specified to analyze restrictive role 
function only. Removed ‘Identity link function, normal distribution’.  Replaced ‘Denominator degrees 
of freedom method: Kenward-Roger’ with ‘SE estimation method: See Section 6.3.1.3’. Removed 
reference to exploratory objective #10. 
Section 6.5.2: Specified to analyze total score only. Removed reference to exploratory objective #11. 
Sections 6.5.3, 6.5.4, and 6.5.5: Removed sections. 
Section 6.6: Specified that only the frequency table of overall COVID-19 impact will be produced. 
Removed tables for COVID-19 visit impact by visit and missing LFT data impacted by COVID-19 by 
visit.  
Section 7: Replaced ‘reference’ with ‘measurement’. Replaced ‘efficacy date’ with ‘efficacy data 
date’. 
Section 7.2: Removed headache days. Replaced ‘efficacy date’ with ‘efficacy data date’. Removed 
PoM, SM, and CGI-c. 
Section 7.3: Modified analysis visit windows for the Screening and Pre-randomization Visits in Table 
5.  
Section 8: Specified that all TLFs described in the SAP are produced for the LSLV final CSR. 
Section 9.1: Changed ‘more than once and assigned’ to under. Removed ‘for the full analysis set’. 
Specified how to determine the protocol version to which subjects originally consented. In the medical 
history section, added ‘present at screening’. Added: ‘Active medical history status is also identified 
by the sponsor medical lead or designee from reviewing by-subject listings of medical history and 
AEs’. Included the definition of ‘Present at screening’. Updated text on randomization stratum 
discrepancies between IWRS and the actual data. Additional checks added under OL zavegepant 
dosing issues. 
 Section 9.2.3: Updated definition of acute migraine medication day. 
Sections 9.3.1 and 9.3.2: Modified the SAS code by adding the ‘empirical’ option and removing ‘/ 
ddfm=kenwardroger’.
9 
Amended version (30-May-2024) based on Protocol Version 6 
Signature page: Updated department name for author and approver. 
Abbreviations: Removed COVID-19, CYP3A4 and P-gp. 
Section 2.4: Specified that SAP Version 9 is based on Protocol Version 6. 
Section 3.2: In the intercurrent events subsection, added language for nonstudy acute migraine-specific 
medication use and nonstudy other medication use to treat headache or aura.  
Sections 3.2.1, 3.2.2 and 3.2.3: Added nonstudy acute migraine-specific medication use and nonstudy 
other medication use to treat headache or aura as intercurrent events for the primary objective, all 
secondary objectives, and exploratory objectives 1-2 and 6-12. 
Sections 3.2.2 and 3.2.3: In summary row for secondary objectives 7-9 and exploratory objectives 8-9, 
removed “and DB or OL zavegepant”. 


 
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Section 4.1: Removed “study population” in bullet for the DB or OL zavegepant safety analysis set. 
Removed the COVID-19 impacted analysis dataset. 
Section 6.1.1.1: In table 4, removed row for “OL zavegepant safety, follow-up safety by treatment 
group/OL zavegepant dose and overall”. Removed ‘and pretreatment safety’ in last sentence. 
Section 6.1.1.2: Removed “All listings except administrative listings identify subjects who are 
impacted by COVID-19.” and “and visits impacted by COVID-19 visit impact”.
Section 6.2.1: Removed “(excluding COVID-19 impacted)”.  
Sections 6.2.3 and 6.2.3.1-6.2.3.5: Removed all bullets/categories relating to COVID-19. 
Section 6.2.3.4: Moved text for “by OL zavegepant dose and overall” from end of section to first 
sentence. 
Section 6.2.3.5: Moved text for “by as-treated treatment group/OL zavegepant status and overall” from 
end of section to first sentence.  
Section 6.2.3.6: Removed section. 
Section 6.2.5: Revised bullet for demographics and other relevant baseline characteristics for the OL 
zavegepant safety analysis set to use the baseline value (at randomization) and to present by OL 
zavegepant dose and overall. Removed “, and in COVID-19 analyses by analysis visit (see Section 
6.6).” 
Section 6.2.5.1: Removed “and calculating age at a reference date” in first sentence. Added 
“categorical variables” at end of second sentence. Removed last two sentences on OL zavegepant 
baseline. 
Section 6.2.5.2: Corrected typo by replacing small circle w
for the migraine days per month by 
pain intensity categories. Removed headache days per month by pain intensity. Specified that 
categories may be redefined or combined based on the availability of the data. 
Section 6.2.6.2: In second bullet of the DBT treatment compliance subsection, added “/OL zavegepant 
start” after “DB study drug end”. In OLE treatment compliance subsection, revised first sentence of 
the second to last bullet to: “OL zavegepant start date before DB study drug end date.” In the eDiary 
usage compliance subsection, added “/OL zavegepant start” after “DB study drug end”. 
Section 6.2.6.3: Updated definition of acute migraine medications.
Section 6.4: Removed “Pretreatment for the DBT safety analysis set by treatment group, zavegepant 
pooled, placebo pooled, and overall”. 
Section 6.4.1: In Section 6.4.1.2 (AE overviews), for overview tables removed “Moderate or Severe” 
row, added “SAEs related to Study Drug” row, and removed “Pretreatment for the safety analysis set”. 
Removed Section 6.4.1.3 (Pretreatment AEs) and renumbered other subsections accordingly. Changed 
“by intensity” to “by worst intensity” in subsections. In new Section 6.4.1.3 (on DBT AEs), removed 
bullet “AEs of special interest” and sub-bullet “Medication-overuse headache AEs”, and removed “by 
relationship to study drug (related, possibly related, unlikely related, not related, not reported)” from 
AE related to study drug table. 
Section 6.4.2.2: Removed “Pretreatment for the safety analysis set”. 
Sections 6.4.3.2 and 6.4.4.2: Removed “using OL zavegepant baseline". 
Section 6.4.6: Updated criteria to identify participants with non-SAEs leading to discontinuation, 
select hepatic-related non-SAEs, cardiovascular non-SAEs, and suicidality non-SAEs. 
Section 6.6: Removed section. 
Section 7.1: Modified the definition of the last contact date to exclude the COVID-19 visit date. 
Section 7.2: Removed “and to assess pretreatment safety endpoints”. Removed the pre-OL zavegepant 
and pre-DB or OL zavegepant safety analysis periods. Modified the purpose of the on-treatment safety 
analysis period. 


 
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Section 7.3: Removed “on-DB or OL zavegepant and” from first sentence after table 5. Removed 
“Zavegepant study days are used to define analysis visit windows in the on-DB or OL zavegepant 
safety analysis period.” and “Analysis visit windows in the on-DB or OL zavegepant safety analysis 
period are defined analogously to those in the on-treatment safety analysis period.”.
Section 9.1: Replaced “taken during the DBT Phase” with “start before DB study drug end”. Added 
“/OL zavegepant start” after “DB study drug end”. For prohibited non-study medications, removed 
CYP3A4 and P-gp inducer and inhibitors.  


 
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1 INTRODUCTION AND OBJECTIVES OF ANALYSIS 
This document presents the statistical analysis plan (SAP) for Protocol BHV3500-302
(C5301006): A Phase 2/3 Randomized, Double-Blind, Placebo-Controlled Study to Evaluate the 
Efficacy and Safety of Oral Zavegepant in Migraine Prevention. 
This SAP contains the analysis details and methodology to answer the study objectives, 
including planned tables, listings, and figures (TLFs), which provide the basis for the results 
section of the clinical study report (CSR). 
This SAP also references the Rimegepant/Zavegepant Core SAP, which is hereafter referred to 
as the “Core SAP”. 
Note that the study was terminated prematurely in December 2023 for business reasons and not a 
safety concern. As a result, the SAP is being amended from Version 7 to 8 to reduce the number 
of TLFs for the CSR in order to focus only on the most relevant objectives. 
1.1 
Research Hypothesis 
Zavegepant 100 mg or zavegepant 200 mg soft gelatin capsule (SGC) oral dose taken daily is 
safe and effective for the prevention of migraine. 
1.2 
Schedule of Analyses  
There is 1 planned database lock, last subject last visit (LSLV) database lock, which occurs when 
the last subject completes the Follow-Up Week 8 Visit. The LSLV final CSR is produced after 
the LSLV database lock. 
No interim analyses are planned. 
2 STUDY DESCRIPTION 
2.1 
Study Design 
The study has 4 phases:
 Observation Phase (OP): Lasts approximately 28 days. Includes the Screening Visit and Pre-
randomization Laboratory Visit which must occur within 96 hours of the Baseline Visit.  
 Double-blind Treatment (DBT) Phase:  
o Includes the Baseline Visit at which randomization occurs, and Week 2, Week 4, Week 8, 
Week 12, and End of Treatment (EOT) Visits.  
 Subjects are randomized to 2:2:1:1 to zavegepant 100 mg, zavegepant 200 mg, 
placebo matching zavegepant 100 mg, or placebo matching zavegepant 200 mg. 
 Randomization is stratified by stable prophylactic migraine medication use through 
randomization (yes or no). 


 
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o All randomized subjects who discontinue early from the DBT Phase should complete the 
EOT Visit. Otherwise, subjects should complete the Week 12 Visit. 
o Subjects are instructed to follow one of the following 2 dosing regimens: 
 Take four (4) 25 mg SGCs of blinded study drug every calendar day, if randomized to 
the zavegepant 100 mg or placebo matching zavegepant 100 mg treatment group 
Take eight (8) 25 mg SGCs of blinded study drug every calendar day, if randomized 
to the zavegepant 200 mg or placebo matching zavegepant 200 mg treatment group. 
 Open-label Extension (OLE) Phase:  
o Subjects who (1) complete the DBT Phase, (2) continue to meet all inclusion/exclusion 
criteria, and (3) have been compliant with the eDiary may enter the OLE Phase, pending 
review of Week 12 laboratory test results.  
o Subjects are instructed to follow one of the following 2 dosing regimens: 
 Take four (4) 25 mg SGCs of OL zavegepant every calendar day, if randomized to the 
zavegepant 100 mg or placebo matching zavegepant 100 mg treatment group in the 
DBT Phase 
 Take eight (8) 25 mg SGCs of OL zavegepant every calendar day, if randomized to 
the zavegepant 200 mg or placebo matching zavegepant 200 mg treatment group in 
the DBT Phase. 
o Lasts up to 52 weeks, and includes the Week 14, Week 16, Week 20, Week 24, Week 28, 
Week 32, Week 36, Week 40, Week 44, Week 48, Week 52, Week 56, Week 60, Week 
64, and EOT Visits. 
o All randomized subjects who discontinue early from the OLE Phase should complete the 
EOT Visit. Otherwise, subjects should complete the Week 64 Visit. 
 Follow-up Phase 
o Lasts up to 8 weeks, and includes Follow-up Week 2 and Follow-up Week 8 Visits 
primarily for safety assessments. These visits should occur approximately 2 weeks and 8 
weeks, respectively, after the last visit in the last treatment phase (i.e., Week 12/EOT 
Visit if the subject did not enter the OLE Phase; Week 64/EOT Visit if the subject 
entered the OLE Phase). 
o All randomized subjects should complete both follow-up visits, regardless of completing 
either treatment phase. 
The design of the study is shown in Figure 1 and Figure 2. Approximately 2900 subjects are 
enrolled in order to randomize approximately 1440 subjects. 


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Figure 1
Study Schematic: Observation, DBT, and Follow-up Phases
Figure 2
Study Schematic: OLE and Follow-up Phases
2.2
Treatment Assignment
The Interactive Web Response System (IWRS) assigns a subject identifier number at the 
Screening Visit.
The IWRS randomizes eligible subjects to a treatment group (see Section 2.1) using permuted 
blocks of size 12 at the Baseline Visit. Randomization is stratified by stable prophylactic 
migraine medication use through randomization (yes or no). 
The IWRS also assigns specific container numbers for study drug to be dispensed at the Baseline 
Visit and subsequent visits in the DBT and OLE Phases.


 
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2.3 
Blinding and Unblinding
This study is blinded to study drug active status (zavegepant versus placebo), but not to the dose 
level (100 or 200 mg), through the LSLV database lock (see Section 1.2). Draft TLFs for the 
LSLV final CSR are produced with dummy treatment groups prior to the LSLV database lock. 
TLFs for the LSLV final CSR are produced unblinded. 
2.4 
Protocol and Protocol Amendments 
BHV3500-302 SAP Versions 1 and 2 are based on BHV3500-302 Protocol Version 4 (28-Jun-
2021). 
BHV3500-302 SAP Versions 3 and 4 are based on BHV3500-302 Protocol Version 5 (16-Nov-
2021), which added the OLE Phase and 2 exploratory objectives.  
BHV3500-302 SAP Versions 5, 6, 7, 8, and 9 are based on BHV3500-302 Protocol Version 6 
(16-May-2022), which modified the language in efficacy objectives and endpoints (i.e., changed 
“baseline” to “the OP”) and added 1 exploratory objective. 
3 STUDY OBJECTIVES AND ESTIMANDS 
3.1 
Objectives 
A month is defined as 4 weeks (28 days) for the purpose of this protocol. 
3.1.1 
Primary Objective 
To compare the efficacy of zavegepant to placebo as a preventive treatment for chronic migraine, 
as measured by the mean reduction from the OP in the number of migraine days per month over 
the entire DBT Phase. 
3.1.2 
Secondary Objectives 
1. To compare zavegepant to placebo on the proportion of subjects with  50% reduction from 
the OP in the number of moderate to severe migraine days per month over the entire DBT 
Phase. 
2. To compare the efficacy of zavegepant to placebo on the mean reduction from the OP in the 
number of migraine days per month in the last 4 weeks of the DBT Phase. 
3. To compare the efficacy of zavegepant to placebo on the mean reduction from the OP in the 
number of migraine days per month in the first 4 weeks of the DBT Phase. 
4. To compare the efficacy of zavegepant to placebo on the mean number of acute migraine-
specific medication days per month over the entire DBT Phase. 
5. To compare the mean change from baseline in the Migraine-Specific Quality-of-Life 
Questionnaire v 2.1 (MSQ) restrictive role function domain score at Week 12 of the DBT 
Phase between zavegepant and placebo. 


 
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6. To compare the mean change from baseline in the Migraine Disability Assessment (MIDAS) 
total score at Week 12 of the DBT Phase between zavegepant and placebo. 
7. To evaluate the safety and tolerability of zavegepant during the DBT and OLE Phases. 
8. To evaluate the frequency of alanine aminotransferase (ALT) or aspartate aminotransferase 
(AST) > 3x upper limit of normal (ULN) concurrent with total bilirubin (TBL) > 2x ULN in 
subjects treated with zavegepant during the DBT and OLE Phases.
9. To evaluate the frequencies of hepatic-related adverse events (AEs) and hepatic-related AEs 
leading to study drug discontinuation in subjects treated with zavegepant during the DBT and 
OLE Phases. 
3.1.3 
Exploratory Objectives
1. To compare the efficacy of zavegepant to placebo on the mean reduction from the OP in the 
number of migraine days per month and number of headache days per month by pain 
intensity (total; moderate or severe) in each month and over the entire DBT Phase. 
2. To compare the efficacy of zavegepant to placebo on the proportions of subjects with  50% 
reduction,  75% reduction, and 100% reduction from the OP in the number of migraine days 
per month and number of headache days per month by pain intensity (total; moderate or 
severe) in each month and over the entire DBT Phase. 
3. To compare the efficacy of zavegepant to placebo on the mean reduction from the OP in the 
number of migraine days per week and number of headache days per week by pain intensity 
(total; moderate or severe) in each of the first 4 weeks of the DBT Phase. 
4. To compare the efficacy of zavegepant to placebo on the proportion of subjects with  50% 
reduction from the OP in the number of migraine days per week and number of headache 
days per week by pain intensity (total; moderate or severe) in each week of the first 4 weeks 
of the DBT Phase. 
5. To compare the efficacy of zavegepant to placebo on the proportions of subjects with a 
migraine day and headache day by pain intensity (total; moderate or severe) on each day of 
the first week of the DBT Phase. 
6. To compare the efficacy of zavegepant to placebo on the mean number of acute migraine-
specific medication days per month in each month and over the entire DBT Phase. 
7. To compare the efficacy of zavegepant to placebo on the mean number of acute migraine 
medication days per month in each month and over the entire DBT Phase. 
8. To evaluate the frequency of liver function test (LFT) elevations (AST, ALT, or TBL) based 
on fold changes above ULN in subjects treated with zavegepant during the DBT and OLE 
Phases. 
9. To evaluate the frequency of ALT or AST elevations > 3x ULN in temporal association with 
nausea, vomiting, anorexia, abdominal pain or fatigue in subjects treated with zavegepant 
during the DBT and OLE Phases. 


 
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10. To compare the mean changes from baseline in the MSQ preventive role function and 
emotional function domain scores at Week 12 of the DBT Phase between zavegepant and 
placebo. 
11. To compare the mean changes from baseline in the MIDAS absenteeism and presenteeism 
scores at Week 12 of the DBT Phase between zavegepant and placebo. 
12. To evaluate the mean changes from baseline in MSQ domain scores and MIDAS scores 
during the OLE Phase. 
13. To evaluate the Preference of Medication (PoM) scale during the DBT and OLE Phases. 
14. To evaluate the Satisfaction with Medication (SM) scale during the DBT and OLE Phases. 
15. To evaluate the Clinical Global Impression – change (CGI-c) scale during the DBT and OLE 
Phases. 
16. To evaluate the pharmacokinetics of zavegepant 100 mg and 200 mg. 
3.2 
Estimands 
An estimand is the target of estimation to address the scientific question of interest posed by a 
study objective. The 4 attributes of an estimand include the population of interest, endpoint of 
interest, summary of the endpoint, and specification of how intercurrent events are reflected in 
the scientific question of interest. 
For all objectives, the population of interest is defined through appropriate inclusion/exclusion 
criteria to reflect the targeted patient population for approval. Refer to the protocol for 
inclusion/exclusion criteria.
For efficacy and outcomes research endpoints, treatment group comparisons are based on 
zavegepant 100 mg verses placebo pooled and zavegepant 200 mg verses placebo pooled. 
Intercurrent Events 
Intercurrent events are those that occur after treatment initiation and either preclude observation 
of the endpoint or affect its interpretation.  
Study drug discontinuation before the time point of interest defining the endpoint is considered 
an intercurrent event.  
 For efficacy objectives assessed with a continuous endpoint during the DBT Phase, study 
drug discontinuation is handled with a “hypothetical strategy,” i.e., the hypothetical scenario 
is that had subjects not discontinued DB study drug, their efficacy would have been similar to 
the efficacy of subjects from the same treatment group and randomization stratum who did 
not discontinue DB study drug. All observed values of the endpoint of interest are excluded 
after DB study drug discontinuation (see Section 7.2), and statistical methods are used to 
estimate the treatment effect that would have been seen had the intercurrent event not 
occurred.  


 
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 For efficacy objectives assessed with a binary endpoint during the DBT Phase, DB study 
drug discontinuation is handled with a “composite strategy,” i.e., the occurrence of the 
intercurrent event is integrated as a component of the endpoint. All observed values of the 
endpoint of interest are excluded after DB study drug discontinuation (see Section 7.2), and 
subjects with missing data are considered failures. 
 For safety objectives, study drug discontinuation is handled with a “while-on-treatment 
strategy”. All observed values of the endpoint of interest are used on or before study drug 
discontinuation + 7 days (see Section 7.2 and the Core SAP).  
 For outcomes research and other objectives, study drug discontinuation is handled with a 
“treatment policy strategy”, i.e., the occurrence of the intercurrent event is considered 
irrelevant, such that all observed values of the endpoint of interest are used regardless of 
study drug discontinuation. 
Non-study prophylactic migraine medication use before the time point of interest defining the 
endpoint is also considered an intercurrent event. For all objectives, this intercurrent event is 
handled with a treatment policy strategy, such that all observed values of the endpoint of interest 
are used. 
Nonstudy acute migraine-specific medication use before the time point of interest defining the 
endpoint is also considered an intercurrent event, except for efficacy objectives based on acute 
migraine-specific medication days or acute migraine medication days.  
 For efficacy objectives based on migraine days, this intercurrent event is handled with a 
composite strategy, such that acute migraine-specific medication use is part of the endpoint 
definition of migraine days.  
 For safety and outcomes research objectives, this intercurrent event is handled with a 
treatment policy strategy, such that all observed values of the endpoint of interest are used. 
Use of nonstudy other medication to treat headache (migraine or nonmigraine) or aura before the 
time point of interest defining the endpoint is also considered an intercurrent event, except for 
the efficacy objective based on acute migraine medication days. For all objectives, this 
intercurrent event is handled with a treatment policy strategy, such that all observed values of the 
endpoint of interest are used. 
See Section 4.1 for analysis sets that are used to assess endpoints. 
Data Sources for Endpoints 
Migraine days, acute migraine-specific medication days, acute migraine medication days, and 
headache days are derived from eDiary data from the external source YPrime. Acute migraine-
specific medications are triptans and ergotamine. Acute migraine medications are triptans, 
ergotamine, and other protocol-allowed medications to treat headache or aura taken on migraine 
days. 
AEs are determined from AE case report forms (CRFs). 


 
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Grade 3 to 4 laboratory test abnormalities are determined from laboratory test values graded 
using standardized criteria. Laboratory test results are from an external central laboratory and 
local laboratory test CRFs. 
C-SSRS parameters, MSQ scores, and MIDAS scores are derived from their respective CRFs.  
3.2.1 
Primary Objective Estimand 
The estimand corresponding to the primary endpoint is shown in Table 1. 
Table 1 
Primary Objective Estimands 
Objective 
Mean reduction from the OP in the number of migraine days per month over 
the entire DBT Phase 
Efficacy Endpoint 
Mean change from OP in the number of migraine days per month over the entire 
DBT Phase (Weeks 1 to 12) 
Summary 
Mean change from OP by treatment group using descriptive statistics and linear 
mixed effects model with repeated measures, and difference between treatment 
groups from model for the migraine analysis set 
Intercurrent Events 
Study drug discontinuation: hypothetical strategy 
Non-study prophylactic migraine medication use: treatment policy strategy 
Nonstudy acute migraine-specific medication use: composite strategy 
Use of nonstudy other medication to treat headache (migraine or nonmigraine) or 
aura: treatment policy strategy 
3.2.2 
Secondary Objective Estimands 
The estimands corresponding to the secondary objectives are shown in Table 2. 
Table 2  
Secondary Objective Estimands 
Objective 1
Proportion of subjects with  50% reduction from the OP in the number of 
moderate or severe migraine days per month over the entire DBT Phase  
Efficacy Endpoint 
Proportion of subjects with  50% reduction from OP in number of moderate or severe 
migraine days per month over the entire DBT Phase (Weeks 1 to 12)
Summary 
Percentages by treatment group, and difference in percentages between treatment 
groups using Mantel-Haenszel risk estimation with stratification by randomization 
stratum for the migraine analysis set  
Intercurrent Events 
Study drug discontinuation: composite strategy 
Non-study prophylactic migraine medication use: treatment policy strategy 
Nonstudy acute migraine-specific medication use: composite strategy
Use of nonstudy other medication to treat headache (migraine or nonmigraine) or aura: 
treatment policy strategy 
Objective 2 
Mean reduction from the OP in the number of migraine days per month in the last 
4 weeks of the DBT Phase 


 
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Efficacy Endpoint 
Mean change from OP in the mean number of migraine days per month in the last 4 
weeks (Weeks 9 to 12) of the DBT Phase
Summary 
Mean change from OP by treatment group using descriptive statistics and linear mixed 
effects model with repeated measures, and difference between treatment groups from 
model for the migraine analysis set 
Intercurrent Events 
Study drug discontinuation: hypothetical strategy 
Non-study prophylactic migraine medication use: treatment policy strategy 
Nonstudy acute migraine-specific medication use: composite strategy 
Use of nonstudy other medication to treat headache (migraine or nonmigraine) or aura: 
treatment policy strategy 
Objective 3
Mean reduction from the OP in the number of migraine days per month in the 
first 4 weeks of the DBT Phase 
Efficacy Endpoint
Mean change from OP in the number of migraine days per month in the first 4 weeks 
(Weeks 1 to 4) of the DBT Phase 
Summary 
Mean change from OP by treatment group using descriptive statistics and linear mixed 
effects model with repeated measures, and difference between treatment groups from 
model for the migraine analysis set 
Intercurrent Events
Study drug discontinuation: hypothetical strategy 
Non-study prophylactic migraine medication use: treatment policy strategy 
Nonstudy acute migraine-specific medication use: composite strategy 
Use of nonstudy other medication to treat headache (migraine or nonmigraine) or aura: 
treatment policy strategy 
Objective 4
Mean number of acute migraine-specific medication days per month over the 
entire DBT Phase 
Efficacy Endpoint 
Mean number of acute-migraine-specific days per month over the entire DBT Phase 
(Weeks 1 to 12)
Summary 
Mean value by treatment group using descriptive statistics and linear mixed effects 
model with repeated measures, and difference between treatment groups from model 
for the migraine analysis set
Intercurrent Events
Study drug discontinuation: hypothetical strategy 
Non-study prophylactic migraine medication use: treatment policy strategy 
Nonstudy acute migraine-specific medication use: not applicable 
Use of nonstudy other medication to treat headache (migraine or nonmigraine) or aura: 
treatment policy strategy 
Objective 5 
Mean change from baseline in the MSQ restrictive role function domain score at 
Week 12 of the DBT Phase 
Outcomes Research 
Endpoint 
Mean change from baseline in the MSQ restrictive role function domain score at Week 
12 of the DBT Phase 
Summary 
Mean change from baseline by treatment group using descriptive statistics and linear 
regression model, and difference between treatment groups from model for the DBT 
efficacy analysis set 
Intercurrent Events 
Study drug discontinuation: treatment policy strategy 
Non-study prophylactic migraine medication use: treatment policy strategy 


 
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Nonstudy acute migraine-specific medication use: treatment policy strategy
Use of nonstudy other medication to treat headache (migraine or nonmigraine) or aura: 
treatment policy strategy 
Objective 6
Mean change from baseline in the MIDAS total score at Week 12 of the DBT 
Phase 
Outcomes Research 
Endpoint 
Mean change from baseline in the MIDAS total score at Week 12 of the DBT Phase 
Summary 
Mean change from baseline by treatment group using descriptive statistics and linear 
regression model and difference between treatment groups from model for the DBT 
efficacy analysis set 
Intercurrent Events
Study drug discontinuation: treatment policy strategy
Non-study prophylactic migraine medication use: treatment policy strategy 
Nonstudy acute migraine-specific medication use: treatment policy strategy
Use of nonstudy other medication to treat headache (migraine or nonmigraine) or aura: 
treatment policy strategy
Objective 7
Safety and tolerability of zavegepant during the DBT and OLE Phases
Safety Endpoint 
Number and percentage of subjects with AEs by intensity, serious adverse events 
(SAEs), AEs leading to study drug discontinuation, and grade 3 to 4 laboratory test 
abnormalities on treatment  
Summary 
Frequency by treatment group for the DBT and OL zavegepant safety analysis sets 
Intercurrent Events 
Study drug discontinuation: while-on-treatment strategy
Non-study prophylactic migraine medication use: treatment policy strategy 
Nonstudy acute migraine-specific medication use: treatment policy strategy 
Use of nonstudy other medication to treat headache (migraine or nonmigraine) or aura: 
treatment policy strategy 
Objective 8
Frequency of ALT or AST > 3x upper limit of normal (ULN) concurrent with 
TBL > 2x ULN in subjects treated with zavegepant during the DBT and OLE 
Phases 
Safety Endpoint 
Number and percentage of subjects with AST or ALT elevations > 3x ULN concurrent 
(i.e., on the same laboratory collection date) with TBL > 2x ULN on treatment 
Summary 
Frequency by treatment group for the DBT and OL zavegepant safety analysis sets with 
LFT data 
Intercurrent Events
Study drug discontinuation: while-on-treatment strategy
Non-study prophylactic migraine medication use: treatment policy strategy Nonstudy 
acute migraine-specific medication use: treatment policy strategy 
Use of nonstudy other medication to treat headache (migraine or nonmigraine) or aura: 
treatment policy strategy 
Objective 9 
Frequencies of hepatic-related AEs and hepatic-related AEs leading to study drug 
discontinuation in subjects treated with zavegepant during the DBT and OLE 
Phases
Safety Endpoint 
Number and percentage of subjects with hepatic-related AEs and hepatic-related AEs 
leading to study drug discontinuation on treatment  
Summary 
Frequency by treatment group for the DBT and OL zavegepant safety analysis sets 


 
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Intercurrent Events
Study drug discontinuation: while-on-treatment strategy
Non-study prophylactic migraine medication use: treatment policy strategy 
Nonstudy acute migraine-specific medication use: treatment policy strategy
Use of nonstudy other medication to treat headache (migraine or nonmigraine) or aura: 
treatment policy strategy 
3.2.3 
Exploratory Objective Estimands 
The estimands corresponding to the exploratory objectives are shown in Table 3 only for the
endpoints to be assessed.
Table 3
Exploratory Objective Estimands 
Objective 1
Mean reduction from the OP in the number of migraine days per month by 
pain intensity (total; moderate or severe) in each month and over the entire 
DBT Phase
Efficacy Endpoint 
Mean changes from OP in the number of migraine days per month during DBT (1) 
over time by month and (2) overall DBT, by pain intensity (total; moderate or 
severe)  
Summary 
Mean changes from OP by treatment group using descriptive statistics and linear 
mixed effects model with repeated measures, and difference between treatment 
groups from model for the migraine analysis set 
Intercurrent Events
Study drug discontinuation: hypothetical strategy 
Non-study prophylactic migraine medication use: treatment policy strategy 
Nonstudy acute migraine-specific medication use: composite strategy 
Use of nonstudy other medication to treat headache (migraine or nonmigraine) or 
aura: treatment policy strategy 
Objective 2 
Proportions of subjects with  50% reduction from the OP in the number of 
migraine days per month by pain intensity (total; moderate or severe) in each 
month and over the entire DBT Phase
Efficacy Endpoint 
Proportions of subjects with  50% reduction from the OP in the number of migraine 
days per month during DBT (1) over time by month and (2) overall DBT, by pain 
intensity (total; moderate or severe)  
Summary 
Percentages by treatment group, and difference in percentages between treatment 
groups using Mantel-Haenszel risk estimation with stratification by randomization 
stratum for the migraine analysis set 
Intercurrent Events
Study drug discontinuation: composite strategy 
Non-study prophylactic migraine medication use: treatment policy strategy
Nonstudy acute migraine-specific medication use: composite strategy 
Use of nonstudy other medication to treat headache (migraine or nonmigraine) or 
aura: treatment policy strategy 
Objective 6 
Mean number of acute migraine-specific medication days per month in each 
month and over the entire DBT Phase 
Efficacy Endpoint 
Mean number of acute migraine-specific medication days per month during DBT (1) 
over time by month and (2) overall DBT 


 
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Summary
Mean values by treatment group using descriptive statistics and linear mixed effects 
model with repeated measures, and difference between treatment groups from model 
for the migraine analysis set
Intercurrent Events
Study drug discontinuation: hypothetical strategy
Non-study prophylactic migraine medication use: treatment policy strategy 
Nonstudy acute migraine-specific medication use: not applicable 
Use of nonstudy other medication to treat headache (migraine or nonmigraine) or 
aura: treatment policy strategy 
Objective 7 
Mean number of acute migraine medication days per month in each month and 
over the entire DBT Phase 
Efficacy Endpoint 
Mean number of acute migraine medication days per month during DBT (1) over 
time by month and (2) overall DBT 
Summary 
Mean values by treatment group using descriptive statistics for the migraine analysis 
set 
Intercurrent Events 
Study drug discontinuation: hypothetical strategy 
Non-study prophylactic migraine medication use: treatment policy strategy 
Nonstudy acute migraine-specific medication use: not applicable 
Use of nonstudy other medication to treat headache (migraine or nonmigraine) or 
aura: not applicable
Objective 8 
Frequency of LFT elevations based on fold changes above ULN in subjects 
treated with zavegepant during the DBT and OLE Phases 
Safety Endpoint 
Number and percentage of subjects with LFT elevations (ALT, AST, or TBL) based 
on fold changes above ULN on treatment 
Summary 
Frequency by treatment group for the DBT and OL zavegepant safety analysis sets 
with LFT data 
Intercurrent Events 
Study drug discontinuation: while-on-treatment strategy 
Non-study prophylactic migraine medication use: treatment policy strategy 
Nonstudy acute migraine-specific medication use: treatment policy strategy 
Use of nonstudy other medication to treat headache (migraine or nonmigraine) or 
aura: treatment policy strategy 
Objective 9 
Frequency of ALT or AST elevations > 3x ULN in temporal association with 
nausea, vomiting, anorexia, abdominal pain or fatigue in subjects treated with 
zavegepant during the DBT and OLE Phases 
Safety Endpoint 
Number and percentage of subjects in the safety analysis set with ALT or AST > 3x 
ULN concurrent with nausea, vomiting, anorexia, abdominal pain or fatigue on 
treatment 
Summary 
Frequency by treatment group for the DBT and OL zavegepant safety analysis sets 
with LFT data
Intercurrent Events
Study drug discontinuation: while-on-treatment strategy 
Non-study prophylactic migraine medication use: treatment policy strategy 
Nonstudy acute migraine-specific medication use: treatment policy strategy 


 
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Use of nonstudy other medication to treat headache (migraine or nonmigraine) or 
aura: treatment policy strategy 
Objective 10 
Mean changes from baseline in the MSQ preventive role function and emotional 
function domain scores at Week 12 of the DBT Phase 
Outcomes Research 
Endpoint 
Mean changes from baseline in the MSQ preventive role function and emotional 
function domain scores at Week 12 of the DBT Phase 
Summary 
Mean changes from baseline by treatment group using descriptive statistics for the 
DBT efficacy analysis set 
Intercurrent Events 
Study drug discontinuation: treatment policy strategy 
Non-study prophylactic migraine medication use: treatment policy strategy
Nonstudy acute migraine-specific medication use: treatment policy strategy 
Use of nonstudy other medication to treat headache (migraine or nonmigraine) or 
aura: treatment policy strategy 
Objective 11 
Mean changes from baseline in the MIDAS absenteeism and presenteeism 
scores at Week 12 of the DBT Phase 
Outcomes Research 
Endpoint 
Mean changes from baseline in the MIDAS absenteeism and presenteeism scores at 
Week 12 of the DBT Phase 
Summary 
Mean changes from baseline by treatment group using descriptive statistics for the 
DBT efficacy analysis set 
Intercurrent Events 
Study drug discontinuation: treatment policy strategy 
Non-study prophylactic migraine medication use: treatment policy strategy 
Nonstudy acute migraine-specific medication use: treatment policy strategy 
Use of nonstudy other medication to treat headache (migraine or nonmigraine) or 
aura: treatment policy strategy 
Objective 12 
Mean changes from baseline in MSQ domain scores and MIDAS scores during 
the OLE Phase 
Outcomes Research
Endpoint 
Mean changes from baseline in the (1) MSQ restrictive role function, preventive role 
function, and emotional function domain scores and (2) MIDAS total, absenteeism, 
and presenteeism scores at Weeks 24 and 64 of the OLE Phase 
Summary  
Mean changes from baseline by treatment group using descriptive statistics for the 
DBT efficacy analysis set
Intercurrent Events 
Study drug discontinuation: treatment policy strategy
Non-study prophylactic migraine medication use: treatment policy strategy 
Nonstudy acute migraine-specific medication use: treatment policy strategy 
Use of nonstudy other medication to treat headache (migraine or nonmigraine) or 
aura: treatment policy strategy
4 ANALYSIS SETS, TREATMENT GROUPS, AND SUBGROUPS 
4.1 
Analysis Sets
The following analysis sets are evaluated and used for presentation and analysis of the data:


 
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 Enrolled: Subjects who sign an informed consent form and are assigned a subject 
identification number, i.e., nonmissing informed consent date. This analysis set is used 
mainly to assess study population and in by-subject listings. 
 Full: Subjects in the enrolled analysis set who receive a randomized treatment assignment 
from the IWRS, i.e., nonmissing IWRS randomization date. This analysis set is used mainly 
to assess study population. 
 Safety: Subjects in the enrolled analysis set who take  1 dose of study drug (zavegepant or 
placebo), i.e., nonmissing study drug start date. This analysis set is used to assess study 
population and produce select by-subject listings. 
o DBT safety: Subjects in the safety analysis set who take  1 dose of DB study drug 
(zavegepant or placebo), i.e., nonmissing DB study drug start date. This analysis set is 
used to assess study population, exposure, and on-DBT safety. 
o OL zavegepant safety: Subjects in the safety analysis set who take  1 dose of OL 
zavegepant, i.e., nonmissing OL zavegepant start date. This analysis set is used to assess 
study population, exposure, and on-OL zavegepant safety. 
 Interim safety: Subjects in the OL zavegepant safety analysis set with OL zavegepant 
start date – DB study drug last date > 7 days. This analysis set is used to assess post-
DBT pre-OL zavegepant safety. 
o DB or OL zavegepant safety: Subjects in the safety analysis set who take  1 dose of DB 
or OL zavegepant, i.e., nonmissing DB or OL zavegepant start date. This analysis set is 
used to assess exposure and on-DB or OL zavegepant safety. 
o Follow-up safety: Subjects in the safety analysis set whose last contact date is in the 
follow-up safety analysis period. This analysis set is used to assess follow-up safety. 
 DBT efficacy: Subjects in the full analysis set who are randomized only once and take  1 
dose of DB study drug (zavegepant or placebo). This analysis set is used mainly to assess 
DBT outcomes research. 
Migraine: Subjects in the DBT efficacy analysis set with  14 days of eDiary efficacy 
data (not necessarily consecutive) in both the OP and  1 month (4-week interval) in the 
DBT Phase (see Section 6.3.1). This analysis set is used to assess migraine days, acute 
migraine-specific medication days, and acute migraine medication days 
See Section 7.1 for derived dates and Section 7.2 for analysis periods. 
4.2 
Treatment Groups 
Treatment groups in the DBT Phase are zavegepant 100 mg, zavegepant 200 mg, placebo 100 
mg, and placebo 200 mg. OL zavegepant dose groups in the OLE Phase are zavegepant 100 mg 
and zavegepant 200 mg.  
The safety analysis sets are assessed by as-treated treatment group (i.e., actual treatment 
received), the randomized, full, efficacy, and migraine analysis sets are assessed by as-
randomized treatment group, and the enrolled analysis set is assessed overall. 


 
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If a subject takes  1 dose of planned randomized DB study drug, then that subject is considered 
to have as-treated treatment group equal to as-randomized treatment group (see Section 6.2.6.2). 
If there are non-randomized subjects who take study drug, then the as-randomized treatment 
group of “not randomized” is included in the full analysis set augmented with the safety analysis 
set. 
4.3 
Subgroups 
The following efficacy subgroups are of interest for the migraine analysis set: 
 Stable prophylactic migraine medication use through randomization (i.e., randomization 
stratum): yes, no (see Section 6.2.5.4). 
Randomization strata are based on the actual data, not those assigned by IWRS. Subgroup tables 
present results by subgroup level and overall for subjects with nonmissing subgroup level data.  
5 SAMPLE SIZE, POWER, AND TYPE 1 ERROR 
With a sample size of approximately 480 randomized subjects per zavegepant treatment group 
and 240 randomized subjects per placebo treatment group, we expect approximately 440 subjects 
per zavegepant treatment group and 220 subjects per placebo treatment group in the migraine 
analysis set. Assuming zavegepant provides a 1-day advantage over placebo pooled on the mean 
change in migraine days per month over the entire DBT Phase (Weeks 1 to 12), common 
standard deviation of 4.2 days, and a 2-sided  = 0.025 level, then the study has  90% power for 
the primary endpoint. The estimates for the migraine analysis set sample size, mean change in 
migraine days per month, and standard deviation (SD) are based on observed pooled data from 
rimegepant study BHV3000-305. 
Type 1 error is not applicable. The significance of the primary and secondary endpoints will not 
be evaluated. 
6 STATISTICAL ANALYSES 
All statistical analyses are performed using SAS statistical software (Version 9.4 or higher).  
6.1 
General 
6.1.1 
Programmed Output 
A list of TLFs and corresponding templates are presented separately in a mock TLF document 
corresponding to this SAP. 
Refer to the Core SAP for additional details about programmed output. 
6.1.1.1 
Tables
Treatment group presentation in tables by analysis set is shown in Table 4. Exceptions are 
specified in subsequent sections as needed. 


 
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Table 4 
Treatment Group Presentation in Tables by Analysis Set 
Analysis Set 
Number of Columns 
Abbreviated Treatment Group  
Enrolled  
1 
Overall 
Full, DBT efficacy, 
migraine, DBT safety, 
interim safety by treatment 
group, {zavegepant 
pooled}, {placebo pooled}, 
and {overall} 
4 to 7
ZAV 100 mg
ZAV 200 mg 
{ZAV Pooled}
PBO 100 mg 
PBO 200 mg
{PBO Pooled} 
{Overall}
OL zavegepant safety by 
OL zavegepant dose and 
overall 
3 
OL ZAV 100 mg 
OL ZAV 200 mg 
Overall 
DB or OL zavegepant 
safety by DB or OL 
zavegepant dose and 
overall 
3 
DB ZAV or PBO 100 mg/OL ZAV 100 mg
DB ZAV or PBO 200 mg/OL ZAV 200 mg
Overall 
Follow-up safety by 
treatment group/OL 
zavegepant status and 
overall
6 
DB ZAV 100 mg/OL ZAV 100 mg 
DB ZAV 200 mg/OL ZAV 200 mg 
DB PBO 100 mg to OL ZAV 100 mg 
DB PBO 200 mg to OL ZAV 200 mg 
DB PBO Pooled No OL ZAV  
Overall  
“ZAV Pooled” is defined as the DB zavegepant 100 mg and DB zavegepant 200 mg treatment 
groups combined. “PBO Pooled” is defined as the DB placebo 100 mg and DB placebo 200 mg 
treatment groups combined. “DB PBO X mg to OL ZAV X mg” denotes as-treated DB placebo X 
mg subjects in the OL zavegepant safety analysis set (X = 100 or 200), and “DB PBO Pooled No 
OL ZAV” denotes as-treated DB placebo pooled subjects not in the OL zavegepant safety 
analysis set; note that these 3 placebo groups add to the “PBO Pooled” group. 
Results for study population also include overall treatment group (see Sections 6.2 and 6.4). 
6.1.1.2 
Listings 
Unless specified otherwise, by-subject listings are sorted by randomization status (randomized, 
not randomized), site-subject ID, and additional variables such as time points, as applicable. 
Listings display as-randomized treatment group abbreviated as (1) “ZAV100” for zavegepant 
100 mg, “ZAV200” for zavegepant 200 mg, “PBO100” for placebo 100 mg, and “PBO200” for 
placebo 200 mg for subjects in the full analysis set, and (2) “NRND” for subjects not in the full 
analysis set. 
Listings of significant protocol deviations, exposure, safety parameters, and outcomes research 
parameters include the following: abbreviated name of the analysis period in which the 
measurement was slotted (i.e., PRETRT, DBT, INT, OLZAV, FU; this does not apply to 
exposure); analysis visit in which the measurement was slotted (this does not apply to exposure 


 
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or AEs); measurement date/time; study day derived from the measurement date, and zavegepant 
study day  1 derived from the measurement date for as-randomized placebo subjects. 
6.1.2 
Statistical Methods 
Refer to the Core SAP for descriptive statistics in summary tables, counting rules in frequency 
tables, and rounding rules in frequency tables. 
6.1.3 
Missing Data 
All analyses are based on observed data unless otherwise specified. See Section 6.3 for statistical 
methods for handling missing data in efficacy analyses. 
6.2 
Study Population 
Refer to the Core SAP for TLF contents. 
6.2.1 
Analysis Sets 
The frequency table of analysis sets described in Section 4.1 is provided by treatment group plus 
placebo pooled (as-randomized for the randomized, full, efficacy, and migraine analysis sets; as-
treated for all safety analysis sets), not randomized, and overall.  
See Section 6.3.1 for months. 
The by-subject listing of analysis sets is provided for the enrolled analysis set.  
The administrative listing of randomization scheme and codes is provided for the full analysis 
set.  
6.2.2 
Enrollment 
Frequency table of enrollment by country and site is provided for the enrolled analysis set, and 
also displays results for the full and safety analysis sets.  
6.2.3 
Subject Disposition 
The by-subject listing of subject discontinuation is provided for the enrolled analysis set and 
displays a separate record for each study phase (i.e., DBT, OLE and Follow-up) that is 
discontinued (i.e., completed or not completed) corresponding to each type of subject status 
CRF. The listing includes the following:  
 Relevant reference dates: i.e., last contact date*, IWRS randomization date 
 Study phase: DBT, OLE, or Follow-up. For each study phase: 
o Last visit date. Derived from visit dates from the Visit Date and Unscheduled Visit 
Checklist CRFs as follows: 
 DBT Phase: latest visit date in the pretreatment or on-DBT safety analysis period 


 
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OLE Phase: latest visit date in the OL zavegepant safety analysis period 
Follow-up Phase: latest visit date in the follow-up safety analysis period 
o Phase completion status: “completed”; or “not completed” concatenated with the reason 
for non-completion (see Sections 6.2.3.1, 6.2.3.2, 6.2.3.3,  6.2.3.4, and 6.2.3.5) 
o Next phase continuation status: “continued” concatenated with the name of the next 
phase (OLE or Follow-up); or “not continued” concatenated with the reason for non-
continuation (see Sections 6.2.3.2, 6.2.3.3, and 6.2.3.4). This does not apply to the 
Follow-up Phase. 
 
A footnote describes the derivation of the last contact date as “* Derived as the death date (if it 
exists); otherwise, the maximum date collected across study population, efficacy safety, and 
outcomes research parameters”. See Section 7.1 for derived dates and Section 7.2 for analysis 
periods.  
6.2.3.1 
Subject Disposition from Enrollment to Randomization 
The frequency table of subject disposition from enrollment to randomization is provided for the 
enrolled analysis set based on the DB Subject Status CRF, and displays the following categories: 
 Randomized (identified as subjects with nonmissing IWRS randomization date) 
 Not randomized (identified as subjects with missing IWRS randomization date) 
o Reasons for discontinuation (i.e., not completing the DBT Phase), including not reported. 
For subjects whose reason is screen failure due to inclusion/exclusion criteria, the reasons 
for screen failure from the Inclusion/Exclusion CRF are also displayed as subcategories. 
 
6.2.3.2 
Subject Disposition from Randomization to Treatment 
 
The frequency table of subject disposition from randomization to treatment is provided by 
treatment group and overall for the full analysis set based on the DB Subject Status CRF, and 
displays the following categories: 
 Treated with study drug (identified as subjects with nonmissing study drug start date) 
 Not treated with study drug (identified as subjects with missing study drug start date) 
o Reasons for discontinuation (i.e., not completing the DBT Phase), including not reported 
 
6.2.3.3 
Subject Disposition during the DBT Phase 
The frequency table of subject disposition during the DBT Phase is provided for the DBT safety 
analysis set by as-treated treatment group, zavegepant pooled, placebo pooled, and overall based 
on the DB Subject Status CRF, and displays the following categories: 


 
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 Ongoing in the DBT Phase. These are identified as subjects with (1) missing response to the 
question “Did the subject complete the DBT Phase?” and (2) missing DB study drug last 
date. This category only exists before the LSLV database lock. After the LSLV database 
lock, subjects with missing response are categorized as “Did not complete the DBT Phase”. 
 Completed the DBT Phase. These are identified as subjects with (1) “yes” response to the 
question “Did the subject complete the DBT Phase?” and (2) nonmissing DB study drug last 
date. 
 Did not complete the DBT Phase. These are identified as subjects with (1) “no” or missing 
response to the question “Did the subject complete the DBT Phase?” and (2) nonmissing DB 
study drug last date.
o Reasons for not completing the DBT Phase, including not reported 
 Continued to the next phase. These are identified as subjects with (1) “yes” response to the 
question “Is the subject continuing to the Follow-up Phase?” and missing response to the 
question “Is the subject continuing to the next phase?”, or (2) “yes” response to the question 
“Is the subject continuing to the next phase?”. 
o Next phase, i.e., OLE or Follow-up. The next phase is determined from the response to 
the “If Yes, select the next phase” question, if available. Otherwise, if there is a “yes” 
response to the question “Is the subject continuing to the Follow-up Phase?”, then the 
next phase is considered to be Follow-up. 
 Did not continue to the next phase. These are identified as subjects with (1) missing response 
to the question “Is the subject continuing to the next phase?” and “no” response to the 
question “Is the subject continuing to the Follow-up Phase?”, or (2) “no” response to the 
question “Is the subject continuing to the next phase?”, or (3) after the LSLV database lock, 
missing responses to both questions about continuing. 
o Reasons for not continuing to the next phase, including not reported. These are based on 
reasons for not continuing to the Follow-up Phase or the next phase. 
6.2.3.4 
Subject Disposition during the OLE Phase 
The frequency table of subject disposition during the OLE Phase is provided by OL zavegepant 
dose and overall for the OL zavegepant safety analysis set based on the OLE Subject Status 
CRF, and displays the following categories: 
 Ongoing in the OLE Phase. These are identified as subjects with (1) missing response to the 
question “Did the subject complete the OLE Phase?” and (2) missing OL zavegepant last 
date. This category only exists before the final database lock; otherwise, subjects with 
missing response are categorized as “Did not complete the OLE Phase”. 
 Completed the OLE Phase. These are identified as subjects with (1) “yes” response to the 
question “Did the subject complete the OLE Phase?” and (2) nonmissing OL zavegepant last 
date. 


 
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 Did not complete the OLE Phase. These are identified as subjects with (1) “no” or missing 
response to the question “Did the subject complete the OLE Phase?” and (2) nonmissing OL 
zavegepant last date. 
o Reasons for not completing the OLE Phase, including not reported 
 Continued to the Follow-up Phase. These are identified as subjects with “yes” response to the 
question “Is the subject continuing to the Follow-up Phase?”. 
 Did not continue to the Follow-up Phase. These are identified as subjects with (1) “no” 
response to the question “Is the subject continuing to the Follow-up Phase?”, or (2) after the 
LSLV database lock, missing response to the question “Is the subject continuing to the 
Follow-up Phase?”. 
o Reasons for not continuing to the Follow-up Phase, including not reported. 
 
6.2.3.5 
Subject Disposition during the Follow-up Phase 
The frequency table of subject disposition during the Follow-up Phase is provided by as-treated 
treatment group/OL zavegepant status and overall for the follow-up safety analysis set based on 
the Follow-up Subject Status CRF, and displays the following categories: 
 Did not formally enter the Follow-up Phase. These are identified as subjects with missing 
response to the question “Did the subject complete the Follow-up Phase?”, and any of the 
following: 
o “No” response to the question “Is the subject continuing to the Follow-up Phase?” and 
missing response to the question “Is the subject continuing to the next phase?” on the DB 
Subject Status CRF 
o “No” response to the question “Is the subject continuing to the next phase?” on the DB 
Subject Status CRF 
o “No” response to the question “Is the subject continuing to the Follow-up Phase?” on the 
OLE Subject Status CRF.  
A footnote explains that these are subjects with data in the follow-up safety analysis period 
who did not continue to the Follow-up Phase as per DB or OLE Subject Status CRF. 
 Ongoing in the Follow-up Phase. These are identified as subjects with missing response to 
the question “Did the subject complete the Follow-up Phase?”, and who are not already 
categorized as “Did not formally enter the Follow-up Phase”.  
This category only exists before the final database lock. After the final database lock, these 
subjects are categorized as “Did not complete the Follow-up Phase”. 
 Completed the Follow-up Phase. These are identified as subjects with “yes” response to the 
question “Did the subject complete the Follow-up Phase?”. 
 Did not complete the Follow-up Phase. These are identified as subjects with “no” response to 
the question “Did the subject complete the Follow-up Phase?”. 


 
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o Reasons for not completing the Follow-up Phase, including not reported 
o  
 
6.2.4 
Protocol Deviations 
6.2.4.1 
Relevant Protocol Deviations 
The frequency table of relevant protocol deviations are provided as the number and percentage of 
subjects in deviation categories by as-randomized treatment group, zavegepant pooled, placebo 
pooled, and overall for the full analysis set. Results are shown by deviation type (eligibility, 
subject management), category, and subcategory in the order specified in Section 9.1. Results for 
all relevant protocol deviation categories and subcategories are displayed, even those with 0 
counts, unless specified otherwise. 
A by-subject listing of relevant protocol deviations is provided for the full analysis set. This 
includes deviation type, category, and subcategory, which are additional sorting variables. 
6.2.4.2 
Significant Protocol Deviations 
The by-subject listing of significant protocol deviations is provided for the full analysis set, and 
is based on the Protocol Deviations CRF. This includes date deviation occurred, violation code, 
inclusion/exclusion number, and description, which are additional sorting variables. Significant 
protocol deviations are defined as those with a “yes” response to the question “Is the deviation 
significant?”. 
6.2.5 
Baseline Characteristics 
Baseline characteristics include (1) demographics and other relevant baseline characteristics, (2) 
baseline disease characteristics (i.e., migraine history, cardiac and other risk factors, and efficacy 
during the OP), (3) medical history, and (4) non-study prior medications. These are detailed in 
Sections 6.2.5.1 through 6.2.5.4, respectively. 
Tables of baseline characteristics are provided for the following analysis sets: 
 Migraine analysis set: Baseline characteristics (1) and (2) by as-randomized treatment group, 
placebo pooled, and overall to support efficacy 
 DBT safety analysis set: Baseline characteristics (1) through (4) by as-treated treatment 
group, zavegepant pooled, placebo pooled, and overall to support safety 
 OL zavegepant safety analysis set: Demographics and other relevant baseline characteristics 
by OL zavegepant dose and overall  to support OL zavegepant safety 
The frequency cross table of randomization stratum (i.e., stable prophylactic migraine 
medication use through randomization  [yes, no]) from IWRS versus actual data is provided for 
the full analysis set by treatment group and overall (see Section 6.2.5.4). 


 
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Baseline for a parameter (e.g., weight) is defined according to analysis set; refer to the Core SAP 
for details, including handling of ties on the same measurement date (entry date/time is the 
“earliest data creation time” variable in the raw CRF datasets). Note that the baseline value is 
independent of the baseline analysis visit defined in Table 5; the latter is used only in by-subject 
listings that display visit. 
By-subject listings are provided for the enrolled analysis set for the following: demographics; 
medical history; and migraine history. 
6.2.5.1 
Demographics and Other Relevant Baseline Characteristics 
Refer to the Core SAP for the table of demographics and other relevant baseline characteristics. 
Other relevant characteristics also include the following categorical variables: 
 Previous study participation (e.g., any study, BHV3500-201, BHV3500-301) 
 
stable prophylactic migraine medication use 
through randomization: yes, no (see Section 6.2.5.4).  
 
6.2.5.2 
Baseline Disease Characteristics 
Migraine History 
Refer to the Core SAP for the table of migraine history.  
Cardiac and Other Risk Factors 
Refer to the Core SAP for the table of cardiac and other risk factors, which is provided only for 
the DBT safety analysis set. 
Migraine-related Event Days during the OP 
The table of migraine-related event days per month during the OP is provided only for the 
migraine analysis set, and summarizes the following parameters descriptively as continuous or 
categorical variables during the OP analysis period: 
 Migraine days per month by pain intensity (total; moderate or severe). Categories are < 6,     
6, < 8, 
8, < 12,  12, < 15, 
15. 
 Acute migraine-specific medication days per month. Categories are same as for migraine 
days per month above. 
 Acute migraine medication days per month. Categories are same as for migraine days per 
month above. 
See Sections 6.3.1 for migraine days per month, Section 6.3.2.2 for acute migraine-specific 
medication days per month, Section 6.3.3.6 for acute migraine medication days per month, and 
Section 7.2 for the OP analysis period. 


 
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Categories may be redefined or combined based on the availability of the data. 
6.2.5.3 
Medical History 
The frequency table of medical history is provided by system organ class (SOC) and preferred 
term (PT), and displayed in descending order of overall frequency within SOC and PT. 
6.2.5.4 
Non-study Prior Medications 
Frequency tables of the following non-study medications are provided by therapeutic class and 
preferred name: 
 Current medications: all; acute migraine; prophylactic migraine 
 Stable prophylactic migraine medications through randomization. 
Medications are displayed in descending order of overall frequency within therapeutic class and 
preferred name. See Section 6.2.6.3. 
Stable medications through randomization are defined as those taken > 12 weeks before 
informed consent and through randomization, i.e., (1) informed consent date – imputed 
medication start date > 84 days, and (2) IWRS randomization date  imputed medication end 
date. 
6.2.6 
Exposure 
Analyses are based on as-treated treatment group to support safety, unless specified otherwise. 
6.2.6.1 
Study Medication 
During the DBT Phase, study drug is zavegepant 100 mg, zavegepant 200 mg, or matching 
placebo daily; subjects take four (4) to eight (8) 25 mg SGCs daily, depending on their 
randomized treatment assignment.  
During the OLE Phase, study drug is zavegepant 100 or 200 mg; subjects take four (4) to eight 
(8) 25 mg SGCs daily, depending on their randomized treatment assignment in the DBT Phase. 
Study drug is dispensed in a wallet-type blister card with a unique wallet ID. Each wallet has 8 
rows of 4 capsules for a total of 32 capsules. Sites report the wallet ID, study medication start 
date, study medication end date, and number of capsules taken on the IP Dosing CRF. Wallet 
IDs are 5 digits for DB study drug and 6 digits for OL zavegepant. 
The kit type identifier associated with a wallet ID is DB zavegepant 100 mg, DB zavegepant 200 
mg, DB placebo 100 mg, DB placebo 200 mg, OL zavegepant 100 mg, or OL zavegepant 200 
mg, and is obtained by merging the IP Dosing CRF data with the DB study drug kit list file data 
and OL zavegepant kit list file data by wallet ID.  
The by-subject listing of study drug is provided for the safety analysis set, and presents study 
medication start date, study medication end date, study day derived from study medication start 


 
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date, number of capsules taken  0, wallet ID, and kit type identifier. The listing also displays 
DB study drug start and end dates, OL zavegepant start and end dates, displays study drug 
exposure parameters (time on DBT, time on OL zavegepant, time on DB or OL zavegepant), and 
identifies invalid wallet IDs. Valid DB wallet IDs are those in the DB study drug kit list file. 
Valid OL wallet IDs are those in the OL zavegepant kit list file. The listing is sorted by site-
subject ID, study medication start date, study medication end date, and wallet ID. 
DB Study Drug Exposure 
The table of DB study drug exposure is provided descriptively by treatment group, zavegepant 
pooled, and placebo pooled for the DBT safety analysis set, and summarizes the following 
parameters descriptively as continuous or categorical variables: 
 Time on DB study drug (weeks), derived as (DB study drug end date – DB study drug start 
date + 1)/7  
 Time on DB study drug (weeks) categories: < 2,  2 to < 4,  4 to < 6,  6 to < 8,  8 to < 10, 
 10 to < 12,  12 
 Cumulative DB study drug exposure (mg), derived by summing {number of days × number 
of capsules taken per day × dose} across records with complete study medication start date 
and valid DB wallet ID  
 Number of days for a record is derived as imputed study medication end date – study 
medication start date + 1. 
 The dose is 25 mg if the kit type identifier is DB zavegepant 100 or 200 mg; otherwise, 
the dose is 0. 
 Average DB study drug exposure (mg per day), derived as cumulative DB study drug 
exposure/time on DB study drug (days) 
 Total DB study drug exposure (capsules) summed across all subjects, derived by summing 
cumulative DB study drug exposure across all subjects 
 Total DB study drug exposure (patient-years), derived by summing (DB study drug end date 
– DB study drug start date + 1)/365.25 across all subjects. 
 
OL Zavegepant Exposure 
The table of OL zavegepant exposure is provided descriptively by OL zavegepant dose and 
overall for the OL zavegepant safety analysis set, and summarizes the following parameters 
descriptively as continuous or categorical variables: 
 Time on OL zavegepant (weeks), derived as (OL zavegepant end date – OL zavegepant start 
date + 1)/7  
 Time on OL zavegepant (weeks) categories:  12,  24, > 24  
 Time on OL zavegepant milestone categories: 


 
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o 
 3 months, defined as  11 weeks 
o 
 6 months, defined as  23 weeks 
o 
 1 year, defined as  51 weeks. 
 Cumulative OL zavegepant exposure (mg), derived by summing {number of days × number 
of capsules taken per day × 25} across records with complete study medication start date and 
valid OL wallet ID 
 Average OL zavegepant exposure (mg per day), derived as cumulative OL zavegepant 
exposure/time on OL zavegepant (days) 
 Total OL zavegepant exposure (capsules) summed across all subjects, derived by summing 
cumulative DB exposure across all subjects 
 Total OL zavegepant exposure (patient-years), derived by summing (OL zavegepant end date 
– OL zavegepant start date + 1)/365.25 across all subjects. 
DB or OL Zavegepant Exposure 
The table of DB or OL zavegepant exposure is provided descriptively by DB or OL zavegepant 
dose and overall for the DB or OL zavegepant safety analysis set, and summarizes the following 
parameters descriptively as continuous or categorical variables: 
 Time on DB or OL zavegepant (weeks), derived as (DB or OL zavegepant end date – DB or 
OL zavegepant start date + 1)/7  
 Time on DB or OL zavegepant (weeks) categories:  12,  24, > 24  
 Time on DB or OL zavegepant milestone categories: 
o 
 3 months, defined as  11 weeks 
o 
 6 months, defined as  23 weeks 
o 
 1 year, defined as  51 weeks 
o 
 15 months, defined as  63 weeks. 
 Cumulative DB or OL zavegepant exposure (mg), derived as {number of days × number of 
capsules taken per day × 25} across records with complete study medication start date and kit 
type identifier of DB zavegepant 100 mg, DB zavegepant 200 mg, OL zavegepant 100 mg, or 
OL zavegepant 200 mg 
 Average DB or OL zavegepant exposure (mg per day), derived as cumulative DB or OL 
zavegepant exposure/time on DB or OL zavegepant drug (days) 
 Total DB or OL zavegepant exposure (capsules) summed across all subjects, derived by 
summing cumulative DB exposure across all subjects 
 Total DB or OL zavegepant exposure (patient-years), derived by summing (DB or OL 
zavegepant end date – DB or OL zavegepant start date + 1)/365.25 across all subjects. 


 
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6.2.6.2 
Measurements of Treatment Compliance 
DB Treatment Compliance 
DB treatment compliance categories are defined as follows for relevant protocol deviations (see 
Sections 6.2.4.1 and 9.1): 
 DB study drug taken but not randomized  
 DB capsule count compliance < 80% from DB study drug start to later of last scheduled DBT 
Phase visit or DB study drug end/OL zavegepant start. Capsule count compliance is derived 
as 100 × actual cumulative DB capsule count/required cumulative DB capsule count, where 
 Actual cumulative DB capsule count is derived by summing the {number of days × 
number of capsules taken per day} across records with complete study medication start 
date and valid DB wallet ID. 
 
Number of days for a record is derived as imputed study medication end date – study 
medication start date + 1. 
 Required DB cumulative capsule count is derived as {DB maxdate – DB study drug start 
date + 1} × {required number of capsules per day}, where 
 
DB maxdate is defined as the latest of the (1) scheduled Week 2, 4, 8, and 12/EOT 
visit dates, and (2) DB study drug end date. Scheduled visits are identified from visit 
labels from the Visit Date CRF, and therefore exclude those containing 
“unscheduled” in the visit label. 
 
If DB maxdate  OL zavegepant start date, then DB maxdate is set to OL zavegepant 
start date – 1 day. 
 
The required number of capsules per day is 4 for subjects in the zavegepant 100 mg 
or matching placebo group, and 8 for subjects in the zavegepant 200 mg or matching 
placebo group. 
 More than the required number of DB capsules per day taken on any 1 day. This is 
determined from either of the following: 
 Records with complete study medication start date, valid DB wallet ID, and number of 
capsules taken per day > required number of capsules per day. 
 Overlapping records with valid DB wallet ID (see Section 9.4). 
 Incorrect DB study drug taken 
 All the time. Defined as as-treated treatment group not equal to as-randomized treatment 
group, i.e., either of the following: 
 
Subjects randomized to zavegepant who took (1)  1 capsule from a DB placebo 
wallet, and (2) no capsules from a DB zavegepant wallet 
 
Subjects randomized to placebo who took (1)  1 capsule from a DB zavegepant 
wallet, and (2) no capsules from a DB placebo wallet. 


 
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 At least once. Defined as (1) subjects randomized to zavegepant who took  1 capsule 
from a DB placebo wallet, or (2) subjects randomized to placebo who took  1 capsule 
from a DB zavegepant wallet. 
OL Zavegepant Treatment Compliance 
OL zavegepant treatment compliance categories are defined as follows for relevant protocol 
deviations (see Sections 6.2.4.1 and 9.1): 
 OL zavegepant capsule count compliance < 80% from OL zavegepant start to later of last 
scheduled OLE Phase visit or OL zavegepant end. Capsule count compliance is derived as 
100 × actual cumulative OL zavegepant capsule count/required cumulative OL zavegepant 
capsule count, where 
 Actual cumulative OL zavegepant capsule count is derived by summing the {number of 
days × number of capsules taken per day} across records with complete study medication 
start date and valid OL wallet ID. 
 Required cumulative OL zavegepant capsule count is derived as {OL maxdate – OL 
zavegepant start date + 1} where 
 
OL maxdate is defined as the latest of the (1) scheduled Weeks 14, 16, 20, 24, 28, 32, 
36, 40, 44, 48, 52, 56, 60, and 64/EOT visit dates, and (2) OL zavegepant end date. 
Scheduled visits are identified from visit labels from the Visit Date CRF, and 
therefore exclude those containing “unscheduled” in the visit label. 
 
The required number of capsules per day is based on the DB treatment group; see 
“DB Treatment Compliance”. 
> 1 OL zavegepant capsule taken on any 1 day. This is determined from either of the 
following: 
 Records with complete study medication start date, valid OL wallet ID, and number of 
capsules taken per day > required number of capsules per day. 
 Overlapping records with valid OL wallet ID (see Section 9.4). 
 OL zavegepant start date before DB study drug end date. Defined as OL zavegepant study 
drug start date  DB study drug end date. 
 OL zavegepant taken but DB study drug never taken. Defined as nonmissing OL zavegepant 
start date and missing DB study drug start date. 
eDiary Usage Compliance 
eDiary DBT usage compliance is derived as follows for relevant protocol deviations (see 
Sections 6.2.4.1 and 9.1): 
 DB study drug start to later of last scheduled DBT Phase visit or DB study drug end/OL 
zavegepant start: 100 × (total number of efficacy data days from the DB study drug start date 
to DB maxdate)/(total number of days from the DB study drug start date to the DB maxdate), 
where DB maxdate is defined previously.


 
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6.2.6.3 
Nonstudy Concomitant Medications 
Imputed medication start and end dates are used to assign non-study medication type (previous, 
current, DBT concomitant, OL zavegepant concomitant, or follow-up) to all non-study 
medications. Refer to the Core SAP for definitions of nonstudy medication types, non-study 
medication counting rules in frequency tables, non-study medication start and end date 
imputation, and TLF contents. 
The by-subject listing of nonstudy medications is provided by therapeutic class and preferred 
name for the enrolled analysis set. Acute migraine and prophylactic migraine medications are 
identified, as well as medication type.  
The following conventions apply to nonstudy medications: 
 Nonstudy medications are identified from those reported on the Concomitant Medication 
CRF.  
 Prophylactic migraine medications are defined as those with an indication of “prophylactic 
migraine medication” on the Concomitant Medications CRF. 
 Acute migraine medications are defined as non-study medications with either (1) an 
indication of “acute migraine medication” from the Concomitant Medications CRF, or (2) 
preferred name containing triptan, ergotamine, lasmiditan, ubrogepant. 
Nonstudy DBT Concomitant Medications 
Frequency tables of the following nonstudy DBT concomitant medications are provided by 
treatment group, zavegepant pooled, and placebo pooled for the DBT safety analysis set: all; 
acute migraine; prophylactic migraine. Medications are displayed in descending order of 
zavegepant 200 mg frequency within therapeutic class and preferred name. 
Nonstudy OL Zavegepant Concomitant Medications 
A frequency table of the nonstudy OL zavegepant concomitant medications is provided by OL 
zavegepant dose and overall for the OL zavegepant safety analysis set. Medications are displayed 
in descending order of overall frequency within therapeutic class and preferred name. 
6.3 
Efficacy 
Efficacy endpoints are assessed by as-randomized treatment group.  
Randomization is stratified using IWRS, but the randomization strata used in analyses are based 
on actual data. The rationale for using the actual data in analyses is that sites may erroneously report 
the wrong stratum in IWRS. Hence, treatment group comparisons of continuous efficacy 
endpoints are adjusted by the randomization stratum, whereas treatment group comparisons of 
binary efficacy endpoints are stratified by the randomization stratum (except in subgroup 
analyses). If there are sparse data within a stratum, then results may be presented unstratified. 


 
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In treatment comparisons of binary efficacy endpoints, CIs are based on a normal approximation 
to the binomial distribution using asymptotic standard error (ASE). Otherwise, CIs for 
continuous efficacy endpoints are based on the normal distribution. All CIs are 2-sided.  
See Sections 7.2 and 7.3 for the definition of efficacy analysis periods and study days. 
The by-subject listing of primary and secondary efficacy endpoints is provided for the full 
analysis set, and includes the reason for exclusion from the migraine analysis set: randomized 
more than once; not treated with study drug; treated with study drug and < 14 days of eDiary 
efficacy data in the OP; treated with study drug and < 14 days of eDiary efficacy data in all 3 
months of the DBT Phase. Results for continuous endpoints are based on observed data, whereas 
results for binary endpoints incorporate missing data imputation. Subjects with 
14 days of 
efficacy data (not necessarily consecutive) in the month defining the endpoint are flagged for 
secondary endpoints based on a single month. 
6.3.1 
Primary Efficacy Endpoint 
Subjects are instructed to report headache occurrence, headache pain features and associated 
symptoms, aura occurrence, and medication used to treat headache or aura in the eDiary 
headache report every day in the OP and DBT Phase.  
Migraine days per month are assessed as “migraine days per 4 weeks” to correspond with the 4-
week visit schedule. Migraine days per month are based on 4-week intervals, and are prorated to 
account for missing migraine reports.  
See Section 9.2.2 for the definition of eDiary efficacy data days, and Section 9.2.5 for the 
definition of migraine days.  
The number of migraine days per month in the DBT Phase is examined relative to the number of 
migraine days per month in the OP for the migraine analysis set, i.e., subjects with  14 days of 
eDiary efficacy data (not necessarily consecutive) in both the OP analysis period and  1 month 
(i.e., 4-week interval) in the on-DBT efficacy analysis period.  
Months in the DBT Phase are defined as follows: 
 Month 1:  4 weeks; study days 1 to 28 
 Month 2: > 4 to  8 weeks; study days 29 to 56 
 Month 3: > 8 to  12 weeks; study days 57 to 84. 
Analyses are based on eDiary efficacy data dates in the OP and on-DBT efficacy analysis 
periods. 
The number of migraine days per month is prorated to 28 days and derived as follows: 
 OP: 28 × (total number of migraine days in the OP analysis period)/(total number of eDiary 
efficacy data days in the OP analysis period). Subjects must have  14 days of eDiary 
efficacy data (not necessarily consecutive) in the OP to be evaluable. 


 
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 Month (i.e., 4-week interval) in the on-DBT efficacy analysis period: 28 × (total number of 
migraine days in the month)/(total number of eDiary efficacy data days in the month). 
Subjects must have  14 days of eDiary efficacy data (not necessarily consecutive) in the 
specified month to be evaluable. 
 Overall DBT: 28 × (total number of migraine days through Month 3 in the on-DBT efficacy 
analysis period)/(total number of eDiary efficacy data days through Month 3 in the on-DBT 
efficacy analysis period). 
6.3.1.1 
Missing Efficacy Data 
The frequency table of missing efficacy data in the OP and DBT Phase is provided for the full 
analysis set, and displays the following categories: 
 Included in the migraine analysis set:  14 days of eDiary efficacy data (not necessarily 
consecutive) in both the OP and  1 month (i.e., 4-week interval) of the DBT Phase 
o Month 1:  4 weeks * 
o Month 2: > 4 to  8 weeks * 
o Month 3: > 8 to  12 weeks * 
 Excluded from the migraine analysis set 
o < 14 days of eDiary efficacy data in the OP  
o < 14 days of eDiary efficacy data in all 3 months of the DBT Phase. 
In the categories marked with “*”, subjects must have  14 days of efficacy data (not necessarily 
consecutive) in the specified month to be evaluable. 
6.3.1.2 
Descriptive Analyses 
The table of values and changes (both absolute and percent) from the OP in the number of 
migraine days per month in the DBT Phase is provided for the migraine analysis set, and 
summarizes parameters descriptively as continuous variables (including 2-sided normal 97.5% 
CIs for mean change) by treatment group and placebo pooled and by pain intensity in each 
month of the DBT Phase and overall DBT. Pain intensity categories are (1) total (mild, moderate, 
severe, or not reported) and (2) moderate or severe. The table also presents results by subgroup 
level for all efficacy subgroups of interest described in Section 4.3. 
In the percent change analyses, subjects must have  1 migraine day (i.e., absolute not prorated) 
of appropriate pain intensity in the OP analysis period to be included. 
6.3.1.3 
Treatment Group Comparisons 
Analyses are based on the migraine analysis set and total pain intensity, unless specified 
otherwise. 
Main Analysis: Migraine Analysis Set 


 
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The main analysis of the primary endpoint uses a linear mixed effects model with repeated 
measures and the following attributes: 
 Variables: change from the OP in number of total migraine days per month as the dependent 
variable; number of total migraine days per month in the OP as a covariate; treatment group, 
randomization stratum, month (i.e., Months 1 to 3 of the DBT Phase), and the month-by-
treatment group interaction as fixed effects. 
 Covariance structure for repeated measures accounting for within-subject correlated errors: 
assumed to be homogeneous across treatment groups, and initially specified as unstructured. 
If the model fails to converge or cannot be fit with an unstructured covariance structure, then 
other covariance structures are specified in the following hierarchical order: Toeplitz (which 
has heterogenous variances and heterogenous correlations between elements); first-order 
autoregressive with heterogeneous variances; and first-order autoregressive with 
homogeneous variances. 
 SE estimation method: Huber-White “sandwich” (refer to the Core SAP). 
Note that Protocol Versions 1 to 6 erroneously specify to include subject as a random effect in 
the model. 
The  table displays the following model estimates: 
 Least-squares mean (LSM) change from OP, SE, and 97.5% CI by month and overall DBT 
for each treatment group and placebo pooled 
 Difference in LSM changes from OP between each zavegepant treatment group and placebo 
pooled (zavegepanti  placebo pooled; i = 100 and 200), SE, and 97.5% CI at each month and 
overall DBT. Results in the overall DBT support the primary objective, results in the last 
month support secondary objective #2, results in the first month support secondary objective 
#3, and results in the second month support exploratory objective #1. 
See Section 9.3.1 for example SAS code. Model estimates by randomization stratum (yes, no) 
are presented in the same table, using additional models that exclude randomization stratum as a 
fixed effect. 
The main analyses are repeated for moderate or severe pain intensity to support exploratory 
objective #1. All variables in the model are the same, except (1) change from the OP in number 
of moderate or severe migraine days per month is the dependent variable, and (2) number of 
moderate or severe migraine days per month in the OP is the covariate. The corresponding model 
table has the same format. 
6.3.2 
Secondary Efficacy Endpoints  
6.3.2.1 
Percentages of Subjects with Reduction in Number of Migraine Days per 
Month 
Analyses are based on the migraine analysis set using eDiary efficacy data dates in the OP and 
on-DBT efficacy analysis periods (see Section 7.2).  


 
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In analyses by months, subjects must (1) achieve the reduction criterion from OP in the number 
of migraine days per month in the specified month, (2) have  14 days of eDiary efficacy data 
(not necessarily consecutive) in the specified month, and (3) have  1 migraine day (absolute not 
prorated) of appropriate pain intensity in the OP analysis period to be classified as responders in 
the specified month. Otherwise, subjects are classified as failures in the specified month.  
In analyses of the overall DBT, subjects must (1) achieve the reduction criterion from OP in the 
number of migraine days in the overall DBT, and (2) have  1 migraine day (absolute not 
prorated) of appropriate pain intensity in the OP analysis period to be classified as responders. 
Otherwise, subjects are classified as failures. 
 
Treatment Group Comparisons 
For each pain intensity (total; moderate or severe), the percentages of subjects with  50% 
reduction in the number of migraine days per month are compared between each zavegepant 
treatment group and placebo pooled using Mantel-Haenszel risk estimation with stratification by 
randomization stratum (yes, no). Percentages are calculated against the number of subjects in the 
migraine analysis set. 
The table displays the following statistics at each month of the DBT Phase and overall DBT by 
pain intensity: 
 Response rate (i.e., “n/N” and percentage), ASE, and 97.5% CI for each treatment group and 
placebo pooled 
 Stratified percentage difference between each zavegepant treatment group and placebo 
pooled (zavegepanti – placebo pooled; i = 100 and 200), ASE, and 97.5% CI 
 Response rate (i.e., “n/N” and percentage), ASE, and 97.5% CI by randomization stratum for 
each treatment group and placebo pooled 
 Percentage difference between each zavegepant treatment group and placebo pooled 
(zavegepanti – placebo pooled; i = 100 and 200), ASE, and 97.5% CI by randomization 
stratum. 
Results for the endpoint of  50% reduction of moderate or severe pain intensity in the overall 
DBT support secondary objective #1. Results for all other endpoints support exploratory 
objective #2. 
Note that Protocol Versions 1 to 6 specify to compare treatment groups using a stratified 
Cochran-Mantel-Haenszel test, which would produce a chi-square statistic. However, this SAP 
specifies Mantel-Haenszel risk estimation, which is more appropriate given the estimand is based 
on a difference in percentages between groups. 


 
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6.3.2.2 
Acute Migraine-specific Medication Days per Month in the DBT Phase 
During the DBT Phase, subjects may record taking triptan, ergotamine, and other medications to 
treat headache or aura yesterday in the eDiary headache report.  
Acute migraine-specific medication days per month are assessed as “acute migraine-specific 
medication days per 4 weeks” to correspond with the 4-week visit schedule. Acute migraine-
specific medication days per month are based on 4-week intervals, and are prorated to account 
for missing migraine reports. See Section 9.2.4 for the definition of acute migraine-specific 
medication days. 
Analyses are based on the migraine analysis set using eDiary efficacy data dates in the on-DBT
efficacy analysis period.  
The number of acute migraine-specific medication days per month in the DBT Phase are 
prorated to 28 days and derived as follows: 
 Month (i.e., 4-week interval) in the on-DBT efficacy analysis period: 28 × (total number of 
acute migraine-specific medication days in the month)/(total number of eDiary efficacy data 
days in the month). Subjects must have  14 days of eDiary efficacy data (not necessarily 
consecutive) in the specified month to be evaluable. 
 Overall DBT: 28 × (total number of acute migraine-specific medication days through Month 
3 in the on-DBT efficacy analysis period)/(total number of eDiary efficacy data days through 
Month 3 in the on-DBT efficacy analysis period). 
Descriptive Analyses 
The table of the number of acute migraine-specific medication days per month in the DBT 
analysis period is provided, and summarizes the parameter descriptively as a continuous variable 
(including 2-sided normal 97.5% CIs for mean) by treatment group and placebo pooled in each 
month of the DBT Phase and overall DBT.  
Treatment Group Comparisons 
Treatment groups are compared using a linear mixed effects modelwith repeated measures and 
the following attributes: 
 Variables: number of acute migraine-specific medication days per month as the dependent 
variable; treatment group, randomization stratum, month (i.e., Months 1 to 3 of the DBT 
Phase), and the month-by-treatment group interaction as fixed effects 
 Repeated measures error structure: See Section 6.3.1.3 
 SE estimation method: See Section 6.3.1.3. 
The table displays the following model estimates: 
 LSM, SE, and 97.5% CI by month and overall DBT for each treatment group and placebo 
pooled 


 
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 Difference in LSMs between each zavegepant treatment group and placebo pooled 
(zavegepanti  placebo pooled; i = 100 and 200), SE, and 97.5% CI at each month and overall 
DBT. Results in the overall DBT support secondary objective #4, whereas results at other 
time points support exploratory objective #6. 
See Section 9.3.1 for example SAS code. Model estimates by randomization stratum (yes, no) 
are presented in the same table, using additional models that exclude randomization stratum as a 
fixed effect. 
6.3.2.3 
Overall Summary of Primary and Secondary Endpoints in Hierarchical 
Testing  
An overall summary table of treatment comparisons of primary and secondary endpoints tested 
hierarchically displays the following statistics: 
 Continuous endpoints involving change from OP or baseline 
 n (i.e., number of subjects in the analysis set), LSM change, and 97.5% CI for each 
zavegepant treatment group and placebo pooled 
 Difference in LSM changes between each zavegepant treatment group and placebo 
pooled, and 97.5% CI..  
This applies to the primary endpoint and the following secondary efficacy and outcomes 
research endpoints: mean change in number of migraine days per month in the last month of 
the DBT Phase (see main analysis in Section 6.3.1); mean change in number of migraine 
days per month in the first month of the DBT Phase (see main analysis in Section 6.3.1); 
MSQoL restrictive role domain score mean change from baseline at Week 12 (see Section 
6.5.1); and MIDAS total score mean change from baseline at Week 12 (see Section 6.5.2). 
 Continuous endpoints not involving change from OP or baseline 
 n, LSM, and 97.5% CI for each zavegepant treatment group and placebo pooled 
 Difference in LSMs between each zavegepant treatment group and placebo pooled, and 
97.5% CI. 
This applies to the secondary efficacy endpoint of the mean number of acute migraine-
specific medication days per month over the entire DBT Phase (see Section 6.3.2.2). 
 Binary endpoints  
 Response rate (“n/N” and percentage) and 97.5% CI for each zavegepant treatment group 
and placebo pooled 
 Stratified percentage difference between each zavegepant treatment group and placebo 
pooled, and 97.5% CI. 
This applies to the secondary efficacy endpoint of percentage of subjects with  50% 
reduction in number of moderate or severe migraine days per month over the entire DBT 
Phase (see Section 6.3.2.1). 
Endpoints are displayed in the order presented in Sections 3.2.1 and 3.2.2.  


 
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6.3.3 
Exploratory Efficacy Endpoints 
6.3.3.1 
Acute Migraine Medication Days per Month in the DBT Phase 
Acute migraine medication days per month are assessed analogously to acute migraine-specific 
medication days per month (see Section 6.3.2.2).   
An acute migraine medication day is defined in Section 9.2.3. 
Analyses are based on the migraine analysis set with eDiary efficacy data dates in the on-DBT 
efficacy analysis period.  
The number of acute migraine medication days per month in the DBT Phase are prorated to 28 
days. 
Descriptive Analyses 
The table of the number of acute migraine medication days per month in the DBT analysis period 
is provided, and has the same format as the one in Section 6.3.2.2. 
6.3.4 
Pharmacokinetics 
Sparse PK sampling is performed at Week 4 and 8 at predose and approximately 1 hour 
postdose. PK last meal/snack date/times, collection date/times, and last IP dosing date/times are 
based on the PK CRF. Plasma zavegepant concentrations and collection date/times are from the 
external source Syneos Health.  
The by-subject listing of plasma zavegepant concentrations is provided for the DBT efficacy 
analysis set, which includes analysis visit, analysis time point, PK collection date/time, last IP 
dose collection date/time, last meal/snack date/time before and after the predose sample 
concentration, study days corresponding to aforementioned date/times, and concentration. BLQ 
values are displayed as “BLQ”. A footnote specifies the lower limit of quantification (LLOQ) of 
0.04 ng/mL and the upper limit of quantification (ULOQ) of 50.00 ng/mL. 
First, PK samples are slotted into analysis visit windows defined in Section 7.3 according to PK 
collection date. Next, PK samples are slotted into analysis time point windows within analysis 
visit windows according to PK collection date/time as follows: 
 Predose: last PK sample with collection date/time before the last IP dose collection date/time 
 1 hour postdose: first PK sample with collection date/time after the last IP dose collection 
date/time. 
CRF and external PK data are merged by PK collection date/time, where the external data take 
precedence. 


 
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6.4 
Safety
Safety parameters include the following: deaths; AEs; laboratory tests; vital signs; physical 
measurements; electrocardiograms (ECGs); and Columbia-Suicidality Severity Rating Scale (C-
SSRS. 
Tables of safety endpoints are provided according to safety analysis period and analysis set as 
follows: 
 On-DBT for the DBT safety analysis set by treatment group, zavegepant pooled, and placebo 
pooled 
 Post-DBT pre-OL zavegepant for the interim safety analysis set by treatment group, 
zavegepant pooled, placebo pooled, and overall 
 On-OL zavegepant for the OL zavegepant safety analysis set by OL zavegepant dose and 
overall 
 On-DB or OL zavegepant for the DB or OL zavegepant safety analysis set by DB or OL 
zavegepant dose and overall 
 Follow-up for the follow-up safety analysis set by treatment group/OL zavegepant status and 
overall.  
Treatment group is as-treated according to Section 6.1.1.1. 
Measurements are slotted into analysis periods and analysis visits using the following steps: 
1) Measurements are slotted into the pretreatment, on-treatment safety, and follow-up safety 
analysis periods. 
2) Measurements are slotted into analysis visits in the analysis periods listed in the previous step 
(see Table 5). This does not apply to AEs. 
3) Measurements in the on-treatment safety analysis period are slotted further into the on-DBT, 
post-DBT pre-OL zavegepant, and on-OL zavegepant safety analysis periods.  
Refer also to the Core SAP for details about measurement slotting. See Sections 6.2.5, 7.2 and 
7.3 for definitions of baseline, analysis periods, and analysis visit windows, respectively.  
6.4.1 
Adverse Events 
Refer to the Core SAP for the following: AE start and end date imputation; death date derivation;  
rules for counting and rounding in AE frequency tables; definitions of AEs related to study drug, 
and AEs of special interest; and TLF contents. 
Frequency tables of AEs by SOC and PT display AEs in descending order of overall frequency 
within SOC and PT, unless otherwise specified. 
The by-subject listing of AEs (i.e., non-SAEs and SAEs) is provided for the enrolled analysis set.  


 
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6.4.1.1 
Deaths 
Deaths are identified from any of the following sources: 
 AE CRF with any of the following: PT or reported term of “death”; outcome of fatal; “yes” 
response to any death-related question (e.g., “Did the AE result in death?”; “Is a death 
certificate available?”; “Is an autopsy report available?”); complete or partially complete 
death date 
 DB Subject Status CRF with any of the following: death as reason for DBT Phase non-
completion; death as reason for not continuing to the next phase (see Section 6.2.3.3) 
 OLE Subject Status CRF with any of the following: death as reason for OLE Phase non-
completion; death as reason for not continuing to the Follow-up Phase (see Section 6.2.3.4) 
 Follow-up Subject Status CRF: death as reason for Follow-up Phase non-completion (see 
Section 6.2.3.5). 
The by-subject listing of deaths is provided for the enrolled analysis set. 
6.4.1.2 
AE Overviews 
An AE overview frequency table displays the following categories without SOC and PT: any 
AE; AE related to study drug; AE leading to study drug discontinuation; SAE; SAE related to 
study drug; medication-overuse headache AE; hepatic-related AE; hepatic-related AE leading to 
study drug discontinuation; potential drug abuse AE; cardiovascular AE; and suicidality AE.  
AE overview frequency tables are produced for the following safety analysis periods and 
analysis sets: 
 On-DBT for the DBT safety analysis set 
 Post-DBT pre-OL zavegepant for the interim safety analysis set 
 On-OL zavegepant for the OL zavegepant safety analysis set 
 On-DB or OL zavegepant for the DB or OL zavegepant safety analysis set 
 Follow-up for the follow-up safety analysis set. 
6.4.1.3 
On-DBT AEs 
Frequency tables of on-DBT AEs are provided for the DBT safety analysis set by SOC and PT 
for the following endpoints: 
 AEs by worst intensity (secondary objective #7) 
 AEs related to study drug by worst intensity  
 SAEs (secondary objective #7) 
 AEs leading to study drug discontinuation 
 Hepatic-related AEs (secondary objective #9) 


 
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 Hepatic-related AEs leading to study drug discontinuation (secondary objective #9) 
 Potential drug abuse AEs, displayed in alphabetical order by worst intensity and PT without 
SOC
 Cardiovascular AEs 
 Suicidality AEs. 
Frequency tables of AEs by SOC and PT display AEs in descending order of zavegepant pooled 
within SOC and PT, unless otherwise specified. 
6.4.1.4 
 On-OL Zavegepant AEs 
Frequency tables of on-OL zavegepant AEs are provided for the OL zavegepant safety analysis 
set by SOC and PT for the same endpoints listed in Section 6.4.1.3. 
6.4.1.5 
Follow-up AEs 
Frequency tables of follow-up AEs are provided by SOC and PT for the follow-up safety 
analysis set for the following endpoints: 
 AEs by worst intensity 
 SAEs. 
6.4.2 
Laboratory Tests 
Laboratory tests are analyzed using results from local laboratory tests reported on CRFs and the 
external central laboratories (i.e., Cerba Research and ACM Global Laboratories). Central 
laboratories report both laboratory collection date and time, whereas CRFs capture only 
laboratory collection date. 
Laboratory tests of clinical interest are collected at the following visits: 
 Hematology: Screening; Pre-randomization; Weeks 4, 12, 16, 24, 48, and 64; and early 
termination  
 Serum chemistry: Screening; Pre-randomization; Weeks 4, 12, 16, 24, 48, and 64; and early 
termination. Exceptions are for the following: 
o LFTs (ALT, AST, ALP, TBL, direct bilirubin, indirect bilirubin): All visits except 
Baseline 
o Lipids (total cholesterol, high-density lipoprotein [HDL] cholesterol, low-density 
lipoprotein [LDL] cholesterol, triglycerides) and HBA1c: Screening; Weeks 12 and 64; 
and early termination 
 Urinalysis: Screening; Weeks 12 and 64; and early termination. 
The following by-subject laboratory test listings are provided for the enrolled analysis set:  


 
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 Laboratory test results (SI units). The listing displays all test results over time for subjects 
with select findings (grade 3 to 4 laboratory test abnormalities or positive pregnancy tests) at 
any time point. 
 LFT values and ratios to ULN (i.e., ALT, AST, TBL and ALP) for SI units. The listing 
displays all LFT results over time for subjects with select LFT elevations (ALT or AST > 3x 
ULN; ALP or TBL > 2x ULN) at any time point.  
Refer to the Core SAP for laboratory tests of clinical interest for analyses (including 
identification of those with toxicity grades) and TLF contents. 
6.4.2.1 
Laboratory Test Abnormalities 
Frequency tables of the worst (highest) laboratory test abnormality for each graded laboratory 
test are provided for the following safety analysis periods and analysis sets: 
 On-DBT for the DBT safety analysis set 
 On-OL zavegepant for the OL zavegepant safety analysis set 
 Follow-up for the follow-up safety analysis set. 
Grade 3 to 4 results support other secondary objective #7. 
6.4.2.2 
LFT Elevations 
LFT Elevations: Cumulative, Mutually Exclusive, and Composite 
Frequency tables of LFT elevations are provided for the following safety analysis periods and 
analysis sets:  
 On-DBT for the DBT safety analysis set 
 On-OL zavegepant for the OL zavegepant safety analysis set 
 On-DB or OL zavegepant for the DB or OL zavegepant safety analysis set 
 Follow-up for the follow-up safety analysis set. 
Results support secondary objective #8 and exploratory objectives #8 and #9. 
A confidence level of 97.5% is used for CIs. 
LFT Plots 
By-subject longitudinal LFT plots are provided for the safety analysis set with select LFT 
elevations in any safety analysis period. Study weeks are defined as study day/7, where study 
day is derived from the laboratory test collection date (see Section 7.3). Each figure also displays 
DB study drug and OL zavegepant dosing days using symbols along the x-axis (see Section 9.4), 
and denotes additional study milestones (e.g., start of the on-DBT safety analysis period, start of 
the OL zavegepant safety analysis period, and start of the follow-up safety analysis period) using 
vertical lines with their corresponding descriptions in footnotes.  


 
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6.4.2.3 
Laboratory Test Changes from Baseline over Time 
The table of values and changes from baseline in hematology and serum chemistry laboratory 
tests is provided by treatment group, zavegepant pooled, placebo pooled, and overall for the 
safety analysis set at the following time points: baseline; each scheduled visit through Week 12 
and EOT in the on-DBT safety analysis period; each scheduled visit from Week 14 through 
Week 64 and EOT in the on-OL zavegepant safety analysis period; and each scheduled visit in 
the follow-up safety analysis period. Results for zavegepant pooled and placebo pooled are 
displayed only at baseline and time points in the on-DBT safety analysis period. Results for 
overall are displayed only at baseline and time points in the on-OL zavegepant and follow-up 
safety analysis periods. 
Note that scheduled visits vary according to laboratory test. 
Refer to the Core SAP for (1) handling multiple values in an analysis visit window or on the 
same laboratory collection date, and (2) deriving the EOT value in an on-treatment safety 
analysis period. Note that Cerba Research provides sample code (vial/tube identifier), whereas 
ACM Global Laboratories provide accession identifier. 
6.4.3 
Vital Signs and Physical Measurements 
Vital signs include systolic blood pressure, diastolic blood pressure, heart rate, temperature, and 
respiratory rate. Physical measurements include height, weight, and body mass index (BMI). 
These parameters are measured with both measurement date and time at early termination and all 
visits except Weeks 2 and 14; height is measured at Screening only.  
Refer to the Core SAP for TLF contents. 
6.4.3.1 
Vital Sign and Physical Measurement Changes from Baseline over Time 
The table of values and changes from baseline in vital signs and physical measurements is 
provided by treatment group, zavegepant pooled, placebo pooled, and overall for the safety 
analysis set at the following time points: baseline; each scheduled visit through Week 12 and 
EOT in the on-DBT safety analysis period; each scheduled visit from Week 14 through Week 64 
and EOT in the on-OL zavegepant safety analysis period; each scheduled visit in the follow-up 
safety analysis period. Results for zavegepant pooled and placebo pooled are displayed at 
baseline and time points in the on-DBT safety analysis period. Results for overall are displayed 
only at baseline and time points in the on-OL zavegepant and follow-up safety analysis periods. 
Refer to the Core SAP for (1) handling multiple values in an analysis visit window or on the 
same measurement date, and (2) deriving the EOT value in an on-treatment safety analysis 
period. 
6.4.3.2 
Vital Sign and Physical Measurement Abnormalities 
Frequency tables of vital sign and physical measurement abnormalities are provided for the 
following safety analysis periods and analysis sets: 


 
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 On-DBT for the DBT safety analysis set 
 On-OL zavegepant for the OL zavegepant safety analysis set 
 Follow-up for the follow-up safety analysis set. 
6.4.4 
Electrocardiograms
ECG parameters include RR, QRS, PR, QT, QTcB, QTcF, and ventricular heart rate. ECGs are 
measured with both acquisition date and time at the following visits: Screening; Weeks 4, 12, 16, 
24, 48, and 64; and early termination. ECGs are analyzed using results from local tests reported 
on ECG CRFs and the external central vendor Bioclinica. Note that the ECG CRF collects RR in 
sec, not msec. 
Refer to the Core SAP for TLF contents. 
6.4.4.1 
ECG Changes from Baseline over Time 
The table of values and changes from baseline in ECG parameters is provided by DB treatment 
group, zavegepant pooled, placebo pooled, and overall for the safety analysis set at the following 
time points: baseline; each scheduled visit through Week 12 and EOT in the on-DBT safety 
analysis period; and each scheduled visit from Week 16 through Week 64 and EOT in the on-OL 
zavegepant safety analysis period. Results for zavegepant pooled and placebo pooled are 
displayed only at baseline and time points in the on-DBT safety analysis period. Results for 
overall are displayed only at baseline and time points in the on-OL zavegepant safety analysis 
period. 
Refer to the Core SAP for (1) handling multiple values in an analysis visit window, and (2) 
deriving the EOT value in an on-treatment safety analysis period. 
If there are multiple values on the same measurement date, then the following hierarchy is used 
to further break ties as available:  
 Last central value collected timewise with the last ECG reference identifier 
 Last local value collected timewise with the last entry date/time. 
6.4.4.2 
ECG Abnormalities 
Frequency tables of ECG abnormalities are provided for the following safety analysis periods 
and analysis sets: 
 On-DBT for the DBT safety analysis set 
 On-OL zavegepant for the OL zavegepant safety analysis set 
 Follow-up for the follow-up safety analysis set. 
ECG abnormalities are presented together with vital sign and physical measurement 
abnormalities in the same tables (see Section 6.4.3.2). 


 
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6.4.5 
C-SSRS 
The C-SSRS is a clinician administered questionnaire used to help immediate risk of suicide. 
The C-SSRS is administered at early termination and all visits except the Pre-randomization 
Laboratory Visit. At the Screening Visit, the recall period for completing is 12 months for 
suicidal ideation and 10 years for suicidal behavior; at all other visits, the recall period for 
completing the C-SSRS is since the last visit. 
Frequency tables of C-SSRS suicidality are provided for the following safety analysis periods 
and analysis sets: 
 On-DBT for the DBT safety analysis set 
 On-OL zavegepant for the OL zavegepant safety analysis set
 Follow-up for the follow-up safety analysis set. 
Refer to the Core SAP for calculation of C-SSRS parameters and TLF contents. 
6.4.6 
Safety Narrative Subject Identifiers 
The by-subject listing of safety narrative subject identifiers is provided for the following select 
events, safety analysis periods, and analysis sets as columns:  
 Death in any safety analysis period for the enrolled analysis set 
 SAE during any of the following safety analysis periods and analysis sets: 
o On-DB or OL zavegepant for the DB or OL zavegepant safety analysis set 
o Follow-up for the DB or OL zavegepant safety analysis set 
 Non-SAE leading to study drug discontinuation in any safety analysis period for the DB or 
OL zavegepant safety analysis set 
 Event of special interest on DB or OL zavegepant for the DB or OL zavegepant safety 
analysis set:  
o ALT or AST > 3x ULN 
o ALT or AST > 3x ULN concurrent with TBL > 2x ULN 
o ALP or TBL > 2x ULN 
o Select hepatic-related non-SAE, i.e., PT containing cirrhosis, hepatic failure, hepatitis, 
jaundice, or liver failure 
o Cardiovascular non-SAE 
o Suicidality non-SAE.  
Refer to the Core SAP for additional details. 
6.5 
Outcomes Research 
Analyses are based on as-randomized treatment group for the DBT efficacy analysis set. 


 
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Randomization strata used in analyses are based on actual data. 
Outcomes research questionnaires and rating scales are MSQoL and MIDAS. These are assessed 
at Baseline, Week 12, Week 24, Week 64, and early termination. MSQoL and MIDAS are 
collected from respective CRFs with an assessment date.  
Measurements are slotted into analysis periods and analysis visits using the following steps: 
1) Measurements are slotted into the pretreatment, DBT outcomes research, and OL zavegepant 
outcomes research analysis periods. 
2) Measurements are slotted into analysis visits in the analysis periods listed in the previous step 
(see Table 5).  
See Sections 6.2.5, 7.2 and 7.3 for definitions of baseline, outcomes research analysis periods, 
and analysis visit windows, respectively. 
A confidence level of 97.5% is used for CIs. 
The by-subject listing of MSQoL and MIDAS is provided for the enrolled analysis set, and 
displays values and changes from baseline in MSQoL domain scores and MIDAS total, 
absenteeism, and presenteeism scores.  
Refer to the Core SAP for the following: detailed descriptions of these questionnaires; 
calculating scores and imputing missing data; deriving categories; handling multiple 
questionnaires values in an analysis visit window or on the same assessment date; and TLF 
contents. 
6.5.1 
MSQoL  
The MSQoL consists of 14 items across the following 3 domains: (1) restrictive role function, (2) 
preventative role function and (3) emotional function.  
Refer to the Core SAP for calculating domain scores and imputing missing data. 
Descriptive Analyses 
The table of values and changes from baseline in scores are provided for each domain by 
treatment group, placebo pooled, and overall for the DBT efficacy analysis set at the following 
time points: baseline; Week 12 in the DBT outcomes research analysis period; Week 24 and 
Week 64 in the OL zavegepant outcomes research analysis period. Results for placebo pooled 
are displayed only at baseline and time points in the DBT outcomes research analysis period. 
Results for overall are displayed only at baseline and time points during the OL zavegepant 
outcomes research analysis period. 
The frequency table of MSQoL domain score increase from baseline categories is provided by 
treatment group and overall for the DBT efficacy analysis set at the following time points: Week 
12 in the DBT outcomes research analysis period; Week 24 and Week 64 in the OL zavegepant 
outcomes research analysis period. Results for placebo pooled are displayed only at baseline and 


 
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time points in the DBT outcomes research analysis period. Results for overall are displayed only 
at baseline and time points during the OL zavegepant outcomes research analysis period. 
Results support exploratory objective #12. 
Treatment Group Comparisons
Analysis of the restrictive role function domain is based on the DBT efficacy analysis set with 
paired data, i.e., restrictive role function domain scores at both baseline and Week 12 of the DBT 
outcomes research analysis period. 
Treatment groups are compared using a linear regression model with the following attributes: 
 Variables: Week 12 change from baseline in the score as the dependent variable; baseline 
score as a covariate; treatment group and randomization stratum as fixed effects.  
 SE estimation method: See Section 6.3.1.3. 
The table provides n (i.e., number of subjects with paired data) and the following model 
estimates: 
 LSM change from baseline at Week 12, SE, and 97.5% CI for each treatment group and 
placebo pooled 
 Difference in LSM changes from baseline at Week 12 between each zavegepant treatment 
group and placebo pooled (zavegepanti placebo pooled; i = 100 and 200), SE, and 97.5% 
CI.  
Results support secondary objective #5. 
See Section 9.3.2 for example SAS code. Model estimates by randomization stratum (yes, no) 
are presented in the same table, using additional models that exclude randomization stratum as a 
fixed effect. 
6.5.2 
MIDAS  
The MIDAS is a retrospective, patient-administered, 5-item questionnaire that measures 
headache-related disability as lost time due to headache from paid work or school, household 
work, and non-work activities.  
Refer to the Core SAP for calculating MIDAS scores (i.e., total, absenteeism, presenteeism, 
item) and imputing missing data. 
Descriptive Analyses 
The table of values and changes from baseline in total, absenteeism, presenteeism, and item 
scores is provided, and has a similar format as the one described in Section 6.5.1.  
Results support exploratory objective #12. 
Treatment Group Comparisons 


 
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Analysis of the total score is based on the DBT efficacy analysis set with total scores at both 
baseline and Week 12 of the DBT outcomes research analysis period. 
Treatment groups are compared using a linear regression model with the same attributes as the 
one described in Section 6.5.1. The table has the same format. 
Results support secondary objective #6. 
7 CONVENTIONS 
7.1
Derived Dates
Derived dates are defined as follows:
 eDiary measurement date: Complete datepart{eDiary finding date/time} – 1 day, if from the 
eDiary headache log; complete datepart{eDiary finding date/time} otherwise 
 eDiary efficacy data date: eDiary measurement date from the eDiary headache log 
 Study drug start date: Earliest complete study medication start date from IP Dosing CRF 
records with number of capsules taken > 0. This is an analysis period reference date.  
 Imputed study medication end date: If the study medication end date is (1) non-complete or 
(2) complete but before the study medication start date, then the imputed end date is set to the 
study medication start date. Otherwise, the imputed end date is set to the complete study 
medication end date. Derived only for IP Dosing CRF records with complete study 
medication start date and number of capsules taken > 0. 
 Study drug end date: Latest of (1) complete study medication start dates, or (2) complete 
study medication end dates from IP Dosing CRF records with number of capsules taken > 0 
 Study drug last date:  
 Before the final database lock: Study drug end date derived only for subjects who have 
either (1) or (2): 
 
(1) “Yes” or “no” response to the phase completion question on the DB Subject 
Status CRF, and {either (1a) “no” response to the continuing to the Follow-up Phase 
question on the DB Subject Status CRF, or (1b) “no” response to the continuing to the 
next phase question on the DB Subject Status CRF, or (1c) “Follow-up” specified as 
the next phase on the DB Subject Status CRF}, and missing OL zavegepant start date 
 
(2) “Yes” or “no” response to the phase completion question on the OLE Subject 
Status or Follow-up Subject Status CRF 
 Final database lock: Study drug end date 
This is an analysis period reference date. 
 DB study drug start date: Earliest complete study medication start date from IP Dosing CRF 
records with number of capsules taken > 0 and valid DB wallet ID. This is an analysis period 
reference date. 


 
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 DB study drug end date: Latest of (1) complete study medication start date, or (2) complete 
study medication end date from IP Dosing CRF records with number of capsules taken > 0
and valid DB wallet ID 
 DB study drug last date:  
 Before the CSR database lock: DB study drug end date derived only for subjects with 
“yes” or “no” response to the phase completion question on the DB Subject Status, OLE 
Subject Status, or Follow-up Subject Status CRF 
 CSR database lock or after: DB study drug end date
This is an analysis period reference date. 
 OL zavegepant start date: Earliest complete study medication start date from IP Dosing CRF 
records with number of capsules taken > 0 and valid OL wallet ID. This is an analysis period 
reference date. 
 OL zavegepant end date: Latest of (1) complete study medication start date, or (2) complete 
study medication end date from IP Dosing CRF records with number of capsules taken > 0 
and valid OL wallet ID 
 OL zavegepant last date: 
 Before the final database lock: OL zavegepant end date derived only for subjects with 
“yes” or “no” response to the phase completion question on the OLE Subject Status or 
Follow-up Subject Status CRF
 Final database lock: OL zavegepant end date 
This is an analysis period reference date. 
 DB or OL zavegepant start date: Study drug start date for subjects whose as-treated DB 
treatment group is zavegepant; OL zavegepant start date for subjects whose as-treated DB 
treatment group is placebo. This is an analysis period reference date. 
 DB or OL zavegepant end date: Study drug end date for subjects whose as-treated DB 
treatment group is zavegepant; OL zavegepant end date for subjects whose as-treated DB 
treatment group is placebo 
 DB or OL zavegepant last date: Study drug last date for subjects whose as-treated DB 
treatment group is zavegepant; OL zavegepant last date for subjects whose as-treated DB 
treatment group is placebo. This is an analysis period reference date. 
 OP start date: Earliest of the following: screening visit date  1 day; eDiary efficacy data 
date. The screening visit date is determined from the visit label from the Visit Date CRF. 
This is an analysis period reference date. 
 OP end date: 
 If the study drug start date is not missing: study drug start date  1 day 
 If the study drug start date is missing and the randomization date is not missing: 
randomization date  1 day 


 
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 If both study drug start date and randomization date are missing: Last contact date 
This is an analysis period reference date. 
 Last contact date:  
1. Earliest complete death date from the AE CRF, if it exists. 
2. Otherwise, the latest complete date of the following: AE start or end; ECG; eDiary 
finding; informed consent; IWRS randomization; laboratory test collection; non-study 
medication start or end; physical exam; physical measurement; procedure; rating scale; 
questionnaire; study medication start or end; vital sign; visit.  
3. If the last contact date is after the most recent raw database creation date, then it is set to 
the most recent raw database creation date. 
 Death date: refer to the Core SAP. 
No imputations are performed on these derived dates, unless specified otherwise.  
Refer to the Core SAP for the definition of complete dates.  
7.2 
Analysis Periods 
Measurements are slotted into analysis periods based on comparing measurement dates to 
analysis period reference dates (time is not applicable).
Analysis periods are defined as follows: 
 eDiary efficacy endpoints (migraine days, acute migraine-specific medication days, acute 
migraine medication days) 
 OP: eDiary efficacy data date on or after the OP start date through the OP end date. Note 
that this is a subset of the pretreatment analysis period. 
 28-day OP: eDiary efficacy data date on or after the OP start date through the earlier of 
{OP start date + 27 days; OP end date}. Note that this is a subset of the OP analysis 
period, and is used only to assess efficacy data issues during the OP as relevant protocol 
deviations. 
 On-DBT efficacy: 
 
If the DB study drug last date or OL zavegepant start date is not missing: eDiary 
efficacy data date on or after the DB study drug start date through the earlier of the 
DB study drug last date and {OL zavegepant start date  1 day} 
 
If the DB study drug last date and OL zavegepant start date are both missing: eDiary 
efficacy data date on or after the DB study drug start date 
This period is used to assess efficacy during the DBT Phase. 
 Pretreatment characteristics and safety endpoints * 
 Pretreatment: This period is abbreviated as “PRETRT” in listings, and is used to derive 
baseline values. 


 
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 On-DBT safety: This period is abbreviated as “DBT” in safety listings, and is used to 
assess safety endpoints on DBT for the DBT safety analysis set.  
 Post-DBT pre-OL zavegepant safety: This period is abbreviated as “INT” in safety 
listings, and is used to assess safety endpoints during the interim period (i.e., post-DBT 
pre-OL zavegepant) for the interim safety analysis set.  
 On-OL zavegepant safety: This period is abbreviated as “OLZAV” in safety listings, and 
is used to assess safety endpoints for the OL zavegepant safety analysis set. 
 On-DB or OL zavegepant safety: This period is used to assess safety endpoints on DB or 
OL zavegepant treatment for the DB or OL zavegepant safety analysis set.  
 On-treatment safety: This period is used to derive analysis visit windows for slotting 
measurements, and may also be used to assess safety endpoints in a blinded integrated 
safety report, as needed.  
 Follow-up safety: This period is abbreviated as “FU” in safety listings, and is used to 
assess safety endpoints during follow-up. 
 Outcomes research endpoints (MSQoL, MIDAS,) * 
 DBT outcomes research: This period is abbreviated as “DBT” in outcomes research 
listings, and used to assess outcomes research endpoints during the DBT Phase. 
 OL zavegepant outcomes research: This period is abbreviated as “OLZAV” in outcomes 
research listings, and used to assess outcomes research endpoints during the OLE Phase. 
For endpoints marked with “*”, refer to the Core SAP for the definitions of analysis periods in 
Phase 2/3/4 multiple-dose studies with both DBT and OLE Phases. See Section 7.1 for derived 
dates for determining analysis periods.  
7.3 
Analysis Visit Windows 
Refer to BHV3500-302 Protocol Section 4.3 (Table 1) for the schedule of assessments.  
Refer to the Core SAP for defining randomization days, study days, zavegepant study days, and 
follow-up days in Phase 2/3/4 multiple-dose studies with both DBT and OLE Phases. 
Analysis visit windows are shown in Table 5.  
Table 5 
Analysis Visit Windows 
Analysis Period 
Analysis Visit 
Abbreviation in Listings 
Analysis Day 
Analysis Visit Window  
Target Day 
Pretreatment
PRETRT 
Randomization Day 
 
Screening * 
 -7 or missing 
 
Pre-randomization * 
Prerand 
-6 to -1 
 
Baseline * 
Baseline 
1 
 
Post-randomization @ 
Postrand 
 2
 


 
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Analysis Period 
Analysis Visit 
Abbreviation in Listings 
Analysis Day 
Analysis Visit Window  
Target Day 
Outcomes Research /On-
treatment Safety 
Outcomes Research: DBT 
or OLZAV/Safety: DBT, 
INT, OLZAV, or ONTRT 
Study Day 
 
Week 2
2 to 21 
14 
Week 4
22 to 42 
28 
Week 8
43 to 70 
56 
Week 12 
71 to 91 
85 
Week 14 
92 to 105 
98 
Week 16 
106 to 126 
112 
Week 20 
127 to 154 
140 
Week 24 
155 to 182 
168 
Week 28 
183 to 210 
196 
Week 32 
211 to 238 
224 
Week 36 
239 to 266 
252 
Week 40 
267 to 294 
280 
Week 44 
295 to 322 
308 
Week 48 
323 to 350 
336 
Week 52 
351 to 378 
364 
Week 56 
379 to 406 
392 
Week 60 
407 to 434 
420 
Week 64 
435 to 462 
448 
Extension @
Ext 
 463 
476 
Follow-up Safety 
FU 
Follow-up Day 
 
Follow-up Week 2
FU Week 2
8 to 35
14
Follow-up Week 8 
FU Week 8 
36 to 77 
56 
Follow-up Extension @ 
FU Ext 
 78 
84 
* For subjects in the enrolled analysis set excluded from the full analysis set, the visit label is used for slotting. 
@ Denotes an extended visit in the analysis period and is displayed only in listings 
Study days are used to define analysis visit windows in all analysis periods except follow-up 
safety. Follow-up days are used to define analysis visit windows in the follow-up safety analysis 
period. 
8 CONTENTS OF REPORTS 
All TLFs described in this SAP are produced for the LSLV final CSR (see Section 1.2).  


 
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9 APPENDICES 
9.1
Relevant Protocol Deviations
Relevant eligibility protocol deviations include the following categories: 
 Previously treated with study drug in another multiple-dose BHV3500 study. Defined as 
subjects with (1) previous BHV3500 study subject identifiers from studies BHV3500-
102/103/105/106/107/109/110/111/202 from the Demographics/Informed Consent CRF, and 
(2) who took  1 dose of study drug (e.g., zavegepant or placebo) in a multiple-dose study.  
 Randomized or treated with study drug under > 1 subject identifier. These are identified from 
the Protocol Deviations CRF. 
 Migraine history issue, defined as any of the following subcategories: 
o 
 3 moderate or severe migraine days per month in the 3 months prior to screening, if 
originally consented to Protocol Version 3 or lower 
o 
 19 moderate or severe migraine days per month in the 3 months prior to screening, if 
originally consented to Protocol Version 3 or lower  
o No history of chronic migraine, if originally consented to Protocol Version 4 or higher. 
Defined as having “no” or missing response to chronic migraine by history from the 
Migraine History CRF. 
o < 1 year between age at informed consent and age at chronic migraine onset, if originally 
consented to Protocol Version 4 or higher 
o 
 7 migraine days per month of any pain intensity in the 3 months prior to screening, if 
originally consented to Protocol Version 4 or higher 
o 
 14 headache days per month in the 3 months prior to screening, if originally consented 
to Protocol Version 4 or higher 
o No headache-free days per month in the 3 months prior to screening, if originally 
consented to Protocol Version 4 or higher. 
These are based on the Migraine History CRF. 
 Cardiovascular disease risk factor, defined as any of the following subcategories: 
o Ischemic coronary artery disease 
o Other significant underlying cardiovascular disease 
o Coronary artery vasospasm including Prinzmetal’s angina 
o Wolff-Parkinson-White syndrome or arrhythmias associated with other cardiac accessory 
conduction pathway disorders 
o Other arrhythmias  
o History of stroke or transient ischemic attack 
o Peripheral vascular disease 


 
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o Ischemic bowel disease 
o Uncontrolled hypertension 
These are identified from “yes” responses to having risk factors listed above on the Cardiac 
and Other Risk Factors CRF. Only subcategories with “yes” responses are presented. 
 Medical history, defined as any of the following subcategories: 
o Basilar migraine or hemiplegic migraine 
o Chronic pain syndrome or other pain syndromes other than migraine present at screening
o Dementia or significant neurological disorder other than migraine present at screening 
o Major depressive disorder with atypical antipsychotics taken as nonstudy prior 
medications, schizophrenia, bipolar disorder, or borderline personality disorder present at 
screening. PTs must contain any of the following: major depress; schizophrenia; bipolar 
disorder; borderline personality disorder. Refer to the Core SAP for atypical 
antipsychotics and nonstudy prior medications. 
o Gilbert’s syndrome or any other active hepatic or biliary disorder present at screening 
o Gastric or small intestinal surgery
For each subcategory, PTs are displayed alphabetically as additional subcategories. Unless 
specified otherwise, PTs are identified by the sponsor medical lead or designee from 
reviewing a list of unique medical history SOC and PTs. Active medical history status is also 
identified by the sponsor medical lead or designee from reviewing by-subject listings of 
medical history and AEs. 
Present at screening is defined as medical history end date of ongoing (refer to the Core SAP) 
or on or after the informed consent date.
 Finding out of range, defined any as any of the following subcategories: 
o Females with a positive pregnancy test on or after informed consent (see Section 6.4.2). 
o Estimated glomerular filtration rate (eGFR) according to the re-expressed abbreviated (4-
variable) Modification of Diet in Renal Disease (MDRD) Study equation  40 
mL/min/1.73m2 during pretreatment * 
o BMI  33 kg/m2 during pretreatment * 
o C-SSRS suicidal ideation with active intent or plan to act, or suicidal behavior present 
during pretreatment. Defined as having a “yes” response to any of the following C-SSRS 
questions during pretreatment: 
 Suicidal ideation question 4 (active suicidal ideation with some intent to act, without 
specific) or 5 (active suicidal ideation with specific plan and intent) 
 Suicidal behavior question 1 (actual attempt), 3 (interrupted attempt), 4 (aborted 
attempt), 5 (preparatory acts or behavior), or 6 (suicidal behavior). 
For the subcategories marked with “*”, all nonmissing values during the pretreatment 
analysis period must meet the deviation criteria in order to be considered a deviation. 


 
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 Efficacy data issue during the OP, defined as any of the following subcategories: 
o 
 5 migraine days, if originally consented to Protocol Version 3 or lower  
o 
 7 migraine days, if originally consented to Protocol Version 4 or higher 
o 
 19 headache days, if originally consented to Protocol Version 3 or lower  
o 
 14 headache days, if originally consented to Protocol Version 4 or higher 
o No headache-free days, if originally consented to Protocol Version 4 or higher. A 
headache-free day is defined as a day of eDiary efficacy data that is not a headache day 
of total pain intensity (see Section 9.2.6). 
o 
 23 days of eDiary efficacy data (see Section 9.2.2). 
These are assessed during the 28-day OP analysis period (see Section 7.2). Migraine days 
and headache days are absolute, not prorated to 28 days per month (see Sections 9.2.5 and 
9.2.6), and of total pain intensity. 
Protocol version for original consent is from the Inclusion/Exclusion CRF. 
Relevant subject management protocol deviations include the following categories: 
 Randomization stratum discrepancies between IWRS and actual data, defined as any of the 
following subcategories: 
o IWRS randomization stratum of yes, but no stable prophylactic migraine medication 
taken through randomization 
o IWRS randomization stratum of no, but stable prophylactic migraine medication taken 
through randomization.  
See Section 6.2.5.4 for the definition of non-study stable medication through randomization. 
 Prophylactic migraine medication usage issue, defined as any of the following subcategories: 
o Prophylactic migraine medication started or stopped from 12 weeks before informed 
consent to randomization. Defined as informed consent date – 84 days  imputed non-
study medication start or end date  IWRS randomization date. 
o > 1 prophylactic migraine medication taken on or after informed consent. “> 1” is defined 
as > 1 unique preferred name. 
 DB study drug dosing issue, defined as any of the following subcategories (see Section 
6.2.6.2): 
o DB study drug taken but not randomized 
o More than the required number of DB capsules taken on any 1 day  
o DB capsule count compliance < 80% from DB study drug start to later of last scheduled 
DBT Phase visit or DB study drug end/OL zavegepant start 
o Incorrect DB study drug taken 


 
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 OL zavegepant dosing issue, defined as any of the following subcategories (see Section 
6.2.6.2): 
o OL zavegepant capsule count compliance < 80% from OL zavegepant start to later of last 
scheduled OLE Phase visit or OL zavegepant end 
o More than the required number of OL zavegepant capsules taken on any 1 day 
o OL zavegepant start before DB study drug end 
o OL zavegepant taken but DB study drug never taken 
 eDiary usage compliance < 80% from DB study drug start to later of last scheduled DBT 
Phase visit or DB study drug end/OL zavegepant start (see Section 6.2.6.2) 
 Prohibited non-study medications, defined as any of the following subcategories: 
o Atypical antipsychotics, divalproex, valproic acid, or valproate taken on or after informed 
consent #  
o Butterbur root or extract taken up to 14 days before randomization or afterward 
o Calcitonin gene-related peptide (CGRP) antagonist biologic or small molecule taken on 
or after informed consent # 
o Ergotamine taken on or after informed consent 
o Lamotrigine taken on or after informed consent 
o Narcotic (barbiturate or opioid) taken up to 2 days before randomization or afterward # 
For the subcategories marked with “#”, preferred names are displayed alphabetically as 
additional subcategories. Medications taken up to X days before a reference date or afterward are 
defined as those with imputed medication start date or imputed end date  reference date – X.  
Refer to the Core SAP for additional details about prohibited non-study medications. 
The IWRS randomization date is the reference date for “randomization”. If the IWRS 
randomization date is missing, then the study drug start date is used. 
9.2 
eDiary Efficacy 
9.2.1 
Efficacy Parameters 
On a given day, subjects use the eDiary to provide responses to the following efficacy 
parameters occurring yesterday:  
 Headache (yes, no) 
 If the response to headache is “yes”, then responses to the following pain features and 
associated symptoms are collected: 
o Lasts at least 30 minutes (yes, no) 
o Pain intensity (mild, moderate, severe) 
o Unilateral (yes, no) 


 
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o Pulsating (yes, no) 
o Worsen or avoid physical activity (yes, no) 
o Nausea (yes, no) 
o Vomiting (yes, no) 
o Photophobia (yes, no) 
o Phonophobia (yes, no) 
 Aura (yes, no) 
 If the response to headache or aura is “yes”, then the responses to the following parameters 
about taking medications to treat headache or aura are collected: 
o Triptan (yes, no) 
o Ergotamine (yes, no) 
o Other medication (yes, no). 
These efficacy parameters are collected together as a set with the same eDiary finding date/time 
for a subject.  It is expected that subjects have only 1 set of efficacy parameters collected on a 
given eDiary finding date. Handling of multiple sets on the same date are discussed in 
subsequent sections. 
9.2.2 
eDiary Efficacy Data Day 
A day of eDiary efficacy data is defined as any complete eDiary efficacy data date (see Section 
7.1).  
9.2.3 
Acute Migraine Medication Day 
An acute migraine medication day is defined as either (1) or (2):  
1) Acute migraine-specific medication day (see Section 9.2.4) 
2) Migraine day (see Section 9.2.5) with a “yes” response to the question about taking other 
medications to treat headache or aura. 
Thus, acute migraine medication days are a subset of migraine days (see Section 9.2.5). If there 
are multiple sets of efficacy parameters on the same finding date, then data from all sets are used 
cumulatively to assess acute migraine medication day status on that day, regardless of finding 
time. For example, if a subject has both “yes” and “no” responses to the question about taking 
triptan on that day, then the subject is considered to have taken acute migraine medication on 
that day. 


 
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9.2.4 
Acute Migraine-specific Medication Day 
An acute migraine-specific medication day is defined as a day of eDiary efficacy data with a 
“yes” response to either of the 2 questions about taking triptan or ergotamine to treat headache or 
aura. 
Thus, acute migraine-specific medication days are a subset of acute migraine medication days 
and migraine days (see Sections 9.2.3 and 9.2.5, respectively). If there are multiple sets of 
efficacy parameters on the same finding date, then data from all sets are used cumulatively to 
assess acute migraine-specific medication day status on that day, regardless of finding time. 
9.2.5 
Migraine Day 
A migraine day is defined as a day of eDiary efficacy data with either (1) or (2): 
1) Qualified migraine headache, defined as meeting both criteria a and b: 
a. Headache lasting  30 minutes: “Yes” response to the question about lasting  30 
minutes 
b. Meeting  1 of the following criteria (i or ii): 
i. 
 2 of the following pain features: 
1. Unilateral: “Yes” response to the question about unilateral 
2. Pulsating: “Yes” response to the question about pulsating  
3. Moderate or severe pain intensity 
4. Worsen or avoid physical activity: “Yes” response to the question about worsen 
or avoid physical activity  
ii. 
 1 of the following associated symptoms: 
1. Nausea: “Yes” response to the question about nausea 
2. Vomiting: “Yes” response to the question about vomiting 
3. Both photophobia and phonophobia: “Yes” responses to the questions about 
photophobia and phonophobia 
2) Acute migraine-specific medication day (see Section 9.2.4). 
Migraine days are a subset of headache days (see Section 9.2.6). 
If there are multiple sets of efficacy parameters on the same finding date, then data from all sets 
are used cumulatively to assess migraine day status on that day, regardless of finding time. 
Migraine pain intensity is set to the greatest pain intensity on that day.  
9.2.6 
Headache Day 
A headache day is defined as a day of eDiary efficacy data with either (1), (2), or (3): 


 
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1) Migraine day (see Section 9.2.5) 
2) Headache that lasts  30 minutes: “Yes” response to the question about lasting  30 minutes 
3) Headache of any duration for which acute headache treatment is administered: Meeting both 
of the following criteria (a and b):
a) “Yes” response to the question about having a headache 
b) “Yes” response to any of the 3 questions about taking medications to treat headache or 
aura (i.e., triptan, ergotamine, or other medications). 
If there are multiple sets of efficacy parameters on the same finding date, then data from all sets 
are used cumulatively to assess headache day status on that day, regardless of finding time. 
Headache pain intensity is set to the greatest pain intensity on that day.
9.3 
SAS Code 
9.3.1 
Linear Mixed Effects Model with Repeated Measures
Consider the following variables used to evaluate the primary efficacy endpoint using a linear 
mixed effects model with repeated measures: 
 mdmchg: change from the OP in migraine days per month; continuous variable 
 mdmop: migraine days per month during the OP; continuous variable 
 month: month; categorical variable with levels of 1, 2, and 3 
 rndstr: randomization stratum; categorical variable with levels of 1 and 2 to denote yes and 
no, respectively 
 trt: treatment group; categorical variable with levels of 1, 2, 3, and 4 to denote zavegepant 
100 mg, zavegepant 200 mg, placebo 100 mg, and placebo 200 mg, respectively 
 usubjid: unique subject identifier; categorical variable. 
 
Then the SAS code is as follows: 
proc mixed alpha=0.025 empirical; 
class usubjid rndstr trt month; 
model mdmchg = mdmop rndstr trt month trt*month; 
repeated month / subject=usubjid type=un; /* unstructured covariance */ 
lsmeans trt trt*month / alpha=0.025 cl diff; 
lsmestimate trt 'placebo pooled overall DBT' 0 0 1 1, 
                         'zav100 vs placebo pooled overall DBT' 2 0 -1 -1,  
                         'zav200 vs placebo pooled overall DBT' 0 2 -1 -1 /  
                         divisor=2 alpha=0.025; 
lsmestimate trt*month 'placebo pooled month 1' 0 0 0 0 0 0 1 0 0 1 0 0, 
                                     'placebo pooled month 2' 0 0 0 0 0 0 0 1 0 0 1 0, 
                                     'placebo pooled month 3' 0 0 0 0 0 0 0 0 1 0 0 1, 
                                     'zav100 vs placebo pooled month 1' 2 0 0 0 0 0 -1 0 0 -1 0 0,  


 
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'zav100 vs placebo pooled month 2' 0 2 0 0 0 0 0 -1 0 0 -1 0,  
'zav100 vs placebo pooled month 3' 0 0 2 0 0 0 0 0 -1 0 0 -1, 
'zav200 vs placebo pooled month 1' 0 0 0 2 0 0 -1 0 0 -1 0 0,  
'zav200 vs placebo pooled month 2' 0 0 0 0 2 0 0 -1 0 0 -1 0,  
'zav200 vs placebo pooled month 3' 0 0 0 0 0 2 0 0 -1 0 0 -1 /  
divisor=2 alpha=0.025;
run; 
9.3.2 
Linear Regression Model 
Consider the following variables used to evaluate either of the 2 secondary outcomes research 
endpoints using a linear regression model: 
 scorechg: score change from baseline at Week 12; continuous variable 
 rndstr: randomization stratum; categorical variable with levels of 1 and 2 to denote yes and 
no, respectively 
 scorebl: baseline score; continuous variable 
 trt: treatment group; categorical variable with levels of 1, 2, 3, and 4 to denote zavegepant 
100 mg, zavegepant 200 mg, placebo 100 mg, and placebo 200 mg, respectively 
 usubjid: unique subject identifier; categorical variable. 
Then the SAS code is as follows: 
proc mixed alpha=0.025 empirical; 
class usubjid rndstr trt; 
model scorechg = scorebl rndstr trt ;
repeated / subject=usubjid; 
lsmeans trt / alpha=0.025 cl diff; 
lsmestimate trt 'placebo pooled overall DBT' 0 0 1 1, 
                         'zav100 vs placebo pooled overall DBT' 2 0 -1 -1,  
                         'zav200 vs placebo pooled overall DBT' 0 2 -1 -1 /  
                         divisor=2 alpha=0.025; 
run; 
9.4 
Study Drug Dosing Day 
A study drug dosing day is defined as a day on which  1 capsule of study drug was taken.  
For each subject, study drug dosing days and the number of capsules per day are determined for 
every day in the interval defined from the study drug start date to the study drug end date 
inclusive.  
First, study medication records with complete study medication start date, complete imputed 
study medication end date, and number of capsules taken per day > 0 are selected. Imputed study 
medication end date, study drug start date, and study drug end date are derived (see Section 7.1). 


 
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Next, records are sorted by study medication start date, imputed study medication end date, 
wallet ID, and number of capsules taken per day. 
Let [study medication start date1, imputed study medication end date1] and [study medication 
start date2, imputed study medication end date2] denote any 2 records. 
Overlapping records are defined as those with maximum(study medication start date1; study 
medication start date2)  minimum(imputed study medication end date1; imputed study 
medication end date2).  
 All days from the maximum to the minimum inclusive are considered overlapping study drug 
dosing days on which the number of capsules taken per day > 1.  
 The number of capsules taken per day is summed across overlapping study drug dosing days 
to determine whether it exceeds the required number of capsules per day (see Section 
6.2.6.1). 
 Note that overlapping records need not be consecutive. 
Gaps between 2 consecutive records are defined as study medication start date2  imputed study 
medication end date1  2 days. All days from the imputed study drug end date1 + 1 day to the 
study medication start date2 – 1 day inclusive are considered days on which no study drug was 
taken (i.e., not study drug dosing days). 
A DB study drug dosing day is defined as a day on which  1 capsule of DB study drug was 
taken. DB study drug dosing days are determined using valid DB wallet IDs.  
An OL zavegepant dosing day is defined as a day on which  1 capsule of OL zavegepant study 
drug was taken. OL zavegepant dosing days are determined using valid OL wallet IDs. 
Example: 
Suppose study medication data are as follows for a given subject in the zavegepant 100 mg 
treatment group: 
Study 
Medication 
Start Date 
Study 
Medication 
End Date
Imputed Study 
Medication End 
Date
Number of 
Capsules 
Taken per Day 
Note 
01JAN2022 
03JAN2022 
03JAN2022 
4 
 
04JAN2022 
05JAN2022 
05JAN2022 
0 
Excluded from analysis 
06JAN2022 
09JAN2022 
09JAN2022 
4 
 
09JAN2022 
11JAN2022 
11JAN2022 
8 
1-day overlap with previous record
13JAN2022 
 
13JAN2022 
4 
1-day gap between previous record 
Then study drug start date = 01JAN2022 and study drug end date = 13JAN2022.  


 
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Study drug dosing days and number of capsules taken per day are derived as follows for the 
subject, taking overlaps and gaps into account: 
Date
Number of Capsules 
per Day 
Study Drug Dosing 
Day Flag 
01JAN2022 
4 
Y 
02JAN2022 
4 
Y 
03JAN2022 
4 
Y 
04JAN2022 
0 
 
05JAN2022 
0 
 
06JAN2022 
4 
Y 
07JAN2022 
4 
Y 
08JAN2022 
4 
Y 
09JAN2022 
12 
Y 
10JAN2022 
8 
Y 
11JAN2022 
8 
Y 
12JAN2022 
0 
 
13JAN2022 
4 
Y 
The subject has a total of 10 study drug dosing days and 56 capsules taken. There are 3 days on 
which the required number of capsules taken was exceeded. 
 
10 REFERENCES 
1.
Reference-based MI via multivariate normal RM (the “five macros” and MIWithD) from 
the Drug Information Association scientific working group on estimands and missing data. 
London School of Hygiene and Tropical Medicine, 2021. at 
https://www.lshtm.ac.uk/research/centres-projects-groups/missing-data#dia-missing-data.) 
2. 
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