Clinical trial NCT04987944
Conditions: Asthma
Keywords: Allergy Asthma
Sponsor: Pfizer
Start date: 2021-10-18; Completion date: 2023-04-04
Enrollment: 45 participants; Allocation: RANDOMIZED; Intervention model: SEQUENTIAL

Brief summary:
This study is a double-blind, parallel-group, randomized study of active drug vs placebo in asthma.

Detailed description:

Arms: arm 1: Zavegepant 150 mg BID arm 2: Matching placebo 150 mg BID
Interventions: intervention 1: Zavegepant intervention 2: Placebo
Intervention descriptions: intervention 1: 150 mg BID intervention 2: Placebo matching active drug

Protocol documents:
Prot_000.pdf: 
Biohaven Pharmaceuticals, Inc. 
Zavegepant BHV-3500 
Protocol: BHV-3500-204 
Amendment 2.0 
Confidential 
Page 1 of 75 
 
 
 
CLINICAL STUDY PROTOCOL 
 
 
Protocol Title: A Phase 1b, Double-blind, Placebo-controlled, Parallel-group Study to Evaluate 
Safety and Efficacy of Oral Zavegepant in Subjects With Mild Allergic Asthma 
Protocol Number: BHV-3500-204 
 
 
 
Name of Investigational Product: 
Oral zavegepant 
Phase of Development: 
1b 
Indication: 
Allergic asthma 
Contract Research Organization: 
Sponsor: 
Syneos Health, LLC 
1030 Sync Street 
Morrisville, North Carolina 27560 
USA 
Tel.: +1-919-876-9300 
Biohaven Pharmaceuticals, Inc. 
215 Church Street 
New Haven, CT 06510 
USA 
Tel.: +1-203-404-0410 
 
Protocol Version: 
Protocol Date: 
2.0 
09 June 2021 
 
 
This document is strictly confidential. It was developed for Biohaven Pharmaceuticals, Inc. by Syneos Health 
and must not be disclosed to a third-party, with the exception of regulatory agencies and study audit personnel, 
without the consent of either Syneos Health or the Sponsor. This document is copyrighted in favor of Syneos 
Health and cannot be reproduced, modified, or adapted, in part or in total, without prior written approval by 
Syneos Health. 


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Protocol: BHV-3500-204 
Amendment 2.0 
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PROTOCOL APPROVAL SIGNATURES 
Protocol Title: 
A Phase 1b, Double-blind, Placebo-controlled, Parallel-group Study 
to Evaluate Safety and Efficacy of Oral Zavegepant in Subjects 
With Mild Allergic Asthma 
Protocol Number:   BHV-3500-204 
 
This study will be conducted in compliance with the clinical study protocol (and 
amendments), International Council for Harmonisation (ICH) guidelines for current Good 
Clinical Practice (GCP), and applicable regulatory requirements. 
 
Sponsor Signatory 
 
PPD 
 
Signature 
Date 
Sponsor Signatory 
 
PPD 
 
 
 
 
 
Clinical Operations 
 
 
Signature 
Date 
Sponsor Signatory 
 
PPD 
 
Sr. Clinical Trial Lead 
 
Date 
 
 
Sponsor Signatory 
 
PPD 
 
 
Biostatistics 
 
Date 
PPD 
PPD 
PPD 
PPD 


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Zavegepant BHV-3500 
Protocol: BHV-3500-204 
Amendment 2.0 
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SUMMARY OF CHANGES 
 
Version Number 
Brief Description Summary of Changes 
Date 
Version 1.0 
Original 
Not Applicable 
25 Mar 2021 
Version 2.0 
Sponsor Signatory section was updated to reflect 
recent staffing updates 
Updated section 5.2.1.5 to include more recent data 
Updated section 5.4.1 to clarify dose selection 
rationale 
Updated section 8.1, Inclusion criteria 3a to include 
an upper age limit of 65 years of age. The Synopsis 
was also updated to reflect this change 
Updated section 8.3 to clarify cervical cap with 
spermicidal gel 
Corrected inconsistencies and typographical errors 
throughout the protocol. 
09 Jun 2021 


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Protocol: BHV-3500-204 
Amendment 2.0 
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INVESTIGATOR SIGNATURE PAGE 
 
Confidentiality and Current Good Clinical Practice (GCP)/E6(R2) Compliance Statement 
 
I, the undersigned, have reviewed this protocol, and I will conduct the study as described in 
compliance with this protocol (and amendments), GCP, and relevant International Council for 
Harmonisation (ICH) guidelines. 
I am thoroughly familiar with the appropriate use of the study drug, as described in this protocol 
and any other information provided by Biohaven Pharmaceuticals, Inc. including but not limited 
to the current Investigator’s Brochure. 
Once the protocol has been approved by the institutional review board (IRB)/research ethics 
board (REB)/independent ethics committee (IEC), I will not modify this protocol without 
obtaining prior approval of Biohaven Pharmaceuticals, Inc. and of the IRB/REB/IEC. I will 
submit the protocol amendments and/or any informed consent form modifications to Biohaven 
Pharmaceuticals, Inc. and the IRB/REB/IEC, and approval will be obtained before any 
amendments are implemented. 
I ensure that all persons or party assisting me with the study are adequately qualified and 
informed about the Biohaven Pharmaceuticals, Inc. study drug and of their delegated study- 
related duties and functions as described in the protocol. 
I ensure that source documents and trial records that include all pertinent observations on each of 
the site’s trial subjects will be attributable, legible, contemporaneous, original, accurate, and 
complete. 
I understand that all information obtained during the conduct of the study with regard to the 
subjects’ state of health will be regarded as confidential. No subjects’ names will be disclosed. 
All subjects will be identified by assigned numbers on all case report forms, laboratory samples, 
or source documents forwarded to the Sponsor. Clinical information may be reviewed by the 
Sponsor or its agents or regulatory agencies. Agreement must be obtained from the subject before 
disclosure of subject information to a third-party. 
Information developed in this clinical study may be disclosed by Biohaven Pharmaceuticals, Inc. 
to other clinical investigators, regulatory agencies, or other health authority or government 
agencies as required. 
 
 
 
Signature 
Date 
 
 
(Printed name) 
 
 
(Institution name) 


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Zavegepant BHV-3500 
Protocol: BHV-3500-204 
Amendment 2.0 
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2 
SYNOPSIS 
 
Title of Study: 
A Phase 1b, Double-blind, Placebo-controlled, Parallel-group Study to 
Evaluate Safety and Efficacy of Oral Zavegepant in Subjects With Mild 
Allergic Asthma 
Protocol Number: 
BHV-3500-204 
Investigators/ 
Study Sites: 
Approximately 6 sites 
Phase of 
Development: 
1b 
Objectives: 
The primary objective: 
To evaluate the allergen-induced late asthmatic response (LAR) 
between subjects treated with zavegepant and placebo after 28 days of 
treatment. 
Secondary objectives: 
To evaluate the allergen-induced early asthmatic response (EAR) 
between subjects treated with zavegepant and placebo. 
To evaluate the allergen-induced airway hyperresponsiveness (AHR) 
measured at 24 hours post-allergen, between subjects treated with 
zavegepant and placebo. 
To assess the safety and tolerability of oral zavegepant. 
CCI 
 
CC 
Study Endpoints: 
Primary endpoint: 
Allergen-induced LAR assessed as maximum percentage decrease in 
forced expiratory volume in 1 second (FEV1) between 3 and 7 hours 
after the administration of the allergen inhalation challenge. 


Biohaven Pharmaceuticals, Inc. 
Zavegepant BHV-3500 
Protocol: BHV-3500-204 
Amendment 2.0 
 
CCI
 
 
 
CCI 
CCI 
Study Design: 
This study is designed as a double-blind, parallel-group, randomized study of 
24 subjects to evaluate the safety and efficacy of 150 mg oral zavegepant 
(N=12) versus placebo (N=12) twice daily (BID) for the treatment of allergen- 
induced asthma. Individuals with stable, mild allergic asthma, with a history of 
episodic wheeze and shortness of breath, will be eligible for enrollment. 
The study will be divided into 2 parts. 
Part 1 (screening period): A screening period of up to 28 days will be 
conducted to obtain a cohort of subjects with documented EAR (defined as 
 20% fall in FEV1 0 to 2 hours after allergen challenge) and LAR (defined as 
 15% fall in FEV1 3 to 7 hours after allergen challenge) to an inhaled 
incremental allergen challenge and AHR defined by methacholine PC20 
 16 mg/mL by inhaled incremental methacholine challenge. Procedures for 
allergen and methacholine challenges are specifically outlined in section 
below—Efficacy/Clinical Performance/Effectiveness. 
At Visit 1, subjects will be confirmed for allergy by a skin prick test and 
assessed for safety by baseline clinical laboratory tests. Upon confirmation 
from blood tests that it is safe to proceed in Part 1, the subject will be 
scheduled for the screening allergen challenge triad which will occur over 
3 consecutive days at Visits 2, 3, and 4. 
 
 


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Protocol: BHV-3500-204 
Amendment 2.0 
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At Visit 2 (Day -15), allergen skin titration (only if procedure was not 
previously performed at Visit 1), methacholine challenge, and sputum 
induction will be performed. 
At Visit 3 (Day -14), allergen challenge and sputum induction will be 
performed. 
At Visit 4 (Day -13), methacholine challenge and sputum induction will be 
performed. 
A rest/washout period of 2 to 4 weeks is scheduled to allow recovery from the 
allergen challenge. If more than 4 weeks is required, Sponsor Medical Monitor 
should be consulted. 
Part 2 (Dosing Period): Duration of study treatment in Part 2 will be 
approximately 28 days. 
At Visit 5 (predose) Day 1, a methacholine challenge will be performed. To 
continue to randomization, the subject’s baseline lung function (FEV1) and 
airway responsiveness to methacholine must show evidence of recovery to 
within 90% of baseline for FEV1 and not more than 1 doubling dose below 
Visit 2 baseline for methacholine PC20. If these criteria are met, sputum will be 
induced. If subjects have not recovered from the screening allergen challenge, 
additional time will be allowed, and Visit 5 pre-dosing procedures may be 
repeated. If this additional retest is required, the screening period may be 
extended. 
Subjects will then be randomized in a 1:1 ratio to receive 150 mg zavegepant 
or matching placebo to be taken BID. Subjects will take their first dose of 
zavegepant on a fasted stomach upon waking, and their second dose in the 
evening. Subjects should not consume food other than water for 1 hour after 
dosing. Further details in Section 9.3. 
All subjects will be scheduled for their 3-day allergen challenge triad 
(Visit 6/~Day 26, Visit 7/~Day 27, and Visit 8/~Day 28). Morning doses will 
be taken before any laboratory procedures, and study treatment will end with 
their evening dose at Visit 8 (~Day 28). 
A follow-up period consisting of an onsite visit (Visit 9) will be conducted 
approximately 7 to 10 days after the last study treatment. 
Selection of 
Subjects: 
Inclusion Criteria: 
1. Subject must have mild intermittent asthma as defined by 
< 2 bronchodilator usage for treatment of asthma symptoms per week. 
2. Baseline FEV1 of  70% of predicted value. 
3. Age and reproductive status: 
a) Male and female subjects aged 
years. 


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Zavegepant BHV-3500 
Protocol: BHV-3500-204 
Amendment 2.0 
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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 8.3 for the definition of women 
of childbearing potential (WOCBP). 
c) Women must not be pregnant, lactating or breastfeeding. 
d) At the baseline Visit 5, prior to dispensing study drug, WOCBP must 
have a negative urine pregnancy test. 
4. Subject’s score on the Sheehan-Suicidality Tracking Scale (S-STS) at 
screening must be 0. 
5. Able to understand and give written informed consent and has signed a 
written informed consent form approved by the investigator’s IRB/REB. 
6. Able to understand and complete study-related questionnaires. 
7. Willing and able to comply with study site visits and study-related 
procedures. 
The following inclusion criteria must be met for entry into the Dosing Phase 
(Part 2): 
8. Positive methacholine challenge (PC20  16 mg/mL). 
9. Positive skin prick test to common aeroallergens (including but not limited 
to cat, dust mite, grass, pollen). 
10. Positive allergen-induced early and late airway bronchoconstriction. 
Exclusion Criteria: 
1. Worsening of asthma or respiratory tract infection within 6 weeks prior to 
study entry. 
2. Participation in any other investigational drug treatment protocol within 
the preceding 30 days or 5 half-lives, whichever is longer, of an 
investigational drug product. 
3. Lung disease other than mild allergic asthma. 
4. Body mass index (BMI)  33.0 kg/m2. 
5. Subjects who anticipate major changes in allergen exposure in their home 
or work environments that are expected to coincide with the baseline or 
the final assessments as assessed by the investigator. 
6. History of liver disease. 
7. History of HIV, hepatitis B or hepatitis C. 
8. Use of tobacco products and/or vaping products within the previous 
12 months or smoking history > 10 pack years. 
9. Subjects should be excluded if they have a positive drug screen for drugs 
of abuse that, in the investigator’s judgment, is medically significant and 
would impact the safety of the subject or the interpretation of the study 
results. In addition: 
a) Detectable levels of amphetamines, barbiturates, benzodiazepines, 
tetrahydrocannabinol, cocaine, opiates, phencyclidine (PCP), or 


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Zavegepant BHV-3500 
Protocol: BHV-3500-204 
Amendment 2.0 
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methadone. Retesting for positive results that are exclusionary is not 
allowed. 
b) Detectable levels of marijuana in the drug screen are not exclusionary 
if, in the investigator’s documented opinion, the subject does not meet 
Diagnostic and Statistical Manual of Mental Disorders Fifth Edition 
(DSM-5) criteria 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. 
10. Subject has a concomitant disease or condition that could interfere with 
the conduct of the study, or for which the treatment might interfere with 
the conduct of the study, or which would, in the opinion of the 
investigator, pose an unacceptable risk to the subject in this study, 
including, but not limited to, cancer, alcoholism, drug dependency or 
abuse, or psychiatric illness. 
11. History of alcohol dependency within the past 12 months, as determined 
by investigator, is exclusionary. 
12. Use of any exclusionary, prohibited, or restricted medications (including 
restricted asthma medications) as outlined in Section 9.6. 
13. Use of any drugs known to induce or inhibit hepatic drug metabolism, 
including St. John’s wort, within 30 days prior to the first dose of study 
drug. 
14. History of anaphylaxis to any substance or a clinically important reaction 
to any drug. 
15. Subject history with current evidence of uncontrolled, unstable, or recently 
diagnosed cardiovascular disease, such as ischemic heart disease, coronary 
artery vasospasm, and cerebral ischemia. 
16. History of myocardial infarction, acute coronary syndrome, percutaneous 
coronary intervention, cardiac surgery, stroke, or transient ischemic attack 
in the 6 months (24 weeks) prior to screening. 
17. History of uncontrolled hypertension or uncontrolled diabetes; however, 
subjects can be included who have stable hypertension and/or diabetes for 
3 months (12 weeks) prior to screening; blood pressure > 140 mmHg 
systolic or 90 mmHg diastolic after 10 minutes of rest is exclusionary. 
18. History of gastric or small intestinal surgery (including gastric bypass, 
gastric banding, gastric sleeve, gastric balloon, etc.), or has a disease that 
causes malabsorption. 
19. History or diagnosis of Gilbert syndrome or any other active hepatic or 
biliary disorder. 
20. History of gallstones or cholecystectomy. 
21. Subject has hematologic or solid malignancy diagnosis within 5 years 
prior to screening. Subjects with a history of localized basal cell or 
squamous cell skin cancer are eligible for the study if they are cancer-free 
prior to the screening visit in this study. 
22. Any of the following laboratory test values above the upper limit of 
normal (ULN) at the screening visit: aspartate aminotransferase (AST), 
alanine aminotransferase (ALT), direct bilirubin, indirect bilirubin, and 
total bilirubin. Only abnormal values between 1 and 1.5 × ULN may be 
repeated once for confirmation to below ULN. 


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Protocol: BHV-3500-204 
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23. Any of the following abnormal laboratory test values at the screening 
visit: 
a) Hemoglobin < 12.0 g/dL for males and < 11.0 g/dL for females 
b) Estimated glomerular filtration rate (eGFR) according to the re- 
expressed abbreviated (4-variable) Modification of Diet in Renal 
 40 mL/min/1.73m2. 
c) Total white blood cell (WBC) count < 3.0 K/µL. 
d) Platelet count < 100 K/µL. 
e) Neutrophils < 1000/µL. 
f) Creatine phosphokinase (CPK) > 5 × ULN. 
24. Any of the following abnormalities on 12-lead electrocardiogram (ECG) 
Visit 1: 
a) Left bundle branch block. 
b) Right bundle branch block 
150 msec. 
c) Intraventricular conduction defect with a 
. 
d) 
470 msec (Fridericia’s corrected QT interval). 
25. Sex and reproductive status 
a) Females of childbearing potential who are unwilling or unable to use 
acceptable contraceptive methods or abstinence to avoid pregnancy 
for the entire study period and for 90 days after the study. See Section 
8.3 for acceptable contraceptive methods. 
b) Women who are pregnant, lactating, or breastfeeding. 
c) Women with a positive pregnancy test. 
26. History of a psychiatric disorder which, in the opinion of the investigator, 
would pose a safety risk to the subject or affect the subject’s participation 
in the trial. 
27. Participation in a clinical research study involving the administration of an 
investigational or marketed drug or device within 30 days prior to the first 
dose of study drug, administration of a biological product in the context of 
a clinical research study within 5 half-lives prior to the first dose of study 
drug, or concomitant participation in an investigational study involving 
drug or device administration. 
28. Any reason which, in the opinion of the investigator, would prevent the 
subject from participating in the study. 
Planned Sample 
Size: 
24 randomized subjects are planned in this study. 
Investigational 
Therapy: 
Oral zavegepant soft gelatin capsules, 150 mg twice daily (BID). 
Reference Therapy: 
Matching placebo soft gelatin capsules, 150 mg twice daily (BID). 
Treatment 
Duration: 
Approximately 28 days. 
Efficacy/ 
Methacholine Inhalation Tests. See Section 11.1.1 for details. 


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Clinical 
Performance/ 
Effectiveness 
Allergen Inhalation Challenge. See Section 11.1.2 for details. 
Sputum Induction. See Section 11.1.3 for details. 
Skin Testing. See Section 11.1.4 for details. 
Allergen Skin Titration. See Section 11.1.5 for details. 
Safety: 
After signing an informed consent, adverse events (AEs) encountered during 
the duration of the study will be recorded on the appropriate pages of the 
electronic case report form (eCRF). 
Unchanged, chronic conditions, or those related to the underlying disease or 
medical conditions that are consistent with natural disease progression, are not 
considered AEs and should not be recorded on AE pages of the eCRF unless 
there is an exacerbation of a chronic condition. 
AEs should be graded as follows: unrelated, unlikely related, possibly related, 
and related to study drug. 
Pharmacokinetics: 
A blood sample for pharmacokinetic (PK) measurement will be obtained 
predose (prior to the morning dose of study drug) on Visits 6, 7, and 8. 
Additional PK samples will be collected on Visit 7 at approximately 
1 (+ 0.5 h) hour and 3 (+/- 0.5 h) hours postdose. Subjects should be instructed 
to hold their daily dose of study drug on the morning of Visits 6, 7, and 8 and 
arrive at the clinic after an overnight fast. Exact times of dosing and PK 
sample collection will be documented. 
Other Assessments: 
CCI 
Statistical Methods 
and Planned 
Analyses: 
The early and late asthmatic response endpoints will be compared between 
zavegepant and placebo using analysis of covariance (ANCOVA) with 
respective baseline EAR and LAR data as covariate. Point estimates, 95% 
confidence intervals (CIs) and 2-sided p-value, will be reported for the 
treatment difference between zavegepant and placebo. 
Graphical summaries of the data from inhaled allergen challenges will be 
presented. 
Descriptive statistics will be provided for demographic, baseline 
characteristics, safety, PK, and biomarker data. Descriptive statistics on 
continuous variables will include number of subjects (N), mean, median, 


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minimum, standard deviation, and ranges. Categorical data will be 
summarized using frequency counts and percentages. 
The number and percentage of subjects reporting any TEAE will be tabulated 
by system organ class and preferred term. Similar summaries will be provided 
for treatment-related AEs, serious AEs (SAEs), and AEs leading to treatment 
discontinuation. Clinically significant laboratory test abnormalities will be 
identified as Grade 3 to 4 laboratory test results. 


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3 
TABLE OF CONTENTS 
1 
CLINICAL STUDY PROTOCOL .................................................................................... 1 
2 
SYNOPSIS ........................................................................................................................ 5 
3 
TABLE OF CONTENTS ................................................................................................. 13 
 
List of In-text Tables .................................................................................................. 17 
 
List of In-text Figures ................................................................................................. 17 
4 
LIST OF ABBREVIATIONS .......................................................................................... 18 
5 
INTRODUCTION ........................................................................................................... 20 
 
Background on Allergic Asthma ................................................................................ 20 
 
Background on Zavegepant ........................................................................................ 21 
5.2.1 
Clinical Experience ............................................................................................ 21 
CCI 
 
 
 
 
 
 
Clinical Risks/Benefits of Zavegepant ....................................................................... 23 
5.3.1 
Risks Associated With SARS-CoV-2 ................................................................ 23 
 
Study Rationale ........................................................................................................... 24 
5.4.1 
Dose Selection Rationale .................................................................................... 24 
6 
STUDY OBJECTIVES AND ENDPOINTS ................................................................... 26 
 
Study Objectives ......................................................................................................... 26 
6.1.1 
Primary Objective ............................................................................................... 26 
6.1.2 
Secondary Objectives ......................................................................................... 26 
CCI  
 
Study Endpoints .......................................................................................................... 26 
6.2.1 
Primary Endpoint ............................................................................................... 26 
6.2.2 
Secondary Endpoints .......................................................................................... 26 
CCI  
7 
INVESTIGATIONAL PLAN .......................................................................................... 28 
 
Description of Overall Study Design and Plan ........................................................... 28 
 
Discussion of Study Design ........................................................................................ 30 
 
End of Study ............................................................................................................... 30 


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8 
SELECTION OF STUDY POPULATION ..................................................................... 31 
 
Inclusion Criteria ........................................................................................................ 31 
 
Exclusion Criteria ....................................................................................................... 31 
 
Contraception and Reproductive Potential ................................................................. 34 
 
Screen Failures ............................................................................................................ 35 
 
Retesting During the Screening Period ....................................................................... 35 
 
Study Withdrawal, Removal, and Replacement of Subjects ...................................... 35 
8.6.1 
Lost to Follow-up ............................................................................................... 36 
9 
STUDY TREATMENT ................................................................................................... 37 
 
Zavegepant Investigational Product............................................................................ 37 
9.1.1 
Physical, Chemical, and Pharmaceutical Properties ........................................... 37 
9.1.2 
Study Drug Preparation ...................................................................................... 37 
9.1.3 
Storage and Use .................................................................................................. 37 
9.1.4 
Packaging and Labeling ..................................................................................... 37 
 
Non-Investigational Product ....................................................................................... 37 
 
Dosage and Administration ......................................................................................... 38 
9.3.1 
Method of Study Treatment Assignment ........................................................... 38 
9.3.2 
Blinding .............................................................................................................. 38 
 
Accountability and Compliance .................................................................................. 39 
 
Dosage Modification ................................................................................................... 39 
 
Prohibited and Concomitant Medications ................................................................... 40 
10 
STUDY PROCEDURES ................................................................................................. 43 
 
Informed Consent ....................................................................................................... 47 
 Study Procedures ........................................................................................................ 47 
10.2.1 
Part 1 – Screening Period ................................................................................... 47 
10.2.2 
Part 2 – Dosing/Treatment Period ...................................................................... 49 
10.2.3 
Visit 9: Onsite (Follow-up) ................................................................................ 51 
10.2.4 
Unscheduled Visit .............................................................................................. 51 
11 
EFFICACY ASSESSMENTS ......................................................................................... 52 
 
Efficacy, Clinical Performance, and Effectiveness ..................................................... 52 
11.1.1 
Methacholine Inhalation Tests ........................................................................... 52 
11.1.2 
Allergen Inhalation Challenge ............................................................................ 52 
11.1.3 
Sputum Induction ............................................................................................... 53 
11.1.4 
Skin Testing ........................................................................................................ 53 


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11.1.5 
Allergen Skin Titration ....................................................................................... 53 
12 
SAFETY ASSESSMENTS .............................................................................................. 55 
 
Adverse Events ........................................................................................................... 55 
 Serious Adverse Events .............................................................................................. 56 
12.2.1 
Definition of Serious Adverse Event .................................................................. 56 
12.2.2 
Collection and Reporting of Serious Adverse Events ........................................ 58 
12.2.3 
Pregnancy ........................................................................................................... 59 
12.2.3.1 
Reporting of Pregnancy ................................................................................ 59 
12.2.4 
Overdose ............................................................................................................. 60 
12.2.5 
Potential Drug Induced Liver Injury .................................................................. 60 
 
Demographics and Medical History ........................................................................... 60 
 Vital Signs .................................................................................................................. 61 
 Physical Examination.................................................................................................. 61 
 Electrocardiograms ..................................................................................................... 61 
 Spirometry .................................................................................................................. 62 
 Sheehan-Suicidality Tracking Scale ........................................................................... 62 
 Clinical Laboratory Tests ........................................................................................... 62 
13 
OTHER ASSESSMENTS ............................................................................................... 65 
CCI 
 
14 
PHARMACOKINETICS ANALYSIS ............................................................................ 66 
15 
STATISTICAL ANALYSIS ........................................................................................... 67 
 
Determination of Sample Size .................................................................................... 67 
 Analysis Populations ................................................................................................... 67 
15.2.1 
Analysis of Primary Efficacy Endpoints ............................................................ 68 
15.2.2 
Analysis of Secondary Efficacy Endpoints ........................................................ 68 
CCI  
 
Safety Analysis ........................................................................................................... 68 
 Interim Analysis .......................................................................................................... 69 
16 
STUDY MANAGEMENT .............................................................................................. 70 
 
Approval and Consent ................................................................................................ 70 
16.1.1 
Regulatory Guidelines ........................................................................................ 70 
16.1.2 
Institutional Review Board/Research Ethics Board/Independent Ethics Committee 
. ............................................................................................................. 70 
16.1.3 
Informed Consent ............................................................................................... 70 


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 Data Handling ............................................................................................................. 70 
 
Source Documents ...................................................................................................... 71 
 Record Retention ........................................................................................................ 71 
 Monitoring .................................................................................................................. 71 
 Quality Control and Quality Assurance ...................................................................... 72 
 Protocol Amendment and Protocol Deviation ............................................................ 72 
16.7.1 
Protocol Amendment .......................................................................................... 72 
16.7.2 
Protocol Deviations ............................................................................................ 72 
 Ethical Considerations ................................................................................................ 73 
 Financing and Insurance ............................................................................................. 73 
 Publication Policy and Disclosure of Data ................................................................. 73 
17 
REFERENCES ................................................................................................................ 74 


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List of In-text Tables 
Table 9-1. Prohibited Medications ............................................................................................40 
Table 9-2. Restricted Medications ............................................................................................41 
Table 10-1. 
Schedule of Assessments ..............................................................................44 
Table 12-1. 
Laboratory Assessments ...............................................................................63 
Table 15-1. 
Confidence Intervals (95%) for Observed Differences Between Zavegepant and 
Placebo in Maximum Percentage Decrease in Late Asthmatic Response (LAR) 
Forced Expiratory Volume in 1 Second (FEV1) ..........................................67 
 
 
 
List of In-text Figures 
Figure 1. Study Schematic ...................................................................................................... 29 


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4 
LIST OF ABBREVIATIONS 
 
Abbreviation 
Definition 
AE 
adverse event 
AHR 
airway hyperresponsiveness 
ALP 
alkaline phosphatase 
ALT 
alanine aminotransferase 
AST 
aspartate aminotransferase 
AUC 
area under the curve 
AUC0-24 
area under the curve 0 to 24 hours 
BID 
twice daily 
BMI 
body mass index 
CFR 
Code of Federal Regulations 
CGRP 
calcitonin gene-related peptide 
CIC 
Clinical Investigator Collaborative 
Cmax 
maximum concentration of drug 
COVID-19 
coronavirus disease 2019 
CTCAE 
Common Terminology Criteria for Adverse Events 
CYP3A4 
cytochrome P450 3A4 
EAR 
early asthmatic response 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
EDC 
electronic data capture 
eGFR 
estimated glomerular filtration rate 
ELISA 
enzyme-linked immunosorbent assay 
FEV1 
forced expiratory volume in 1 second 
GCP 
Good Clinical Practice 
GGT 
gamma-glutamyl transferase 
GMP 
Good Manufacturing Practice 
GM 
geometric mean 
GMP 
Good Manufacturing Practice 
HIPAA 
Health Insurance Portability Accountability Act 
IB 
Investigator’s Brochure 


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ICF 
informed consent form 
ICH 
International Council for Harmonisation 
IEC 
Independent Ethics Committee 
IN 
intranasal 
IP 
investigational product 
IRB 
Institutional Review Board 
ITT 
intent-to-treat 
IWRS 
interactive web-based response system 
LAR 
late asthmatic response 
MAD 
multiple ascending dose 
ODT 
orally disintegrating tablet 
PBS 
phosphate buffered saline 
PC20 
provocation concentration causing a 20% decline in forced 
expiratory volume in 1 second (FEV1) 
P-gp 
P-glycoprotein 
PK 
pharmacokinetic 
PNEC 
pulmonary neuroendocrine cells 
PPD 
Pharmaceutical Product Development 
QD 
once daily 
REB 
research ethics board 
SAD 
single ascending dose 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SGC 
soft gelatin capsule 
SOP 
standard operating procedure 
S-STS 
Sheehan-Suicidality Tracking Scale 
TEAE 
treatment-emergent adverse event 
TRP 
transient receptor potential 
ULN 
upper limit of normal 
WOCBP 
women of childbearing potential 


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5 
INTRODUCTION 
 
Background on Allergic Asthma 
Asthma is a chronic inflammatory disease with the defining feature of airway 
hyperresponsiveness (AHR). There are many causes of asthma, leading to multiple endotypes, 
with allergic or atopic asthma being the most common. Allergic asthma is an antigen-specific, 
T cell mediated disease that leads to increased bronchoconstriction, eosinophil infiltration, and 
cytokine release, which amplifies and perpetuates the response. Shortly after allergen inhalation, 
patients with allergic asthma experience airway obstruction leading to an early asthmatic 
 20% drop in forced expiratory volume in 1 second (FEV1) 
within 1 to 2 hours. Roughly 50% of these patients will experience a second bronchoconstriction 
event that is driven by inflammation during the 3 to 7 hours after exposure, leading to a drop in 
FEV1 
 15% known as the late asthmatic response (LAR). The LAR may last for hours to 
days, is less amenable to bronchodilator therapy, and contributes to the chronic pathophysiologic 
changes of asthma that affect patient quality of life. 
The neuroimmune axis plays several important roles in asthma, including AHR, antigen-sensing, 
immune response amplification, and in mediating the cough associated with asthma. Calcitonin 
gene-related peptide (CGRP) is a neuropeptide that plays a critical role in neuroimmune 
communication and has been shown in the literature to play a key role mediating the 
neuroimmune impacts on T cells, innate-immune cells, bronchoconstriction, and vasodilation. 
There are 2 primary sources of CGRP in the lung: transient receptor potential (TRP)-containing 
neurons and pulmonary neuroendocrine cells (PNECs). CGRP is a major component of vesicles 
within TRP-containing neurons, and animal models have suggested that these vesicles induce 
smooth muscle contraction in the airways (Tränkner et al 2014; Kim et al 2020; Springer et al 
2004). PNECs are located at branch-junction points in both the human and mouse lung in close 
proximity to innate lymphoid cells which are implicated as key mediators of allergic asthma. 
When PNECs encounter inhaled antigens, they release CGRP to directly activate type 2 innate 
lymphoid cells (ILC2s) and amplify their production of type 2 inflammatory cytokine responses 
such as IL-5 and IL-13 (Sui et al 2018). 
Lung samples from asthmatic patients show increased numbers of PNECs and increased CGRP 
reactivity, and asthmatic patients have elevated levels of CGRP in bronchial alveolar lavage fluid 
during the LAR (Sui et al 2018; Kay et al 2007). Furthermore, CGRP has been shown to bias 
CD4 + T cell polarization in animal models of inflammation, leading to amplified Th9 and Th17 
responses (Ding et al 2016; Mikami et al 2012). Taken together, these data indicate a potential 
pathogenic role of aberrant CGRP signaling in asthmatic patients by causing AHR, amplifying 
innate-immune responses to allergen, and polarizing CD4 + T cell responses toward an asthmatic 
T2 phenotype. 


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Both asthma and migraine can be viewed as chronic inflammatory diseases characterized by 
recurrent flares (“migraine attack”, “acute bronchoconstriction”) due to triggers (e.g., 
environmental allergens or dietary triggers) that stimulate an aberrant biological response due to 
an underlying hyperresponsive neuroimmune system. In fact, there is a significant overlap of 
migraine and asthma patients, with migraine patients also having an increased risk of asthma 
(Buse et al 2020). 
CGRP signaling impacts neurons, immune cells, and smooth muscle cells, and the CGRP 
receptor is located in central and peripheral nerves, smooth muscle cells, lymphocytes, dendritic 
cells, and macrophages. Zavegepant is a selective, competitive CGRP receptor antagonist being 
developed for the treatment of migraine. Zavegepant is being developed for intranasal (IN), oral 
soft gelatin capsule (SGC) and sublingual administration. Migraine, similar to asthma, is a 
chronic neuroinflammatory condition characterized by recurrent attacks triggered by external or 
internal stimuli with an underlying hyperresponsive state. CGRP receptor antagonism has been 
demonstrated to be safe and effective for both acute and preventive treatment of migraine. When 
used as an acute treatment for migraine attacks, CGRP receptor antagonists have been shown to 
reduce the frequency of subsequent attacks. This suggests that treatment of acute attacks 
decreases the hyperresponsiveness of the underlying disease state. 
The aim of this study is to test the hypothesis that CGRP receptor antagonism will mitigate the 
LAR and airway hyperresponsiveness by reducing excessive CGRP in allergic asthma. The study 
will use the third-generation small molecule CGRP receptor antagonist zavegepant. 
 
Background on Zavegepant 
CCI 
 
 
 
See Section 9.1 for further investigational product (IP) details; see also Sponsor’s zavegepant 
(BHV-3500) Investigator’s Brochure (IB) version 4.0 for IP SGC composition details. 
5.2.1 Clinical Experience 
A summary of the nonclinical and clinical investigational programs can be found in Sponsor’s 
current zavegepant BHV-3500 IB. 
CCI 
 
 


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CCI 
 
 
 
 
5.2.1.3  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. Preliminary data from 


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BHV3500-201 indicate that zavegepant as a single IN spray containing 5 mg, 10 mg, or 20 mg 
was well tolerated in adult subjects with moderate to severe migraine attacks and demonstrated a 
favorable safety profile compared 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 are 
provided in the current BHV-3500 IB. 
CCI 
 
 
 
 
 
Clinical Risks/Benefits of Zavegepant 
There are no changes in the overall risk benefit profile of zavegepant relative to version 4.0 of 
the IB. CCI 
 
Administration of 
zavegepant as a single IN 5 mg, 10 mg, and 20 mg spray was well tolerated in adult subjects with 
moderate to severe migraine and demonstrated a favorable safety profile CCI 
. 
Ongoing evaluation of blinded data in trials for oral zavegepant (BHV3500-103, BHV3500-107) 
suggest that the drug is well tolerated. The overall risk benefit profile remains unchanged. 
5.3.1 Risks Associated With SARS-CoV-2 
Certain provisions may be implemented to minimize potential hazards to study participants due 
to coronavirus disease 2019 (COVID-19). These provisions may allow adjustments to visit 
intervals; however, prior discussion and approval by Sponsor is required. 


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Investigators should be alerted to the development of COVID-19 and consider whether or not 
participation is in the subject’s best interest to continue participation in the trial. Investigators 
should consider early termination for subjects that develop COVID-19 confirmed or presumed 
infection during the screening period or before Visit 5. 
 
Study Rationale 
Biohaven Pharmaceuticals, Inc. is developing multiple formulations of zavegepant for treatment 
and prevention of migraines, including a new oral SGC of zavegepant (BHV-3500) for the 
treatment of migraine. Asthma, like migraine, can be viewed as a chronic inflammatory disease 
characterized by recurrent flares (“migraine attack”, “acute bronchoconstriction”) due to triggers 
(e.g., environmental allergens or dietary triggers) that stimulate an aberrant biological response 
due to an underlying hyperresponsive neuroimmune system. When used as an acute treatment for 
migraine attacks, CGRP receptor antagonists have been shown to reduce the frequency of 
subsequent attacks. This suggests that treatment of acute attacks decreases the 
hyperresponsiveness of the underlying disease state. 
The aim of this study is to test the hypothesis that CGRP receptor antagonism will mitigate the 
LAR and airway hyperresponsiveness by reducing excessive CGRP in allergic asthma. The goal 
of this study is to assess the efficacy and safety of twice daily (BID) dosing of zavegepant at an 
oral dose that produces systemic exposures similar to or greater than those produced from daily 
exposures from the 10 mg clinical dose given intranasally to treat acute migraine. Overall, the 
goal is to begin to evaluate CGRP receptor antagonism for long-term treatment of asthma. This is 
done with Global Initiative for Asthma (GINA) goals for asthma medications at the forefront, 
which are: (1) to achieve and maintain control symptoms; (2) to maintain normal activity levels, 
including exercise; (3) to maintain pulmonary function as close to normal as possible; (4) to 
prevent asthma exacerbations; (5) to avoid adverse effects from asthma medications; and (6) to 
prevent asthma mortality. 
Proof of concept will be demonstrated by measuring and comparing the LAR in zavegepant- 
treated versus placebo-treated mild allergic asthmatics who are exposed to allergen stimulus of 
their airways. This allergen-induced LAR will be evaluated after 28 days of BID dosing of 
150 mg oral zavegepant (total daily dose 300 mg) through direct comparison of the maximum 
percentage decrease in FEV1 between 3 and 7 hours after the allergen challenge in both groups. 
5.4.1 Dose Selection Rationale 
CCI 
 
 


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CCI 
 
In 
order to achieve s similar maximal inhibition of CGRP at peak concentration to that from a 10 
mg IN dose (minimum effective dose for the acute treatment of migraine headache), and 
continuous inhibition of CGRP throughout a dosing interval, a 150 mg BID dosing regimen has 
been selected for the current study. CCI 
 


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6 
STUDY OBJECTIVES AND ENDPOINTS 
 
Study Objectives 
6.1.1 Primary Objective 
 
To evaluate the allergen-induced LAR between subjects treated with zavegepant and 
placebo after 28 days of treatment. 
6.1.2 Secondary Objectives 
 
 
 
 
 
 
 
CCI  
To evaluate the allergen-induced EAR between subjects treated with zavegepant and 
placebo. 
To evaluate the allergen-induced AHR measured at 24 hours post-allergen, between 
subjects treated with zavegepant and placebo. 
To assess the safety and tolerability of oral zavegepant. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Study Endpoints 
6.2.1 Primary Endpoint 
 
Allergen-induced LAR assessed as maximum percentage decrease in FEV1 between 
3 and 7 hours after the administration of the allergen inhalation challenge. 
6.2.2 Secondary Endpoints 
Allergen-induced EAR assessed as maximum percentage decrease in FEV1 between 
0 and 2 hours after the administration of the allergen inhalation challenge. 
Allergen-induced change in AHR (methacholine PC20) at 24 hours post-allergen 
challenge. 
CCI 


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CCI  
Safety and tolerability of oral zavegepant assessed using the frequency of TEAEs and 
serious TEAEs through end of study, and clinically significant laboratory abnormalities. 
 
 


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7 
INVESTIGATIONAL PLAN 
 
Description of Overall Study Design and Plan 
This Phase 1b study is designed as a double-blind, parallel-group, randomized study of 
24 subjects to evaluate the safety and efficacy of 150 mg oral zavegepant (N=12) versus placebo 
(N=12) BID for the treatment of allergen-induced asthma. Individuals with stable, mild allergic 
asthma, with a history of episodic wheeze and shortness of breath, will be eligible for enrollment. 
The study will be divided into 2 parts. 
Part 1 (Screening period): A screening period of up to 28 days will be conducted to obtain a 
cohort of subjects with documented EAR (defined as  20% fall in FEV1 0 to 2 hours after 
allergen challenge) and LAR (defined as  15% fall in FEV1 3 to 7 hours after allergen 
challenge) to an inhaled incremental allergen challenge and AHR defined by methacholine PC20 
 16 mg/mL by inhaled incremental methacholine challenge. Procedures for allergen and 
methacholine challenges are specifically outlined in Section 11.1. 
At Visit 1, subjects will be confirmed for allergy by a skin prick test and assessed for safety by 
baseline clinical laboratory tests. Upon confirmation from blood tests that it is safe to proceed in 
Part 1, the subject will be scheduled for the screening allergen challenge triad which will occur 
over 3 consecutive days at Visits 2, 3, and 4. 
At Visit 2 (Day -15), subjects will be confirmed for allergy by a skin prick (only if procedure 
was not previously performed at Visit 1). At approximately 24 hours before the allergen 
challenge, subjects will be assessed for AHR by methacholine challenge (methacholine PC20 
must be  16 mg/mL), and a sputum sample will be induced. 
At Visit 3 (Day -14), subjects will be challenged with an allergen for which they tested positive 
on skin prick testing. At approximately 7 hours post-allergen challenge, a sputum sample will be 
induced. Spirometry will be measured regularly until 7 hours post-allergen challenge and a 
sputum sample will be induced after the last spirometry measurement. 
At Visit 4 (Day -13), at approximately 24 hours post-allergen challenge, methacholine challenge 
and sputum induction will be performed. 
Washout period: A rest/washout period of 2 to 4 weeks to confirm subject lung function and 
airway responsiveness to methacholine has recovered (e.g., return of FEV1 to within 90% of 
baseline and methacholine PC20 not more than 1 doubling dose lower than baseline). If more than 
4 weeks is required, Sponsor Medical Monitor should be consulted. 
Part 2 (Dosing period): Duration of study treatment in Part 2 will be approximately 28 days. 
At Visit 5/Day 1 (predose), a methacholine challenge will be performed. To continue to 
randomization, the subject’s baseline lung function (FEV1) and airway responsiveness to 
methacholine must show evidence of recovery to within 90% of baseline for FEV1 and not more 


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than 1 doubling dose below Visit 2 baseline for methacholine PC20. If these criteria are met, 
sputum will be induced. If subjects have not recovered from the screening allergen challenge, 
additional time will be allowed, and Visit 5 pre-dosing procedures may repeated. If additional 
retest is required, the screening period may be extended beyond 4 weeks. 
Subjects will then be randomized in a 1:1 ratio to receive 150 mg zavegepant or matching 
placebo to be taken BID. Subjects will take their first dose of zavegepant on a fasted stomach 
upon waking, and their second dose in the evening. Subjects should not consume food other than 
water for 1 hour after dosing. 
All subjects will be scheduled for their 3-day allergen challenge triad (Visit 6/~Day 26, 
Visit 7/~Day 27, and Visit 8/~Day 28). Morning doses will be taken before any laboratory 
procedures. Study treatment will end with the subject’s evening dose at Visit 8 (~Day 28). A 
follow-up period consisting of an onsite visit (Visit 9) will be conducted approximately 7 to 10 
days after the last study treatment. 
Additional dosing/fasting details are provided in Section 9.3. 
Figure 1 presents the general study schematic. 
Figure 1. 
Study Schematic 
 


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Discussion of Study Design 
Neuroimmune interactions have been linked to several chronic and inflammatory conditions, 
including asthma. While a heterogeneous disease comprising many different endotypes, all types 
of asthma share the pathognomonic feature of AHR. While multiple animal models deficient in 
CGRP signaling demonstrate blunted or resistant responses to allergen challenge, to date there 
has been no clinical study of a CGRP signaling antagonist in asthmatics. Based on the body of 
evidence, a trial of a safe CGRP signaling antagonist is warranted in the asthmatic setting. 
Zavegepant is an oral CGRP receptor antagonist with a strong safety profile, currently being 
studied in Phase 3 trials for the treatment of migraine. 
As CGRP is found in elevated concentrations in the sputum from those patients who experience 
an LAR event compared to non-responding patients, and there are observed changes in immune 
responses when CGRP is elevated toward an allergic asthmatic Th2/Th17 response, this study 
will focus on the allergic asthmatic population, and specifically the EAR and LAR to allergen. 
 
End of Study 
A subject will have fulfilled the requirements for study completion if/when the subject has 
completed all study periods, including follow-up, as indicated in the Schedule of Assessments 
(Table 10-1). 


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8 
SELECTION OF STUDY POPULATION 
Section 7.1 provides information regarding number of subjects planned to be enrolled and 
randomized in the study. 
 
Inclusion Criteria 
Individuals must meet all of the following criteria to be included in the study: 
 Subject must have mild intermittent asthma as defined by < 2 bronchodilator usage for 
treatment of asthma symptoms per week. 
 Baseline FEV1 
 70% of predicted value. 
 Age and reproductive status: 
a) Male and female subjects aged  18 
 years. 
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 8.3 for the definition 
of women of childbearing potential (WOCBP). 
c) Women must not be pregnant, lactating or breastfeeding. 
d) At the baseline Visit 5, prior to dispensing study drug, WOCBP must have a negative 
urine pregnancy test. 
  Subject’s score on the Sheehan-Suicidality Tracking Scale (S-STS) at screening must be 0. 
 Able to understand and give written informed consent and has signed a written informed 
consent form (ICF) approved by the investigator’s Institutional Review Board (IRB)/research 
ethics board (REB). 
  Able to understand and complete study-related questionnaires. 
  Willing and able to comply with study site visits and study-related procedures. 
The following inclusion criteria must be met for entry into the dosing phase (Part 2): 
 Positive methacholine challenge (PC20 
 
 Positive skin prick test to common aeroallergens (including but not limited to cat, dust mite, 
grass, pollen). 
 Positive allergen-induced early and late airway bronchoconstriction. 
 
Exclusion Criteria 
Individuals meeting any of the following criteria at screening or baseline are ineligible to 
participate in this study: 
 
 weeks prior to study entry. 
  Participation in any other investigational drug treatment protocol within the preceding 
30 days or 5 half-lives, whichever is longer, of an investigational drug product. 
 
 other than mild allergic asthma. 


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  Body mass index (BMI)  33.0 kg/m2. 
 Subjects who anticipate major changes in allergen exposure in their home or work 
environments that are expected to coincide with the baseline or the final assessments as 
assessed by the investigator. 
  History of liver disease. 
  History of HIV, hepatitis B or hepatitis C. 
 Use of tobacco products and/or vaping products within the previous 12 months or smoking 
history > 10 pack years. 
 Subjects should be excluded if they have a positive drug screen for drugs of abuse that, in the 
investigator’s judgment, is medically significant and would impact the safety of the subject 
or the interpretation of the study results. In addition: 
a) Detectable levels of amphetamines, barbiturates, benzodiazepines, tetrahydrocannabinol, 
cocaine, opiates, phencyclidine (PCP), or methadone. Retesting for positive results that 
are exclusionary is not allowed. 
b) Detectable levels of marijuana in the drug screen are not exclusionary if, in the 
investigator’s documented opinion, the subject does not meet Diagnostic and Statistical 
Manual of Mental Disorders Fifth Edition (DSM-5) criteria 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 has a concomitant disease or condition that could interfere with the conduct of the 
study, or for which the treatment might interfere with the conduct of the study, or which 
would, in the opinion of the investigator, pose an unacceptable risk to the subject in this 
study, including, but not limited to, cancer, alcoholism, drug dependency or abuse, or 
psychiatric illness. 
 History of alcohol dependency within the past 12 months, as determined by investigator, is 
exclusionary. 
 Use of any exclusionary, prohibited, or restricted medications (including restricted asthma 
medications) as outlined in Section 
. 
 Use of any drugs known to induce or inhibit hepatic drug metabolism, including St. John’s 
wort, within 30 days prior to the first dose of study drug. 
 History of anaphylaxis to any substance or a clinically important reaction to any drug. 
 Subject history with current evidence of uncontrolled, unstable, or recently diagnosed 
cardiovascular disease, such as ischemic heart disease, coronary artery vasospasm, and 
cerebral ischemia. 
 History of myocardial infarction, acute coronary syndrome, percutaneous coronary 
 months (24 weeks) 
prior to screening. 
 History of uncontrolled hypertension or uncontrolled diabetes; however, subjects can be 
included who have stable hypertension and/or diabetes for 3 months (12 weeks) prior to 


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Platelet count < 
 
screening; blood pressure > 140 mmHg systolic or 90 mmHg diastolic after 10 minutes of 
rest is exclusionary. 
 History of gastric or small intestinal surgery (including gastric bypass, gastric banding, 
gastric sleeve, gastric balloon, etc.), or has a disease that causes malabsorption. 
 History or diagnosis of Gilbert syndrome or any other active hepatic or biliary disorder. 
 History of gallstones or cholecystectomy. 
 Subject has hematologic or solid malignancy diagnosis within 5 years prior to screening. 
Subjects with a history of localized basal cell or squamous cell skin cancer are eligible for the 
study if they are cancer-free prior to the screening visit in this study. 
bilirubin, indirect bilirubin, and total bilirubin. Only abnormal values between 1 and 1.5 × 
 
 Any of the following abnormal laboratory test values at the screening visit: 
a) Hemoglobin < 12.0 
b) Estimated glomerular filtration rate (eGFR) according to the re-expressed abbreviated 
(4-variable) Modification of Diet in Renal Disease (MDRD) Study equation 
 40 
 
c) Total white blood cell (WBC) count < 
 
 
d) 
e) 
f) Creatine phosphokinase (CPK) > 5 × 
 
 Any of the following abnormalities on 12-lead ECG or blood pressure at screening Visit 1: 
a) 
b) 
 150 msec. 
c) Intraventricular conduction defect with a QRS duration  150 msec. 
d) 
  470 msec (Fridericia’s corrected QT interval). 
 Sex and reproductive status 
a) Females of childbearing potential who are unwilling or unable to use acceptable 
contraceptive methods or abstinence to avoid pregnancy for the entire study period and 
for 90 days after the study. See Section 8.3 for acceptable contraceptive methods. 
b) Women who are pregnant, lactating, or breastfeeding. 
c) Women with a positive pregnancy test. 
 History of a psychiatric disorder which, in the opinion of the investigator, would pose a 
safety risk to the subject or affect the subject’s participation in the trial. 
 Participation in a clinical research study involving the administration of an investigational or 
marketed drug or device within 30 days prior to the first dose of study drug, administration of 


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a biological product in the context of a clinical research study within 5 half-lives prior to the 
first dose of study drug, or concomitant participation in an investigational study involving 
drug or device administration. 
 Any reason which, in the opinion of the investigator, would prevent the subject from 
participating in the study. 
 
Contraception and Reproductive 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 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  12 consecutive months without another cause and a documented serum 
follicle stimulating hormone (FSH) level > 
. Note: FSH level testing is not 
required for women  
 of age with amenorrhea of  1 year 
-OR- 
 
 
Woman on hormone replacement therapy who no longer menstruate. 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 IP 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 in 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 signing the consent form through 90 days after 
dosing with study drug). The 2 methods should include 1 barrier method (e.g., condom with 
spermicidal gel, non-hormonal intrauterine devices, cervical cap with spermicidal gel) 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]) started at least 4 weeks prior to sexual intercourse. 
Males with partners who are WOCBP agree to use condoms with a spermicide during treatment 
and agree to encourage their partners to use one additional form of contraception for the duration 
of the study (i.e., this study begins with signing the consent form through 90 days after dosing 
with study drug). This additional form of contraception could be either a barrier method or a 


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hormonal contraceptive (e.g., hormonal or non-hormonal intrauterine devices, cervical cap with 
spermicidal gel, oral contraceptives, injectable contraceptives, patch, contraceptive implant). 
Males with vasectomies are considered surgically sterile provided the procedure occurred greater 
) 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 dose of study drug. 
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. 
All WOCBP must complete the pregnancy test schedule per Schedule of Assessments 
(Table 10-1). Women who suspect that they have become or may have become pregnant despite 
using proper birth control methods, should not take study drug and should immediately contact 
the investigator. 
 
Screen Failures 
Individuals who sign the ICF to participate in the study but who do not subsequently meet all the 
requirements as outlined in the inclusion and exclusion criteria will screen fail. There are some 
exceptions where retesting is permitted, as outlined in Section 8.5. 
 
Retesting During the Screening Period 
Retesting during the screening period does not require subject to reconsent for the trial. 
Subjects who fail the baseline requirement of FEV1 
 70% of predicted value or who do not meet 
 retested 1 time for each outcome. 
 
Study Withdrawal, Removal, and Replacement of Subjects 
Although the importance of completing the entire clinical study will be explained to the subjects, 
any subject is free to withdraw consent from the study at any time and for whatever reason, 
without any prejudice. The Sponsor and the investigator or designee may discontinue study drug 
or withdraw any participant from the study for reasons described below: 
 
subject request (consent withdrawal); 
 
safety reasons; 
 
non-compliance with study drug or protocol requirements; 
 
significant protocol deviation; 
 
positive pregnancy test. 


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If a subject discontinues study treatment and is withdrawn from the study for any reason, the 
study site must immediately notify the medical monitor. The date and the reason for study 
discontinuation must be recorded on the electronic case report form (eCRF). Subjects who 
complete or discontinue early from the study will be asked to complete the Visit 9 follow-up 
within 7 to 10 days of the last administration of study drug to complete assessments as indicated 
in the Schedule of Assessments (Table 10-1). 
In the event that a subject discontinues prematurely from the study because of a TEAE or serious 
TEAE, the TEAE or serious TEAE will be followed up until it resolves (returns to normal or 
baseline values) or stabilizes, or until it is judged by the investigator and medical monitor to no 
longer be clinically significant. 
Once a subject is withdrawn from the study, the subject may not reenter the study. 
Participants who withdraw or are withdrawn from the study after dosing may be replaced at 
Sponsor’s discretion. 
As soon as participant withdrawal is confirmed, sampling and scheduling will be stopped. Study 
exit procedures will be performed at the time of withdrawal from the study or as soon as possible 
thereafter. 
Additionally, the Sponsor may stop the study at any time for safety, regulatory, legal, or other 
reasons aligned with Good Clinical Practice (GCP). This study may be terminated at the 
discretion of the Sponsor or any regulatory agency. An investigator may choose to discontinue or 
stop the study at his or her study site for any reason, including safety or low enrollment. 
8.6.1 Lost to Follow-up 
A subject 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 subject fails to return to the clinic for a required study 
visit: 
The site must attempt to contact the subject 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 subject wishes to and/or should continue in the 
study. 
Before a subject is deemed lost to follow-up, the investigator or designee must make 
every effort to regain contact with the subject (where possible, 3 telephone calls and, if 
necessary, a certified letter to the subject’s last known mailing address). These contact 
attempts should be documented in the subject’s study files. 
Should the subject continue to be unreachable, he/she will be considered to have 
withdrawn from the study. 


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9 
STUDY TREATMENT 
 
Zavegepant Investigational Product 
Zavegepant (BHV-3500), formerly BMS-742413 vazegepant, is a high-affinity (Ki = 0.023 nM) 
small molecule antagonist at the human CGRP receptor under development for the treatment of 
migraine. A full complement of pharmacology, safety pharmacology, PK, metabolism, and 
toxicology studies were conducted to assess the efficacy and safety of zavegepant; details are 
provided in Sponsor’s IB. 
9.1.1 Physical, Chemical, and Pharmaceutical Properties 
Zavegepant SGC are manufactured by suspending the BHV-3500 hydrochloride in a mixture of 
medium chain triglycerides, glycerol monocaprylo caprate, polysorbate 80, colloidal silicone 
dioxide and D- 
-alpha tocopherol as excipients. Each SGC contains 25 mg of zavegepant 
(free base) for oral administration. 
9.1.2 Study Drug Preparation 
 
9.1.3 Storage and Use 
Zavegepant SGC capsules should be stored at 20 °C to 25 °C (
 °F to 77 °F) protected from 
light. Excursions to 15 °C to 30 °C are permitted. 
9.1.4 Packaging and Labeling 
All study drug supplies will be provided by the Sponsor (or third-party designee). 
Zavegepant 25 mg SGC or matching placebo will be packaged in blister packs and will hold 
48 capsules that are heat sealed into a wallet; 8 wallets will be placed into a subject specific 
carton/kit. The kits and wallets will have a unique identifier (kit/wallet number) included on the 
label. Each wallet will cover 4 day
apsules) dosing. Please 
reference the Pharmacy Manual for additional details. 
An interactive web-based response system (IWRS) system will be used to assign kits/wallets by 
a unique identifier to be dispensed to the subject. 
The blister packs will not require labeling, but kits/wallets will have a full clinical label on the 
outside and will contain information required by local regulations. 
 
Non-Investigational Product 
 applicable. 


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Dosage and Administration 
After subjects have met all eligibility requirements in Part 1 and completed the rest/washout 
period, they will be randomized in a 1:1 ratio to receive zavegepant or placebo. Investigational 
product will be dispensed at Visit 5. Subjects will take  25-mg capsules BID, in the morning 
and evening, for at least 28 days. Subjects should dose consistently at the same time of day, 
preferably in the morning and evening. Each dose of study drug should be taken while fasting 
(e.g., at least 1 hour before breakfast/first meal of the day for the first dose, and at least 4 hours 
after the previous meal for the second dose). Subjects should not consume food other than water 
for 1 hour after dosing. 
9.3.1 Method of Study Treatment Assignment 
After informed consent is obtained and study criteria is met at screening, the investigator or 
designee will obtain a subject number and treatment assignment via an IWRS. The IWRS system 
will assign a subject specific blinded study treatment kit that will contain 8 wallets, enough for 
the total treatment duration, to be dispensed to subjects. Once the kits/wallets have been 
assigned, they cannot be dispensed to another study subject. Sites will be responsible for 
recording the kit and wallet numbers dispensed to the subject on the Drug Accountability Form 
provided in the regulatory 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 
study participation. 
9.3.2 Blinding 
After the subject’s treatment assignment number is obtained from the IWRS, the number will be 
provided to the investigator or designee at the study center who is responsible for distribution of 
study treatment. The IP and placebo will be identical in appearance and labeled in a blinded 
manner. 
 subject, Sponsor personnel, or Sponsor designee will be 
unblinded to treatment assignment throughout the duration of the study unless unblinding is 
required. If an investigator becomes unblinded to a given subject’s study treatment, that subject 
will be discontinued from the study unless there are ethical reasons for the subject not to be 
discontinued; approval from the Sponsor’s medical monitor must be obtained in such instances. 
In the event that an emergency unblinding is required for a subject because of an AE or concerns 
for the subject’s safety or wellbeing, the investigator may break the randomization code for the 
subject via the IWRS. The investigator is responsible for notifying the medical monitor and/or 
Sponsor of such an event as soon as possible. The unblinding and its cause will also be 
documented in the eCRF. 


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Accountability and Compliance 
The blinded pharmacist or other designated individual at the study site will maintain records of 
study treatment delivered, manage inventory at the site, distribution and use by each subject, and 
the return of materials to the Sponsor for storage or disposal. These records should include dates, 
quantities, lot/kit/wallet numbers, expiration dates, in-clinic temperature log, and unique code 
numbers assigned to the product and study subjects. 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. The unused study drugs can only be destroyed after being inspected and 
reconciled by the responsible Study Monitor or the Sponsor’s designee. 
At each visit after initiation of treatment, study site personnel will record compliance of the 
subject with the assigned regimen. The same study drug kits/wallets dispensed at Visit 5 will be 
used for study drug dosing through Visit 8. Subjects will be instructed to bring kits/wallets 
containing unused/partially used/empty wallets back for inspection at each study visit, or 
unscheduled site visit, if applicable. Subjects are to be reminded of the importance of compliance 
with their assigned regimen, with an emphasis on taking their study drug on schedule and 
maintaining the prescribed interval between doses. 
Investigative site staff will maintain records that adequately document that the subjects were 
provided with the correct study treatment kits/wallets and reconcile the products received from 
the drug dispensing center. Investigational product will not be returned to the Sponsor until 
accountability is completed at the end of the study and all wallets and IP documentation has been 
fully monitored. 
Medication kits/wallets must be returned to the site at the end of the trial, as compliance will be 
assessed by capsule counts. Subjects have to be counseled on the importance of taking the study 
drug as directed. If poor compliance continues, (i.e., more than 1 missed dose in a week or 
cancellation of any site visit) discontinuation of the subject from the trial should be considered. If 
there are concerns about subject compliance, contact the clinical research organization 
(CRO)/Sponsor for guidance. 
The morning dose of study drug treatment at Visits 5 through 8 will be supervised for 
compliance by study site personnel. 
 
Dosage Modification 
Dose modification is not allowed in this trial. 


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Prohibited and Concomitant Medications 
All concomitant medication and therapy, including vaccines, used from 30 days before trial 
participation through end of study should be documented on the eCRF. This includes both 
prescription and non-prescription drugs. 
The use of any CGRP receptor antagonist treatment or CGRP antibody is prohibited from 
 months prior to the screening until study completion/early termination. 
Chronic use of any other medication for treatment of allergic lung disease other than short-acting 
ß2-agonists is prohibited. 
See Table 9-1 and Table 9-2 for prohibited and restricted medications, respectively. 
Table 9-1. 
Prohibited Medications 
 
Prohibited medications 
Restriction window/Washout 
CGRP-targeting medications (prophylactic or 
acute) 
 Screening 
Anti-IgE therapy 
Allergy immunotherapy 
5 months before Screening 
4 months before Screening 
Investigational drug 
30 days or 5 half-lives (whichever is longer) 
before Screening 
Systemic corticosteroids 
Inhaled corticosteroids 
Topical nasal corticosteroids 
Immunosuppressives 
Anticoagulants 
Theophylline 
 
Modafinil 
St. John’s wort 
28 days before Screening 
Atypical antipsychotics such as aripiprazole, 
olanzapine, quetiapine, ziprasidone, or 
risperidone 
12 months prior to Screening 
Mood stabilizers such as lithium, lamotrigine or 
divalproex/valproic acid/valproate 
12 months prior to Screening 
Strong cytochrome P450 3A4 (CYP3A4) 
inhibitors or inducers (list below is not all- 
inclusive): 
Inhibitors: clarithromycin, cobicistat, conivaptan, 
danoprevir and ritonavir, elvitegravir and 
ritonavir, indinavir and ritonavir, itraconazole, 
ketoconazole, lopinavir and ritonavir, 
nefazodone, nelfinavir, paritaprevir and 
28 days or 5 half-lives (whichever is longer) 
before Screening 
If use of a strong CYP3A4 inhibitor or inducer is 
required during the trial, dosing should be 
stopped and should not start again until 14 days 
after the last dose of the strong CYP3A4 
inhibitor/inducer 


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Prohibited medications 
Restriction window/Washout 
ritonavir and (ombitasvir and/or dasabuvir), 
posaconazole, ritonavir, saquinavir and 
ritonavir, tipranavir and ritonavir, 
troleandomycin, voriconazole 
Inducers: apalutamide, carbamazepine, 
phenobarbital, phenytoin, rifampin, rifapentine, 
St. John’s wort 
Potent P-glycoprotein (P-gp) inhibitors or 
inducers (list below is not all-inclusive): 
Inhibitors: amiodarone, clarithromycin, 
cyclosporine, dronedarone, itraconazole, 
lapatinib, propafenone, quinidine, ritonavir, 
verapamil 
Inducers: carbamazepine, phenobarbital, 
phenytoin, rifampin, St. John’s wort 
28 days or 5 half-lives (whichever is longer) 
before Screening 
If use of potent P-gp inhibitor or inducer is 
required during the trial, dosing should be 
stopped and should not start again until 14 days 
after the last dose of potent P-gp 
inhibitor/inducer 
 
-acting beta-agonists 
-acting anticholinergics 
Antimuscarinics 
14 days before Screening 
-steroidal anti-inflammatory drugs 
3 days before Screening 
Sources: US FDA Table of Substrates, Inhibitors and Inducers; Hachad et al., 2010 
Table 9-2. 
Restricted Medications 
 
Restricted Medications 
Restriction Window 
Short-acting beta2 agonists 
Short-acting anticholinergics 
8 hours before all study visits 
Aspirin 
7 days before allergen challenge and dosing 
Short-acting antihistamines 
3 days before allergen challenges 
Intermediate-acting antihistamines 
4 days before skin testing and allergen challenges 
-acting antihistamines 
9 days before skin testing and allergen challenges 
Acetaminophen 
imited to no more than 1000 mg/day for a 
maximum of 2 consecutive days 
Inhaled corticosteroids 
Systemic corticosteroids 
If rescue treatment is required during the screening 
period, 1-week washout from acute dosing 
Methlyxanthines 
4 hours before spirometry 
-acting beta-agonist 
If rescue treatment is required during the screening 
period, 2-week washout from acute dosing 
OTC drugs, including cold and allergy 
medications 
72 hours prior to methacholine and allergen 
challenges 


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 include: 
 
 
 
hours prior to study visits. 
study visits. 
-containing products or medications for 12 hours prior to methacholine and 
allergen challenges. 


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10  STUDY PROCEDURES 
Table 10-1 outlines the timing of procedures and assessments to be performed throughout the 
study. See Section 11 and Section 12 for additional details regarding efficacy assessments and 
safety assessments, respectively. Section 12.9 specifies laboratory assessment samples to be 
obtained. 


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Table 10-1. 
Schedule of Assessments 
 
Part 1: Screeninga 
2-4 Week 
Washout 
From 
Screening 
Part 2: Dosing/Treatment 
Follow-up 
Visit # 
1 
2 
3 
4 
5 
6 
7 
8 
9 
3-Day Allergen Triad 
3-Day Allergen Triad 
Day(s) 
-29 
to -16 
-15 
(±3d) 
-14 
(±3d) 
-13 
(±3d) 
1b 
~26 
(+ 3d) 
~27 
(+ 3d) 
~28 
(+ 3d) 
~35 - 41 
Informed consent 
X 
Inclusion/Exclusion 
criteria 
X 
X 
X 
X 
Demographics/ 
Medical history/medication 
history 
X 
Vital signs 
X 
X 
X 
X 
X 
Physical examination, 
including BMIc 
X 
X 
Electrocardiogram 
X 
X 
Spirometry 
X 
X 
X 
X 
X 
X 
X 
X 
Pregnancy testd 
X 
X 
X 
Clinical laboratory tests 
(hematology, chemistry) 
X 
X 
X 
X 
Urinalysis 
X 
X 
X 
Urine drug testing 
X 
Allergy skin (prick) test 
X 
Methacholine challenge 
X 
X 
X 
X 
X 
Sputum induction 
X 
X 
X 
X 
X 
X 
X 
Allergen skin titration teste 
X 
X 


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Part 1: Screeninga 
2-4 Week 
Washout 
From 
Screening 
Part 2: Dosing/Treatment 
Follow-up 
Visit # 
1 
2 
3 
4 
5 
6 
7 
8 
9 
3-Day Allergen Triad 
3-Day Allergen Triad 
Day(s) 
-29 
to -16 
-15 
(±3d) 
-14 
(±3d) 
-13 
(±3d) 
1b 
~26 
(+ 3d) 
~27 
(+ 3d) 
~28 
(+ 3d) 
~35 - 41 
Allergen inhalation 
challenge 
X 
X 
Randomization and 
Dosingf, g 
X 
X 
X 
X 
Meal and Daily Study 
Drug Dosing Diaryh 
X 
X 
X 
X 
Pharmacokinetic samplingi 
X 
X 
X 
Ongoing and concomitant 
medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Adverse events 
X 
X 
X 
X 
X 
X 
X 
X 
S-STS 
X 
X 
X 
Abbreviations: BMI=body mass index; d=day; ECG=electrocardiogram; FEV1= forced expiratory volume in 1 second; h=hour(s); max=maximum; 
min=minimum; PC20=provocation concentration causing a 20% decline in FEV1; SABA= short-acting beta-agonists; S-STS=Sheehan-Suicidality Rating Scale; 
WOCBP=women of childbearing potential. 
 
a Part 1: All screening procedures will be completed and results returned within Days -29 to Day -13. 
b Part 2/Day 1: Subjects will be confirmed as recovered on Day 1 (e.g., confirmation of hyperresponsiveness recovery of methacholine PC20 not more than 
1 doubling dose lower than baseline; return to FEV1 within 90% of baseline) prior to initiation of dosing. 
c A full examination will be performed at screening and at follow-up. BMI will be calculated at Screening Visit 1. 
d Serum pregnancy test conducted at screening; urine pregnancy testing at all other visits as indicated. Results of the pregnancy test are required before dosing. 
Source documents should document that WOCBP agree to use 2 effective forms of contraception and men with WOCBP partners agree to use condoms with a 
spermicide during treatment. 
e Allergen skin titration test can be performed at either Visit 1 or Visit 2 to allow for flexibility. 
f After randomization, daily dosing in Part 2 from Visit 5 through Visit 8, inclusive. 
 onsite visit required after start of study medication at Visit 5 to start of 
allergen triad (Visit ). Every effort should be made to conduct the study visits within the specified windows in Part 2. However, if necessary due to local 
COVID-19 safety requirements, visits may be performed outside of these windows in order to minimize any potential risks to subject safety and to comply 
with governmental and institutional guidance. 


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g Subjects should dose consistently at the same time of day, preferably in the morning and evening. Each dose of study drug should be taken while fasting (e.g., 
at least 1 h before breakfast/first meal of the day for the first dose, and at least 4 h after the previous meal for the second dose). Subjects should not consume 
food other than water for 1 h after dosing. 
h Subjects will be asked to complete a daily diary to capture date and times of both meals and study drug administration. 
i Pharmacokinetic sampling to be conducted predose on Visits 6, 7, and 8, and additionally at Visit 7 at approximately 1 (+ 0.5 h) h and 3 (+/- 0.5 h) h postdose. 
Subjects should be instructed to hold their daily dose of study drug on the morning of Visits 6, 7, and 8 and arrive at the clinic after an overnight fast. Exact 
times of dosing and PK sample collection will be documented. 


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 Informed Consent 
Before performing any study-related procedures, the investigator (or designee) will obtain a 
signed ICF from each subject. Further guidance requirements for ICFs are outlined in 
Section 16.1.3. 
For rescreening of subjects, see Section 8.4 for informed consent requirements. 
 Study Procedures 
Assessments and their timing are to be performed as outlined in the Schedule of Assessments 
(Table 10-1). If necessary due to local COVID-19 safety requirements, visits may be performed 
outside of these windows in order to minimize any potential risks to subject safety and to comply 
with governmental and institutional guidance. 
Efficacy, clinical performance, and effectiveness assessments are described in Section 11 and 
include methacholine inhalation tests, allergen inhalation challenge, sputum induction, allergy 
skin test, and allergy skin titration. 
Safety assessments are described in Section 12 and include AEs, physical examinations, vital 
signs, ECGs, and laboratory assessments. 
10.2.1 Part 1 – Screening Period 
The screening period includes screening procedures to determine initial eligibility (Visit 1) and 
methacholine and allergen challenge assessments (Visits 2, 3, and 4). The subject must undergo 
and pass all eligibility assessments in order to participate in the Part 2 dosing phase of the study. 
Visit 1: Day -29 to Day -16 (onsite) 
 
Written informed consent will be obtained. 
 
Inclusion/exclusion will be assessed. 
 
Demographics, medical history, and medication history will be obtained and recorded. 
 
Concomitant and ongoing medications will be recorded. 
 
Vital signs will be measured (sitting blood pressure [systolic and diastolic blood 
pressure], heart rate, respiratory rate, body temperature). 
 
A physical examination will be performed, including BMI. 
 
A resting 12-lead ECG will be performed; subject should be in a resting, supine, or 
semi-recumbent position for at least 5 minutes. 
 
Spirometry measurements will be performed. 
 
WOCBP will undergo serum pregnancy testing. This pregnancy test must be negative in 
order for the subject to participate in the study and receive drug. WOCBP must await the 
results of the pregnancy test before receiving drug. WOCBP and men with partners of 


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childbearing potential must also use effective contraception during treatment; see 
Section 8.3 for details. 
 
Blood samples for hematology and chemistry will be obtained; urine samples will be 
obtained for urinalysis and drug testing. 
 
Allergic status will be documented by skin prick testing against common airborne 
allergens (e.g., cat, dust mite, grass, pollen). 
 
An S-STS will be conducted; subject score must be 0 to be eligible to enroll. 
Visits 2, 3, and 4: ~Days -15, -14, -13 
 
Inclusion/exclusion will be assessed. 
 
AEs, concomitant medications, and ongoing medications will be recorded. 
 
Spirometry measurements will be taken. 
3-Day Allergen Triad 
Visit 2: Allergen skin titration (only if procedure was not previously performed at Visit 1), 
methacholine challenge, and sputum induction will be performed. At approximately 24 hours 
before the allergen challenge, subjects will be assessed for AHR by methacholine challenge 
(methacholine PC20 
 and a sputum sample will be induced. 
Visit 3: Allergen inhalation challenge and sputum induction will be performed. Subjects will 
be challenged with an allergen to which they tested positive on skin prick testing. Spirometry 
will be measured regularly until 7 hours post-allergen challenge and a sputum sample will be 
induced after the last spirometry measurement. 
Visit 4: Methacholine challenge and sputum induction will be performed at approximately 
24 hours post-allergen challenge. 
remental allergen and 
methacholine challenges will be eligible for entry into Part 2 of the study. 
Washout Period (2-4 weeks) 
A rest/washout period will follow to confirm subject lung function and airway responsiveness 
(AHR) to methacholine has recovered (e.g., return of FEV1 to within 90% of baseline and 
methacholine PC20 not more than 1 doubling dose lower than baseline). If more than 4 weeks is 
required, Sponsor Medical Monitor should be consulted. 


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10.2.2 Part 2 – Dosing/Treatment Period 
Visit 5: Onsite Day 1 (predose) 
 
Review inclusion/exclusion criteria to verify eligibility to enter the dosing period. 
Note: If subject does not recover to an FEV1 within 90% of baseline, additional washout 
time will be allowed, and the Visit 5 predose procedures may be repeated. If additional 
retest is required, the screening period may be extended beyond 4 weeks. If these criteria 
are met, sputum will be induced. 
 
Vital signs will be recorded. 
 
Spirometry measurements will be recorded. 
 
AEs, concomitant medications, and ongoing medications will be recorded. 
 
Blood samples for hematology and chemistry will be obtained. 
 
A urine sample for urinalysis will be obtained. 
 
WOCBP will have a urine pregnancy test performed; a negative result must be obtained 
before study drug treatment may be administered. 
 
A methacholine challenge will be performed; sputum will be induced. 
 
S-STS will be conducted. 
 
Dispensation of Meal and Daily Study Drug Dosing Diary. 
Randomization and first dose: After predose assessments are conducted during Visit 5, 
subjects will be randomized (per IWRS) to receive zavegepant or placebo study treatment. 
Subjects will take their first prescribed dose onsite at the clinic and should continue to take their 
dose consistently at the same time of day, preferably once in the morning and once in the 
evening, through Visit 8. Each dose of study drug should be taken while fasting (e.g., at least 
1 hour before breakfast/first meal of the day for the first dose, and at least 4 hours after the 
previous meal for the second dose). Subjects should not consume food other than water for 
1 hour after dosing. 
3-Day Allergen Triad 
Visit 6: Onsite (pre-allergen challenge) 
 
Subjects will be asked to provide the time of their evening dose and meal on evening 
before this visit. 
 
After having fasted overnight; a blood sample for PK measurement will be collected for 
zavegepant concentration measurement (predose). Subjects will take the morning dose 
onsite at the clinic and should not consume food other than water for 1 hour after dose. 
Exact time of dosing and PK sample collection will be documented. Study procedures 
may begin immediately after dosing. 
 
Vital signs will be recorded. 
 
Spirometry measurements will be recorded. 


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AEs, concomitant medications, and ongoing medications will be recorded. 
 
A methacholine challenge will be conducted; sputum will be induced postdose. 
 
Verification that subject is completing their Meal and Daily Study Drug Dosing Diary. 
Visit 7: Onsite (allergen challenge) 
 
Subjects will be asked to provide the time of their evening dose and meal on evening 
before this visit. 
 
After having fasted overnight; a blood sample for PK measurement will be collected for 
zavegepant concentration measurement (predose). 
 
Subjects will take the morning dose onsite at the clinic and should not consume food 
other than water for 1 hour after dose. Study procedures may begin immediately after 
dosing. 
 
Allergen inhalation challenge will be conducted postdose in the morning; spirometry will 
be measured until 7 hours, and sputum will be induced 7 hours post-allergen challenge. 
 
Additional blood samples to measure zavegepant concentrations will be collected at 
approximately 1 (+ 0.5h) hour and 3 (+/- 0.5h) hours postdose. Exact times of dosing and 
PK sample collection will be documented. 
 
Vital signs and spirometry will be recorded. 
 
AEs, concomitant medications, and ongoing medications will be recorded. 
 
Verification that subject is completing their Meal and Daily Study Drug Dosing Diary. 
Visit 8: Onsite (post-allergen) 
 
Subjects will be asked to provide the time of their evening dose and meal on evening 
before this visit. 
 
After having fasted overnight; a blood sample for PK measurement will be collected for 
zavegepant concentration measurement (predose). Subjects will take the morning dose 
onsite at the clinic and should not consume food other than water for 1 hour. Exact times 
of dosing and PK sample collection will be documented. 
 
Vital signs will be measured. 
 
Spirometry measurements will be performed. 
 
Pregnancy test conducted for WOCBP. 
 
Hematology, chemistry, and urine samples will be obtained. 
 
AEs, concomitant medications, and ongoing medications will be recorded. 
 
A methacholine challenge will be performed postdose in the morning (24 hours 
[± 3 hours] after the Visit 7 allergen challenge); sputum will be induced. 
 
Final S-STS will be conducted. 
 
Verification and collection of Meal and Daily Study Drug Dosing Diary. 


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10.2.3 Visit 9: Onsite (Follow-up) 
 
A physical examination will be performed, including BMI. 
 
A resting 12-lead ECG will be performed; subject should be in a resting, supine, or 
semi-recumbent position for at least 5 minutes. 
 
Clinical laboratory tests 
 
AEs, concomitant medications, and ongoing medications will be recorded. 
10.2.4 Unscheduled Visit 
The investigator may, at his/her discretion, arrange for a subject to have an unscheduled 
assessment, especially in the case of AEs that require follow-up or are considered by the 
investigator to be possibly related to the use of study drug. The unscheduled visit page in the 
eCRF must be completed. 
Study discontinuation procedures are described in Section 8.6. 


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11  EFFICACY ASSESSMENTS 
 Efficacy, Clinical Performance, and Effectiveness 
Spirometry and lung function will be assessed after each study dose treatment at Visit 5 through 
Visit 8 per Table 10-1. Methacholine PC20 and airway inflammation will be assessed before and 
after study dose treatment, and allergen-induced methacholine PC20, allergen-induced 
bronchoconstriction, and allergen-induced airway inflammation will be assessed following 
allergen challenges. 
11.1.1 Methacholine Inhalation Tests 
Methacholine inhalation will be carried out using the method described by Cockcroft et al. and in 
accordance with AllerGen standard operating procedure (SOPs). A filter will be positioned on 
the exhalation-side of the 3-way valve to prevent methacholine from being nebulized/exhaled 
into the room. Briefly, methacholine is inhaled from a Hans Rudolf valve connected to a Wright 
breathe normally from the mouthpiece during the 2-minute inhalation period. Subjects inhale 
normal saline, then double concentrations of methacholine for 2 minutes. FEV1 is measured at 
30 and 90 seconds after each inhalation and, if necessary, at 180 and 300 seconds and beyond 
until the lowest response is captured. The test is terminated when a fall in FEV1 of at least 20% 
(lowest post diluent FEV1 versus lowest post methacholine concentration FEV1) occurs, and the 
methacholine PC20 is calculated. The PC20 assessment will be performed at the start of each 
treatment period, then 24 hours before and 24 hours following allergen challenge as a measure of 
AHR. 
11.1.2 Allergen Inhalation Challenge 
Allergen inhalation challenge will be performed as described by O’Byrne (O’Byrne et al 1987), 
in accordance with AllerGen SOPs. The concentration of allergen extract for inhalation will be 
determined from a formula described by Cockcroft (Cockcroft et al 2005b). Doubling 
concentrations of allergen will be given until a 20% decline in FEV1 is measured 10 minutes 
post-allergen inhalation versus baseline FEV1. The FEV1 will then be measured at regular 
intervals: 10, 20, 30, 45, 60, 90, 120 minutes, and 3, 4, 5, 6 and 7 hours after allergen inhalation 
 20% fall in FEV1 (EAR) and  15% fall in FEV1 
); the same final 
3 doses of allergen administered during the screening period are administered during the dosing 
period challenge. The early bronchoconstrictor response (i.e., EAR) is taken to be the largest fall 
in FEV1 within 2 h
 
the largest fall in FEV1 between 3 and 7 hours after allergen inhalation. 
Allergen extracts manufactured following Good Manufacturing Practice (GMP) guidelines will 
be selected, prepared by study staff, and administered to the subjects by inhalation in accordance 
with procedures approved by Health Canada. Doubling concentrations of allergen will be 


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prepared by staff and administered to the subjects by the 2-minute tidal breathing inhalation 
method as described for methacholine and in accordance with procedures approved by Health 
Canada. A filter will be positioned on the exhalation-side of the 3-way valve to prevent allergens 
from being nebulized/exhaled into the room. 
11.1.3 Sputum Induction 
Sputum will be induced and processed using the method described by Pizzichini (Pizzichini et al 
2002) and summarized. This procedure will be performed during the screening period at 
24 hours before allergen challenges, and at 7 and 24 hours after allergen challenges, at the start 
of each treatment period, again at 24 hours before allergen challenges, and at 7 and 24 hours 
after allergen challenges. CCI 
CCI 
 
 
11.1.4 Skin Testing 
An allergy skin test, also called a skin prick test, will be used to determine the allergen that is 
given to each patient in the inhalation allergen challenge. It is performed by applying an extract 
of an allergen to the skin, scratching or pricking the skin to allow exposure, and then evaluating 
the local reaction in the skin. Standard allergen extracts for the following allergens will include, 
but are not limited to, ragweed, tree mix, grass mix, dog, cat, horse, feathers, dust mites 
(Dermatophagoides farinae and D. pteronyssinus), Alternaria, and Aspergillus. A positive 
 to the skin. If an 
allergen provokes an allergic reaction, a raised itchy bump (wheal) and redness (flare) develops. 
The size of the wheal (the raised area, not the redness) will be measured and recorded with a 
ruler in millimeters in the horizontal and vertical directions, perpendicular to each other after 
approximately 15 minutes. The size of the wheal for each antigen will be recorded on the Skin 
Test Form, along with any observed adverse reaction or event and any actions taken. A reaction 
greater than 2 × 2 mm will be regarded as positive, provided that the positive and negative 
controls are appropriately positive (histamine) and negative (diluent), respectively. The 
investigator will choose an allergen for inhalation on the basis of the largest skin response. This 
procedure will be completed in accordance with the CIC allergy skin testing by epicutaneous 
method (prick) SOP at McMaster University (Hamilton, Ontario, Canada). 
11.1.5 Allergen Skin Titration 
An allergy skin titration test is used to identify the lowest titration of allergen that causes a skin 
wheal at least 2 × 2 mm in size. It is performed by applying serial dilutions of a selected allergen 
extract to the skin, scratching or pricking the skin to allow exposure, and then measuring the 
skin's reaction with a ruler. The diameter of each wheal is measured in 2 perpendicular directions 


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after 10 minutes. The average wheal diameter for each dilution in the horizontal and vertical 
directions is recorded on the worksheet (i.e., 4 × 3 mm). The weakest dilution of allergen that 
produces an average wheal of at least 2 × 2 mm is the “skin test endpoint.” This measurement is 
used to calculate the starting allergen dose for inhalation. 


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12  SAFETY ASSESSMENTS 
 Adverse Events 
An AE is defined as any new untoward medical occurrence or worsening of a pre-existing 
medical condition in a subject or clinical investigation subject administered an investigational 
(medicinal) product and that does not necessarily have a causal relationship with this treatment. 
An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory 
finding for example) symptom, or disease temporally associated with the use of the IP, whether 
or not considered related to the IP. 
AEs 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. 
The collection of non-serious AE information should begin from the time of informed consent 
through the follow-up period (7 to 10 days after last visit). Non-serious AE information should 
also be collected from the start of a placebo lead-in phase or other observation period intended to 
establish a baseline status for a subject. 
Unchanged, chronic conditions, or those related to the underlying disease or medical conditions 
that are consistent with natural disease progression are not considered AEs and should not be 
recorded on AE pages of the eCRF unless there is an exacerbation of a chronic condition. 
Definition of terms related to all Adverse Events (both 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. 
 
-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. 


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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 judgment and 
according to the following categories: 
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 2 types of AEs: SAEs and non-serious AEs. 
 Serious Adverse Events 
SAEs will be collected from the time of informed consent and for the duration of the study. 
SAEs and AEs listed in the Sponsor’s IB will be considered expected events. See the Sponsor IB 
for additional details of drug expected AEs. 
12.2.1 Definition of Serious Adverse Event 
An SAE is any event that meets any of the following criteria at any dose: 
 
results in death, 
 
is life-threatening, 
 
results in inpatient hospitalization or prolongation of existing hospitalization, 
 
results in persistent or significant disability/incapacity 


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is a congenital anomaly/birth defect. 
 
Other: Important medical events that may not result in death, be life-threatening, or 
require hospitalization, may be considered an SAE when, based upon appropriate 
medical judgment, they may jeopardize the subject and may require medical or 
surgical intervention to prevent one of the outcomes listed in this definition. 
Examples of such events are (but not limited to): 
 
o Intensive treatment in an emergency room or at home for allergic bronchospasm 
o Blood dyscrasias or convulsions that do not result in inpatient hospitalization 
o Development of drug dependency or drug abuse 
o Potential drug induced liver injury (see Section 12.2.5) 
o Abuse or overdose of medication 
 
Potential study medication abuse (including cases of excessive non- 
compliance with study medication dosing instructions or subjects who 
discontinue treatment without returning study medication) should be 
documented in the source record and reported as an AE or SAE as 
appropriate. Investigators must monitor subjects for possible cases of 
abuse of study medication (subjects taking study drug for non-therapeutic 
purposes, e.g., for psychoactive effects such as high feeling or euphoria). 
Investigators should obtain more information and explanation from 
subjects when there are study drug accountability discrepancies. 
 
Potential study medication overdose is defined in Section 12.2.4. 
 
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); 


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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. 
12.2.2 Collection and Reporting of 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 at follow-up, up to 10 days after last 
dose treatment. 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. 
All SAEs, whether considered related or not related to study drug, overdose, potential drug 
induced liver injury (
), or pregnancy, 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 IRB/REB as per the reporting requirements. Additionally, the investigator, or designated 
staff, is responsible for entering the SAE information into the eCRF with event term, start/stop 
dates, causality, and severity. 
For this study, SAEs will be captured through electronic data capture (EDC) and on the SAE 
report form. Any SAE must be reported immediately (or no later than 24 hours after awareness 
of the event) to Pharmaceutical Product Development (PPD) Pharmacovigilance (PVG) using the 
SAE report form and transmitted by facsimile (fax), which is the preferred method of 
submission: 
 
North America – 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 – 1-800-201-8725 


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If only limited information is initially available, follow-up reports are required. If an ongoing 
SAE changes in its intensity or relationship to study drug or if new information becomes 
available, a follow-up SAE report should be sent within 24 hours of the investigator becoming 
aware of the updated information using the same procedure used for the transmission of the 
initial SAE and the same event term should be used. 
The minimum information required for an initial SAE report is: 
 
Sender of report (site number, investigator name) 
 
Subject identification (subject number) 
 
Protocol number (BHV-3500-204) 
 
SAE term (if an SAE is being reported) 
12.2.3 Pregnancy 
Following the baseline visit or at any time during the study it is discovered that a subject is 
pregnant or may have been pregnant at the time of the study drug exposure, including during at 
least 6 half-lives after study drug administration, the study drug 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 by the 
subject (i.e., follow-up procedures per Table 10-1). 
12.2.3.1 Reporting of Pregnancy 
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 Medical Monitor (or 
designee) of the event and complete the Pregnancy Report Form in accordance with SAE 
reporting procedures as described in Section 12.2.2. The pregnancy should be reported using 
paper forms, which should be faxed to PPD PVG, which is the preferred method of submission, 
within 24 hours after investigator/site awareness of the event: 
North America – 1-888-488-9697 
In the event the Pregnancy Report Form cannot be faxed or emailed, it must be reported via 
phone to the PPD Safety Hotline at: 
North America – 1-800-201-8725 
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. 


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Any pregnancy that occurs in a female partner of a male study participant should be reported to 
the Sponsor (or designee), and information on the pregnancy will be collected on the Pregnancy 
Report Form, as appropriate. 
12.2.4 
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 zavegepant BHV-3500) 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 > 12 capsules instead of prescribed dose of 
12 capsules in one calendar day) should be reported as a protocol deviation. 
12.2.5 
Potential Drug Induced Liver Injury 
Wherever possible, timely confirmation of the initial liver-related laboratory abnormalities 
 
meeting the defined criteria, must be reported as SAEs as per Section 12.2.2. 
 
1.  
 3 × 
 
AND 
2. 
 2 × the 
s (elevated serum 
alkaline phosphatase) 
AND 
3. 
 
 
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. 
 
 
(or designee) should immediately be contacted for further instruction and decision of whether the 
subject must be discontinued from the trial and appropriate follow-up requirements. 
 Demographics and Medical History 
Subject demographics will be recorded at screening and include date of birth (or age according to 
applicable regulations), sex, race, and ethnicity. 
Medical history will also be recorded at screening. Investigators should document the 
occurrence, signs, and symptoms of the subject’s pre-existing conditions, including all prior 


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significant illnesses, up to and including 5 years before screening. Additional pre-existing 
conditions present at the time when informed consent is given and up to the time of first dosing 
(Visit 5) are to be regarded as concomitant. Medical history will include alcohol consumption 
and smoking history, if applicable. 
Illnesses first occurring or detected during the study and/or worsening of a concomitant illness 
during the study are to be documented as AEs on the eCRF in accordance with Section 12. All 
changes not present at baseline or described in the past medical history and identified as 
clinically noteworthy must be recorded as AEs. 
 Vital Signs 
Vital signs (body temperature, respiratory rate, heart rate, and systolic and diastolic blood 
pressure measurements) will be evaluated at the visits indicated in the Schedule of Assessments 
(Table 10-1). All vital signs will be measured after the subject has been resting in a sitting 
position for at least 10 minutes. Blood pressure measurements are to be taken in the same arm for 
the duration of the study. 
Vital sign measurements will be repeated if clinically significant or machine/equipment errors 
occur. Out-of-range blood pressure, respiratory rate, or heart rate measurements determined by 
investigator judgment will be repeated at the investigator’s discretion. Any confirmed, clinically 
significant vital sign measurements must be recorded as AEs. 
 Physical Examination 
A complete physical examination (head, eyes, ears, nose and throat; heart; lungs; abdomen; skin; 
cervical and axillary lymph nodes; and neurological and musculoskeletal systems) will be 
performed at the visits indicated in the Schedule of Assessments (Table 10-1). 
Body weight (without shoes) will be recorded whenever physical examinations are recorded; 
height (without shoes) will be recorded and BMI will be calculated by the site at screening 
(Visit 1) only. All physical examinations will be performed by a physician. 
Symptom-driven, limited physical examinations will be performed as clinically indicated at any 
study visit. 
 Electrocardiograms 
A 12-lead, resting ECG will be measured in triplicate after the subject has rested in a supine or 
semi-recumbent position for 5 minutes or more at screening and at subsequent visits per 
Schedule of Assessments (Table 10-1). The ECG will be performed before spirometry. 
At screening, the investigator will examine the ECG traces for signs of cardiac disease that could 
exclude the subject from the study. An assessment of normal or abnormal will be recorded; if the 
ECG is considered abnormal, the abnormality will be documented in the eCRF. Investigator 


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assessment of the abnormality will also be documented in the eCRF. Electrocardiograms will be 
repeated if clinically significant abnormalities are observed or artifacts are present. 
 Spirometry 
Spirometry will be measured at time points in the Schedule of Assessments (Table 10-1), and 
after a physical examination and an ECG has been performed. Further, spirometry is used to 
monitor baseline lung function (safety and eligibility) and gauge level of bronchoconstriction 
during methacholine and allergen challenges. 
 Sheehan-Suicidality Tracking Scale 
The S-STS is a prospective, clinician-administered rating questionnaire that tracks both 
treatment-emergent suicidal ideation and behaviors. The S-STS will be performed as outlined in 
Table 10-1. 
This scale will be clinician-administered by a trained rater, completed onsite, and will be in 
paper format. The source document will be provided by the Sponsor. At the screening visit, the 
recall period for completing the S-STS will be the last 30 days prior; at all other visits, the recall 
period for completing the S-STS will be since the subject’s last visit. 
Subjects who have an S-STS score of > 0 should be evaluated by the investigator. If the 
investigator determines that a subject is at risk of suicide or self-harm, appropriate measures to 
ensure the subject’s safety must be made and mental health evaluation must be implemented. In 
such circumstances, the subject must immediately be discontinued from the study. The event 
should be recorded as determined by the investigator and reported within 24 hours to the 
Sponsor. 
 Clinical Laboratory Tests 
Laboratory samples include, but are not limited to, assessments in Table 12-1, and are to be 
obtained at designated visits as detailed in the Schedule of Assessments (Table 10-1). 


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Table 12-1. 
Laboratory Assessments 
 
Hematology 
Serum Chemistry 
Urinalysis 
Full and differential blood count 
albumin 
appearance 
Hct 
ALT 
pH 
Hb 
ALP 
protein 
MCH 
AST 
glucose 
MCHC 
BUN or urea 
ketone bodies 
MCV 
carbon dioxide 
specific gravity 
Platelet count 
creatinine 
urobilinogen 
RBC count 
WBC count with differential 
eGFR 
creatine phosphokinase 
electrolytes (sodium, potassium, 
chloride, calcium, phosphorus) 
bilirubin 
occult blood 
nitrates 
leukocytes 
GGT 
glucose 
LDH 
total bilirubin 
direct and indirect bilirubin 
total cholesterol 
LDL 
HDL 
triglycerides 
Pregnancy test: A human chorionic gonadotropin (hCG) blood test will be conducted on all WOCBP at 
screening; an hCG urine test will be conducted at all subsequent visits according to Table 10-1. 
Urine drug screen: Drugs of abuse include, but are not limited to, amphetamines, barbiturates, benzodiazepines, 
tetrahydrocannabinol, cocaine, opiates, and PCP (see Table 10-1). Retesting for positive results that are 
exclusionary is not allowed. 
Sputum test: Refer to Section 13.1 of protocol. 
Abbreviations: ALP=alkaline phosphatase; ALT=alanine aminotransferase; AST=aspartate aminotransferase; 
BUN=blood urea nitrogen; eGFR=estimated glomerular filtration rate; GGT=gamma-glutamyl transpeptidase; 
Hb=hemoglobin; HBV=hepatitis B; Hct= hematocrit; HDL=high-density lipoproteins; LDH=lactate dehydrogenase; 
LDL=low-density lipoproteins; MCH=mean corpuscular hemoglobin; MCHC=mean corpuscular hemoglobin 
concentration; MCV=mean corpuscular volume; PCP=phencyclidine; pH=potential hydrogen; RBC=red blood cell; 
WBC=white blood cell; WOCBP=women of childbearing potential. 
 
Blood and urine samples will be analyzed at a central laboratory facility. Urine samples will be 
analyzed by dipstick, and a microscopic analysis will be performed if the results of dipstick 
indicate abnormalities to be further investigated. eGFR will be calculated using the estimated 
MDRD formula and reported by the central laboratory at each visit that chemistry tests are 
collected as outlined in Table 10-1. 
Additional tests may be obtained to evaluate laboratory abnormalities and/or adverse 
events; please refer to the Laboratory Manual. 


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All laboratory reports must be reviewed, signed, and dated by the investigator. A legible copy of 
all reports must be filed with both the subject’s eCRF and medical record (source document) for 
that visit. Any laboratory test result considered by the investigator to be clinically significant 
should be considered an AE (clinically significant AEs include those that require an 
intervention). Clinically significant abnormal values occurring during the study will be followed 
up until repeat test results return to normal, stabilize, or are no longer clinically significant. 


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13  OTHER ASSESSMENTS 
CCI 
 
CCI 
 
 


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14  PHARMACOKINETICS ANALYSIS 
Blood samples for PK analysis of plasma zavegepant levels will be collected at the time points 
indicated in the Schedule of Assessments (Table 10-1). The actual date and time of each blood 
sample collection will be recorded. 
Details of PK blood sample collection, processing, storage, and shipping procedures are provided 
in a separate laboratory manual. 


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15  STATISTICAL ANALYSIS 
A statistical analysis plan (SAP) will be prepared after the protocol is approved. This document 
will provide further details regarding the definition of analysis variables and analysis 
methodology to address all study objectives. The SAP will serve as a complement to the protocol 
and supersedes it if there are differences. 
The statistical evaluation will be performed using SAS® software version 9.4 or higher 
(SAS Institute, Cary, NC). All data will be listed, and summary tables will be provided. 
Summary statistics will be presented by dose group. For continuous variables, data will be 
summarized with the number of subjects (N), mean, standard deviation (SD), median, minimum, 
and maximum by treatment group. For categorical variables, data will be tabulated with the 
number and proportion of subjects for each category by treatment group. 
 Determination of Sample Size 
The sample size was determined based on practical considerations, as well as statistical 
considerations. Assuming SD=9, with N=24 subjects (12 per arm), at a 2-sided 5% alpha-level, 
the study will have more than 80% power to detect an absolute between treatment difference of 
11 percentage points in the primary endpoint (maximum percentage decrease in the FEV1 
measured 3 to 7 hours after allergen challenge). 
Table 15-1 presents the 95% confidence intervals (CIs) for observed differences between 
treatment in maximum percentage decrease in LAR FEV1. 
Table 15-1. Confidence Intervals (95%) for Observed Differences Between Zavegepant 
and Placebo in Maximum Percentage Decrease in Late Asthmatic Response 
(LAR) Forced Expiratory Volume in 1 Second (FEV1) 
 
Observed Absolute Difference in Maximum % 
Decrease in LAR FEV1 
2-sided 95% CI 
9% 
(1.4%, 16.6%) 
11% 
(3.4%, 18.6%) 
13% 
(5.4%, 20.6%) 
Abbreviations: CI=confidence interval; FEV1= forced expiratory volume in 1 second; LAR=late asthmatic response. 
 Analysis Populations 
Enrolled population: The enrolled population will include all subjects who sign the ICF and are 
assigned a subject identification number. 
Randomized population: Enrolled subjects who receive a randomization treatment assignment 
from the IWRS. 
Treated population: Randomized subjects who received at least 1 dose of study therapy. 


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Modified Intent-to-Treat (mITT) population: Randomized subjects that received at least 
1 dose of study therapy and provided at least 1 non-missing post-baseline LAR assessment. 
15.2.1 Analysis of Primary Efficacy Endpoints 
The LAR, as assessed by maximum percentage decrease in FEV1 between 3 and 7 hours 
post-allergen challenge, will be compared between zavegepant and placebo using analysis of 
covariance (ANCOVA), with treatment group as main variable and respective baseline LAR 
value as covariate. Point estimate, 95% CIs, and 2-sided p-value will be reported for the 
difference in LARs comparing zavegepant and placebo. 
The LAR will also be assessed by AUC for the percent decrease in FEV1 between 3 and 7 hours, 
using similar methods as above. 
Additional supportive endpoints, including minimum absolute FEV1 value in 3 to 7 hours and 
AUC of the absolute FEV1 values in 3 to 7 hours, will also be similarly analyzed. 
The time-response curve of allergen-induced percentage decrease in FEV1 will be plotted for 
baseline (screening) and Visit 7. 
15.2.2 Analysis of Secondary Efficacy Endpoints 
The EAR, as assessed by maximum percentage decrease in FEV1 between 0 and 2 hours 
post-allergen challenge, (AUC for the percent decrease in FEV1 between 0 and 2 hours, 
minimum absolute FEV1 value in 0 to 2 hours, AUC of the absolute FEV1 values in 0 to 2 hours) 
will be analyzed using the same methods as for primary endpoint. 
The methacholine PC20 will be normalized by log transformation. Pre- and post-allergen 
challenge methacholine PC20 will be summarized with geometric mean and range. The pre- 
versus post-allergen shift in PC20 will be compared between zavegepant and placebo with 
baseline shift as covariate. The methacholine PC20 will be presented graphically. 
CCI 
 
 
 
 Safety Analysis 
All reported AEs will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA) latest version available at start of the study. The incidence of treatment-emergent 


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AEs (TEAEs; events with onset dates on or after the start of the study drug) will be included in 
incidence tables. Events with missing onset dates will be included as treatment-emergent. If a 
subject experiences more than 1 occurrence of the same AE, the occurrence with the greatest 
severity and the closest association with the study drug will be used in the summary tables. 
Treatment-related AEs, SAEs and AEs causing discontinuation will be tabulated. All AEs will be 
listed by subject, along with information regarding onset, duration, relationship and severity to 
study drug, action taken with study drug, treatment of event, and outcome. 
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 AEs. If a participant has 
a laboratory test abnormality with different toxicity grades over time, then only the highest 
toxicity grade will be reported in the lab abnormality summary table. 
Clinical laboratory data and vital signs will be summarized using descriptive statistics, including 
mean values and mean change from baseline values, as well as numbers of subjects with values 
outside limits of the normal range at each time point. 
Summary tables will be provided for concomitant medications initiated during the study period. 
 Interim Analysis 
No interim analysis is planned for this study. 


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16  STUDY MANAGEMENT 
 Approval and Consent 
16.1.1 Regulatory Guidelines 
This study will be conducted in accordance with the accepted version of the Declaration of 
Helsinki and/or all relevant regulations, as set forth in Parts 50, 56, 312, Subpart D, of Title 21 of 
the United States Code of Federal Regulations (CFR), in compliance with International Council 
for Harmonisation (ICH), and GCP guidelines and according to the appropriate regulatory 
requirements in the countries where the study was conducted. 
16.1.2 Institutional Review Board/Research Ethics Board/Independent Ethics Committee 
Conduct of the study must be approved by an appropriately constituted IRB/REB/independent 
ethics committee (IEC). Approval is required for the study protocol, protocol amendments (if 
applicable), IB, ICFs, recruitment material and subject information sheets, and other subject- 
facing material. 
16.1.3 Informed Consent 
For each study subject, written informed consent will be obtained before any protocol-related 
activities. As part of this procedure, the investigator or designee must explain orally and in 
writing the nature of the study, its purpose, procedures, expected duration, alternative therapy 
available, and the benefits and risks involved in study participation. The subject should be 
informed that he/she may withdraw from the study at any time, and the subject will receive all 
information that is required by local regulations and guidelines for ICH. The investigator will 
provide the Sponsor or its representative with a copy of the IRB-/REB-/IEC-approved ICF 
before the start of the study. 
 Data Handling 
Any data to be recorded directly on the eCRFs (to be considered as source data) will be 
identified at the start of the study. Data reported on the eCRF that are derived from source 
documents should be consistent with the source documents, or the discrepancies must be 
explained. See also Section 16.3. 
Clinical data will be entered by site personnel on eCRFs for transmission to the Sponsor. Data on 
eCRFs transmitted via the web-based data system must correspond to and be supported by source 
documentation maintained at the study site, unless the study site makes direct data entry to the 
databases for which no other original or source documentation is maintained. In such cases, the 
study site should document which eCRFs are subject to direct data entry and should have in 
place procedures to obtain and retain copies of the information submitted by direct data entry. 
All study forms and records transmitted to the Sponsor must only include coded identifiers such 


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that directly identifying personal information is not transmitted. The primary method of data 
transmittal is via the secure, internet-based EDC system maintained by Syneos Health. Access to 
the EDC system is available to only authorized users via the study’s internet web site, where a 
user unique assigned username and password are required for access. 
Any changes made to data after collection will be made through the use of the EDC system. 
eCRFs will be considered complete when all missing and/or incorrect data have been resolved. 
 Source Documents 
Source documents are considered to be all information in original records and certified copies of 
original records of clinical findings, observations, data, or other activities in a clinical study 
necessary for the reconstruction and evaluation of the study. The investigator will provide direct 
access to source documents and/or source data in the facilitation of trial-related monitoring, 
audits, review by IRBs/REBs/IECs, and regulatory inspections. 
The investigator/institution should maintain adequate and accurate source documents and trial 
records that include all pertinent observations on each of the site’s trial subjects. Source data 
should be attributable, legible, contemporaneous, original, accurate, and complete. Changes to 
source data should be traceable, not obscure the original entry, and be explained if necessary. 
 Record Retention 
Study records and source documents must be preserved for at least 25 years after the completion 
or discontinuation of/withdrawal from the study, at least 2 years after the study drug in this trial 
has received its last approval for sale, or at least 2 years after the study drug development has 
stopped, and in accordance with the applicable local privacy laws, whichever is the longer time 
period. 
The investigator agrees to comply with all applicable federal, state, and local laws and 
regulations relating to the privacy of subject health information, including, but not limited to, the 
Standards for Individually Identifiable Health Information, 45 CFR, Parts 160 and 164 (the 
Health Insurance Portability Accountability Act of 1996 [HIPAA] Privacy Regulation). The 
investigator shall ensure that study subjects authorize the use and disclosure of protected health 
information in accordance with HIPAA Privacy Regulation and in a form satisfactory to the 
Sponsor. 
 Monitoring 
The study will be monitored according to the Sponsor’s monitoring plan to ensure that it is 
conducted and documented properly according to the protocol, GCP, and all applicable 
regulatory requirements. 
Monitoring visits, both onsite and remote (telephone call), will be outlined in the study 
monitoring plan. The investigator will assure he/she and adequate site personnel are available 


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throughout the study to collaborate with clinical monitors. Clinical monitors must have direct 
access to source documentation in order to check the completeness, clarity, and consistency of 
the data recorded in the eCRFs for each subject. 
The investigator will make available to the clinical monitor all source documents and medical 
records necessary to review protocol adherence and eCRFs. In addition, the investigator will 
work closely with the clinical monitor and, as needed, provide them appropriate evidence that the 
study is being conducted in accordance with the protocol, applicable regulations, and GCP 
guidelines. 
 Quality Control and Quality Assurance 
The Sponsor or its designee will perform the quality assurance and quality control activities of 
this study; however, responsibility for the accuracy, completeness, security, and reliability of the 
study data presented to the Sponsor lies with the investigator generating the data. 
The Sponsor may arrange audits as part of the implementation of quality assurance to ensure that 
the study is being conducted in compliance with the protocol, standard operating procedures, 
GCP, and all applicable regulatory requirements. Audits will be independent of and separate 
from the routine monitoring and quality control functions. Quality assurance procedures will be 
performed at study sites and during data management to assure that safety and efficacy data are 
adequate and well documented. 
 Protocol Amendment and Protocol Deviation 
16.7.1 Protocol Amendment 
Amendments to the protocol that entail corrections of typographical errors, clarifications of 
confusing wording, changes in study personnel, and minor modifications that have no effect on 
the safety of subjects or the conduct of the study will be classed as administrative amendments 
and will be submitted to the IRB/REB/IEC for information only. The Sponsor will ensure that 
acknowledgment is received and filed. Amendments that are classed as substantial amendments 
must be submitted to the appropriate regulatory authorities and the IECs/REBs/IRBs for approval 
and will not be implemented at sites until such approvals are received other than in the case of an 
urgent safety measure. 
16.7.2 Protocol Deviations 
Should a protocol deviation occur, the Sponsor must be informed as soon as possible. Protocol 
deviations and/or violations and the reasons they occurred will be included in the clinical study 
report. Reporting of protocol deviations to the IRB/REB/IEC and in accordance with applicable 
regulatory authority mandates is an investigator responsibility. 
All protocol deviations will be identified, evaluated, and closed before the respective database 
lock (final analysis) and will be described in the clinical study report. 


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Protocol deviations incurred as a direct result of the COVID-19 pandemic should be specifically 
recorded as a “COVID-19” deviation so that they can be easily identified and incorporated into 
the clinical study report. 
 Ethical Considerations 
This study will be conducted in accordance with this protocol, the accepted version of the 
Declaration of Helsinki and/or all relevant federal regulations, as set forth in Parts 50, 56, 312, 
Subpart D, of Title 21 of the CFR, and in compliance with GCP guidelines. 
IECs/REBs/IRBs will review and approve this protocol and the ICF. All subjects are required to 
give written informed consent before participation in the study. 
 Financing and Insurance 
Before the study commences, the Sponsor (or its designee) and the investigator (or the 
institution, as applicable) will agree on costs necessary to perform the study. This agreement will 
be documented in a financial agreement that will be signed by the investigator (or the institution 
signatory) and the Sponsor (or its designee). 
The investigator is required to have adequate current insurance to cover claims for negligence 
and/or malpractice. The Sponsor will provide no-exclusion insurance coverage for the clinical 
study as required by national regulations. 
 Publication Policy and Disclosure of Data 
Both the use of data and the publication policy are detailed within the clinical study agreement. 
Intellectual property rights (and related matters) generated by the investigator and others 
performing the clinical study will be subject to the terms of a clinical study agreement that will 
be agreed between the institution and the Sponsor or their designee. With respect to such rights, 
the Sponsor or its designee will solely own all rights and interests in any materials, data, and 
intellectual property rights developed by investigators and others performing the clinical study 
described in this protocol, subject to the terms of any such agreement. In order to facilitate such 
ownership, investigators will be required to assign all such inventions either to their institution or 
directly to the Sponsor or its designee, as will be set forth in the clinical study agreement. 


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17  REFERENCES 
 Buse DC, Reed ML, Fanning KM, et al. Comorbid and co-occurring conditions in migraine 
and associated risk of increasing headache pain intensity and headache frequency: results of 
the migraine in America symptoms and treatment (MAST) study. J Headache Pain. 
2020;21(1):23. doi: 10.1186/s10194-020-1084-y 
 Cockcroft DW, Davis BE, Todd DC, Smycniuk AJ. Methacholine challenge: comparison of 
two methods. Chest. 2005a;127(3):839-844. doi: 10.1378/chest.127.3.839 
 Cockcroft DW, Davis BE, Boulet L-P, et al. The links between allergen skin test sensitivity, 
airway responsiveness and airway response to allergen. Allergy. 2005b;60(1):56-59. 
doi: 10.1111/j.1398-9995.2004.00612.x 
 Ding W, Stohl LL, Xu L, et al. Calcitonin gene-related peptide-exposed endothelial cells bias 
antigen presentation to CD4+ T cells toward a Th17 response. J Immunol 2016;196(5):2181- 
2194. doi: 10.4049/jimmunol.1500303 
 Table of Substrates, Inhibitors and Inducers. US Food & Drug Administration website. 
https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-drug- 
interactions-table-substrates-inhibitors-and-inducers#table%203-2. Table 3-2, Table 3-3, and 
Table 5-2. Accessed March 24, 2021. 
 Global Initiative for Asthma (GINA). Interim guidance about COVID-19 and asthma, 
updated 20 Dec 2020. https://ginasthma.org 
 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. doi: 10.1186/1479-7364-5-1-61. 
http://www.druginteractionsolutions.org 
 Kay AB, Ali FR, Heaney LG, et al. Airway expression of calcitonin gene-related peptide in 
T-cell peptide-induced late asthmatic reactions in atopics. Allergy. 2007;62(5):495-503. 
doi: 10.1111/j.1398-9995.2007.01342.x 
 Kim B-G, Park M-K, Lee P-H, et al. Effects of nanoparticles on neuroinflammation in a 
mouse model of asthma. Respir Physiol Neurobiol. 2020;271:103292. 
doi: 10.1016/j.resp.2019.103292 
 Mikami N, Watanabe K, Hashimoto N, et al. Calcitonin gene-related peptide enhances 
experimental autoimmune encephalomyelitis by promoting Th17-cell functions. Int Immunol. 
2012;24(11):681-691. doi: 10.1093/intimm/dxs075 
 O’Byrne PM, Hargreave FE, Kirby JG. Airway inflammation and hyperresponsiveness. Am 
Rev Respir Dis. 1987;136(4 Pt 2):S35-S37. doi 10.1164/ajrccm/136.4_Pt_2.S35 
Eur Respir J Suppl. 2002;37:9s-18s. doi:10.1183/09031936.02.00000902 
 Springer J, Amadesi S, Trevisani M, et al. Effects of alpha calcitonin gene-related peptide in 
human bronchial smooth muscle and pulmonary artery. Regul Pept. 2004;118(3):127-134. 
doi: 10.1016/j.regpep.2003.11.006 


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 Sui P, Wiesner DL, Xu J, et al. Pulmonary neuroendocrine cells amplify allergic asthma 
responses. Science. 2018;360(6393):eaan8546. doi: 10.1126/science.aan8546 
 Tränkner D, Hahne N, Sugino K, Hoon MA, Zuker C. Population of sensory neurons 
essential for asthmatic hyperreactivity of inflamed airways. Proc Natl Acad Sci U S A. 
2014;111(31):11515-11520. doi: 10.1073/pnas.1411032111 
 Vazegepant (BHV-3500) Investigator’s Brochure. Version No. 4.0, dated 24 Nov 2020. 

SAP_001.pdf: 
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Statistical Analysis Plan for Interventional Studies 
Text Only 
 
Protocol Number: BHV-3500-204 (C5301005) 
Protocol Title: A Phase 1b, Double-blind, Placebo-controlled, Parallel-group Study to Evaluate Safety 
and Efficacy of Oral Zavegepant in Subjects with Mild Allergic Asthma 
 
Protocol Version and Date: (DD-Mmm-YYYY): Version 3.0 22-Mar-2023 
 
Syneos Health Project Code: 7019323 
Authors: PPD 
, Biostatistician 
PPD 
, Senior Biostatistician 


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Revision History 
 
Version # 
Date 
(DD-Mmm-YYYY) 
Document Owner 
Revision Summary 
0.1 
09-Aug-2021 
PPD 
 
First Draft 
0.2 
17-Sep-2021 
PPD 
 
Revisions per Biohaven’s comments 
0.3 
20-Oct-2021 
PPD 
 
Revisions per Biohaven’s comments 
0.4 
10-Dec-2021 
PPD 
 
Revisions per Biohaven’s comments 
0.5 
22-Dec-2021 
PPD 
 
Revisions per Biohaven’s comments 
1.0 
05-Jan-2022 
PPD 
 
Final version 
1.1 
02-Mar-2023 
PPD 
 
Amendement per Pfizer’s comments for dry run 
2.0 
16-Jun-2023 
PPD 
 
Amendement per Pfizer’s comments to reduce the TLFs 
and streamline the CSR. 


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I confirm that I have reviewed this document and agree with the content. 
 
 
 
Approvals 
Syneos Health Approval 
PPD 
 Biostatistician 
Name, Title 
Lead Biostatistician 
 
Signature 
Date (DD-Mmm- 
YYYY) 
PPD 
 
PPD 
 Biostatistics 
 
Signature 
Name, Title 
Senior Reviewing Biostatistician 
Date (DD-Mmm- 
YYYY) 
PPD 
, Senior Pharmacokineticist 
Name, Title 
Pharmacokineticist 
Signature 
Date (DD-Mmm- 
YYYY) 
Pfizer, Inc. Approval 
PPD 
 
PPD 
, Statistics Group Lead 
Name, Title 
Sponsor Contact 
 
Signature 
Date (DD-Mmm- 
YYYY) 


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Table of Contents 
Revision History .......................................................................................................................................... 2 
Approvals ................................................................................................................................................... 3 
 
Glossary of Abbreviations ................................................................................................................ 7 
 
Purpose .............................................................................................................................................. 9 
 
Study Objectives ............................................................................................................................. 10 
CCI 
 
Study Details/Design ................................................................................................................................ 11 
 
 
 
 
 
 
Estimands ........................................................................................................................................ 16 
 
 
CCI 
 
 
Analysis Sets, Treatment Groups, and Subgroups .................................................................... 18 
 
 
 
 
General Aspects for Statistical Analysis ...................................................................................... 19 
 
 
 
 
 
Disposition, Demographic, Other Baseline Characteristics and Medication .......................... 21 


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Efficacy ............................................................................................................................................. 25 
 
 
 
 
 
CCI 
 
 
Pharmacokinetics ............................................................................................................................ 28 
 
Safety ................................................................................................................................................ 29 
 
 
 
 
 
 
 
 


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Conventions ..................................................................................................................................... 34 
 
Interim Analyses .............................................................................................................................. 36 
 
Changes from Analysis Planned in Protocol ............................................................................... 37 
 
Quality Control ................................................................................................................................. 38 
 
Shells ................................................................................................................................................ 39 
 
Appendices ...................................................................................................................................... 40 
Appendix A Relevant Protocol Deviations ............................................................................................. 41 


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Glossary of Abbreviations 
 
 
Abbreviation 
Description 
AE 
Adverse Event 
AHR 
Allergen-induced Airway Hyperresponsiveness 
ANCOVA 
Analysis of Covariance 
ATC 
Anatomical Therapeutic Chemical 
ATC4 
Anatomical Therapeutic Chemical Classification Level 4 
AUC 
Area Under the Curve 
BLQ 
Below the Limit of Quantification 
BMI 
Body Mass index 
CGRP 
Calcitonin Gene-related Peptide 
CI 
Confidence Interval 
CRF 
Case Report Form 
eCRF 
Electronic Case Report Form 
CTCAE 
Common Terminology Criteria for Adverse Events 
CV 
Coefficient of Variance 
DAIDS 
Division of Aids 
EAR 
Early Asthmatic Response 
ECG 
Electrocardiogram 
ELISA 
Enzyme-Linked Immunosorbent Assay 
FEV1 
Forced Expiratory Volume in 1 Second 
FVC 
Forced Vital Capacity 
GCP 
Good Clinical Practice 
ICH 
International Conference on Harmonization 
IP 
Investigational Product 
IRB 
Institutional Review Board 
IWRS 
Interactive Web-based Response System 
LAR 
Late Asthmatic Response 
MedDRA 
Medical Dictionary for Regulatory Activities 
mITT 
Modified Intent-to-Treat 


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Abbreviation 
Description 
NCA 
Non-compartmental Analysis 
PK 
Pharmacokinetic 
PT 
Preferred Term 
REB 
Research Ethics Board 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SOC 
System Organ Class 
SOP 
Standard Operating Procedure 
S-STS 
Sheehan Suicidality Tracking Scale 
TFL 
Table, Figure and Listing 
WHO 
World Health Organization 


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Purpose 
 
The purpose of this statistical analysis plan (SAP) is to ensure that the data listings, summary tables and 
figures which will be produced, and the statistical methodologies which will be used, are complete and 
appropriate to allow valid conclusions regarding the study objectives. This SAP is based on BHV3500- 
204 Protocol Version 3.0 (22Mar2023). 
 
The Rimegepant (BHV3000)/Zavegepant (BHV3500) Core Statistical Analysis Plan (the “Core SAP”) 
describes analysis details and methodologies common to the BHV3500 program and is incorporated by 
reference. The Core SAP assumes primacy for any matter where this SAP is silent (and the relevant 
content of the Core SAP could feasibly apply) or where the Core SAP is directly referenced as applicable. 
Otherwise, should any discrepancy exist between the Core SAP and this SAP, this SAP assumes 
primacy. 
 
Note that the study was terminated prematurely in 1Q2023 due to low enrollment. Thus, the SAP is being 
amended from Version 1.1 to 2.0 to reduce the number of TLFs to streamline the CSR. 
 
 
Responsibilities 
Syneos Health will perform the statistical analyses and is responsible for the production and quality 
control of all tables, figures and listings. 
 
Timings of Analyses 
The primary analysis of safety and efficacy is planned after all subjects complete the final study visit or 
terminate early from the study. Unless otherwise specified, the analysis includes all data collected in the 
database through the time of database lock. 


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Study Objectives 
 
Primary Objective 
The primary objective of this study is to evaluate the allergen-induced late asthmatic response (LAR) 
between subjects treated with zavegepant and placebo after 28 days of treatment. 
Secondary Objectives 
The secondary objectives of this study are: 
 
• 
To evaluate the allergen-induced early asthmatic response (EAR) between subjects treated with 
zavegepant and placebo. 
 
• 
To evaluate the allergen-induced airway hyperresponsiveness (AHR) measured at 24 hours post- 
allergen challenge, between subjects treated with zavegepant and placebo. 
 
• 
To assess the safety and tolerability of oral zavegepant. 
CCI 
 


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Study Details/Design 
 
Brief Description 
This is a multicenter, phase 1b, double-blind, parallel-group, randomized study of 24 subjects to evaluate 
the safety and efficacy of 150 mg oral zavegepant versus placebo twice daily for the treatment of 
allergen-induced asthma. Individuals with stable, mild allergic asthma, with a history of episodic wheeze 
and shortness of breath, will be eligible for enrollment. The study will be divided into 2 parts. Part 1 is the 
screening period of up to 28 days to obtain a cohort of subjects with documented EAR (defined as ≥20% 
fall in forced expiratory volume in 1 second (FEV1) 0 to 2 hours after allergen challenge) and LAR 
(defined as ≥15% fall in FEV1 3 to 7 hours after allergen challenge) to an inhaled incremental allergen 
challenge and AHR defined by methacholine PC20 ≤16 mg/mL by inhaled incremental methacholine 
challenge. Part 1 consists of Visits 1 through 4. Part 2 is the dosing period of approximately 28 days. 
Part 2 consists of Visits 5 through 9. Subjects will be randomized in a 1:1 ratio to receive 150 mg 
zavegepant or matching placebo to be taken twice daily. All subjects will undergo a 3-day allergen 
challenge triad, morning doses will be taken before any laboratory procedures and study treatment will 
end with their evening dose at the end of the challenge. A follow-up period consisting of an onsite visit 
will be conducted approximately 7 to 10 days after the last study treatment. 
 
Figure 1 presents the general study schematic. 
Figure 1. Study Schematic 
 
Determination of Sample Size 
This study will enroll 24 subjects, 12 per arm. The sample size was determined based on practical 
considerations, as well as statistical considerations. Assuming standard deviation (SD)=9, with N=24 
subjects (12 per arm), at a 2-sided 5% alpha-level, the study will have more than 80% power to detect an 
absolute between treatment difference of 11 percentage points in the primary endpoint (maximum 
percentage decrease in the FEV1 measured 3 to 7 hours after allergen challenge). 
 
Table 1 presents the 95% confidence intervals (CIs) for observed differences between treatment in 
maximum percentage decrease in LAR FEV1. 


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Table 1. CIs (95%) for Observed Differences Between Zavegepant and Placebo in Maximum Percentage 
Decrease in LAR FEV1 
 
Observed Absolute Difference in Maximum % 
Decrease in LAR FEV1 
2-sided 95% CI 
9% 
(1.4%, 16.6.%) 
11% 
(3.4%, 18.6%) 
13% 
(5.4%, 20.6%) 
 
 
Treatment Assignment and Blinding 
The investigator or designee will obtain a subject number and treatment assigned via an Interactive Web- 
based Response System (IWRS). The IWRS system will assign a subject specific blinded study 
treatment kit that will contain 8 wallets, enough for the total treatment duration, to be dispensed to 
subjects. Once the kits/wallets have been assigned, they cannot be dispensed to another study subject. 
 
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 study participation. 
 
After the subject’s treatment assignment number is obtained from the IWRS, the number will be provided 
to the investigator or designee at the study center who is responsible for distribution of study treatment. 
The IP and placebo will be identical in appearance and labeled in a blinded manner. No study site 
personnel, subject, Sponsor personnel, or Sponsor designee will be unblinded to treatment assignment 
throughout the duration of the study unless unblinding is required. If an investigator becomes unblinded to 
a given subject’s study treatment, that subject will be discontinued from the study unless there are ethical 
reasons for the subject not to be discontinued; approval from the Sponsor’s medical monitor must be 
obtained in such instances. 
 
In the event that an emergency unblinding is required for a subject because of an adverse event (AE) or 
concerns for the subject’s safety or well being, the investigator may break the randomization code for the 
subject via the IWRS. The investigator is responsible for notifying the medical monitor and/or Sponsor of 
such an event as soon as possible. The unblinding and its cause will also be documented in the 
electronic case report form (eCRF). 
 
Administration of Study Medication 
After subjects have met all eligibility requirements in Part 1 and completed the rest/washout period, they 
will be randomized in a 1:1 ratio to receive zavegepant or placebo. IP will be dispensed at Visit 5. 
Subjects will take 6 25-mg capsules twice daily, in the morning and evening, for at least 28 days. 
Subjects should dose consistently at the same time of day, preferably in the morning and evening. Each 
dose of study drug should be taken while fasting (e.g., at least 1 hour before breakfast/first meal of the 
day for the first dose, and at least 4 hours after the previous meal for the second dose). Subjects should 
not consume food other than water for 1 hour after dosing. 


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Study Procedures and Flowchart 
The schedule of assessments is provided in Table 2 as below. 


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Table 2. Schedule of Assessments 
 
Part 1: Screeninga 
2-4 Week 
Washout 
From 
Screenin 
g 
Part 2: Dosing/Treatment 
Follow 
-up 
Visit # 
1 
2 
3 
4 
5 
6 
7 
8 
9 
3-Day Allergen 
Triad 
3-Day Allergen Triad 
Day(s) 
-29 
to -1 
6 
-15 
(±3d 
) 
-14 
(±3d 
) 
-13 
(±3d 
) 
1 
b 
~26 
(+ 3d 
) 
~27 
(+ 3d 
) 
~28 
(+ 3d 
) 
~35 - 
41 
Informed consent 
X 
Inclusion/Exclusio 
n criteria 
X 
X 
X 
X 
Demographics/ 
Medical 
history/medication 
history 
X 
Vital signs 
X 
X 
X 
X 
X 
Physical 
examination, 
including BMIc 
X 
X 
Electrocardiogram 
X 
X 
Spirometry 
X 
X 
X 
X 
X 
X 
X 
X 
Pregnancy testd 
X 
X 
X 
Clinical laboratory 
tests (hematology, 
chemistry) 
X 
X 
X 
X 
Urinalysis 
X 
X 
X 
Urine drug testing 
X 
Allergy skin 
(prick) test 
X 
Methacholine 
challenge 
X 
X 
X 
X 
X 
Sputum induction 
X 
X 
X 
X 
X 
X 
X 
Allergen skin 
titration teste 
X 
X 
Allergen inhalation 
challenge 
X 
X 
Randomization and 
Dosingf, g 
X 
X 
X 
X 
Meal and Daily 
Study Drug Dosing 
Diaryh 
X 
X 
X 
X 
Pharmacokinetic 
X 
X 
X 


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Part 1: Screeninga 
2-4 Week 
Washout 
From 
Screenin 
g 
Part 2: Dosing/Treatment 
Follow 
-up 
Visit # 
1 
2 
3 
4 
5 
6 
7 
8 
9 
3-Day Allergen 
Triad 
3-Day Allergen Triad 
Day(s) 
-29 
to -1 
6 
-15 
(±3d 
) 
-14 
(±3d 
) 
-13 
(±3d 
) 
1 
b 
~26 
(+ 3d 
) 
~27 
(+ 3d 
) 
~28 
(+ 3d 
) 
~35 - 
41 
samplingi 
Ongoing and 
concomitant 
medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Adverse events 
X 
X 
X 
X 
X 
X 
X 
X 
S-STS 
X 
X 
X 
Abbreviations: BMI=body mass index; d=day; ECG=electrocardiogram; FEV1= forced expiratory volume in 1 
second; h=hour(s); max=maximum; min=minimum; PC20=provocation concentration causing a 20% decline in 
FEV1; SABA= short-acting beta-agonists; S-STS=Sheehan-Suicidality Rating Scale; WOCBP=women of 
childbearing potential. 
 
a Part 1: All screening procedures will be completed and results returned within Days -29 to Day -13. 
b Part 2/Day 1: Subjects will be confirmed as recovered on Day 1 (e.g., confirmation of hyperresponsiveness 
recovery of methacholine PC20 not more than 1 doubling dose lower than baseline; return to FEV1 within 90% of 
baseline) prior to initiation of dosing. 
c A full examination will be performed at screening and at follow-up. BMI will be calculated at Screening Visit 1. 
d Serum pregnancy test conducted at screening; urine pregnancy testing at all other visits as indicated. Results of the 
pregnancy test are required before dosing. Source documents should document that WOCBP agree to use 2 
effective forms of contraception and men with WOCBP partners agree to use condoms with a spermicide during 
treatment. 
e Allergen skin titration test can be performed at either Visit 1 or Visit 2 to allow for flexibility. 
f After randomization, daily dosing in Part 2 from Visit 5 through Visit 8, inclusive. No onsite visit required after 
start of study medication at Visit 5 to start of allergen triad (Visit 6). Every effort should be made to conduct the 
study visits within the specified windows in Part 2. However, if necessary due to local COVID-19 safety 
requirements, visits may be performed outside of these windows in order to minimize any potential risks to 
subject safety and to comply with governmental and institutional guidance. 
g Subjects should dose consistently at the same time of day, preferably in the morning and evening. Each dose of 
study drug should be taken while fasting (e.g., at least 1 h before breakfast/first meal of the day for the first dose, 
and at least 4 h after the previous meal for the second dose). Subjects should not consume food other than water 
for 1 h after dosing. 
h Subjects will be asked to complete a daily diary to capture date and times of both meals and study drug 
administration. 
i Pharmacokinetic sampling to be conducted predose on Visits 6, 7, and 8, and additionally at Visit 7 at 
approximately 1 (+ 0.5 h) h and 3 (+/- 0.5 h) h postdose. Subjects should be instructed to hold their daily dose of 
study drug on the morning of Visits 6, 7, and 8 and arrive at the clinic after an overnight fast. Exact times of 
dosing and PK sample collection will be documented. 


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Estimands 
 
An estimand is the target of estimation to address the scientific question of interest posed by a study 
objective. The four attributes of an estimand include the population of interest, endpoint of interest, 
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. 
 
Intercurrent Events 
 
Intercurrent events are those that occur after treatment initiation and either preclude observation of the 
endpoint or affect its interpretation. 
 
• 
For efficacy 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. This strategy 
aligns with the assumption that zavegepant is expected to confer benefits to the subject after 
study drug discontinuation. Thus, premature study drug discontinuation is ignored for these 
efficacy endpoints. 
 
 
Primary Endpoint 
Table 1: 
Primary Objective Estimand 
 
Objective 
To evaluate the allergen-induced LAR 3 to 7 hours after the 
administration of the allergen inhalation challenge between subjects 
treated with zavegepant and placebo. 
Efficacy Endpoint 
Maximum percentage decrease from baseline in FEV1 at any time between 3 
and 7 hours post-allergen challenge in the modified intent-to-treat (mITT) 
analysis set. 
Summary 
Difference in maximum percentage decrease from baseline in FEV1 between 
the zavegepant and placebo groups using an ANCOVA model. 
Intercurrent Events 
Treatment policy strategy: All available assessments on the subject are used 
regardless of intercurrent events. 
 
 
Secondary Endpoints 
Table 2: 
Secondary Objective Estimands 
 
1 
Objective 
To evaluate the allergen-induced EAR 0 to 2 hours after the administration of 
the allergen inhalation challenge between subjects treated with zavegepant 
and placebo. 
Efficacy 
Endpoint 
Maximum percentage decrease from baseline in FEV1 at any time between 0 and 2 
hours post-allergen challenge in the mITT analysis set. 


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CCI 
 
Summary 
Same as that of primary estimand, with respect to EAR. 
Intercurrent 
Events 
Treatment policy strategy: All available assessments on the subject are used 
regardless of intercurrent events. 
2 
Objective 
To evaluate the AHR measured at 24 hours post-allergen challenge between 
subjects treated with zavegepant and placebo. 
Efficacy 
Endpoint 
Shift from pre-allergen challenge (Visit 6) to post-allergen challenge (Visit 8) of PC20 
in the mITT analysis set. 
Summary 
Difference in shift from pre to post-allergen challenge between the zavegepant and 
placebo groups using an ANCOVA model. 
Intercurrent 
Events 
Treatment policy strategy: All available assessments on the subject are used 
regardless of intercurrent events. 
3 
Objective 
To assess the safety and tolerability of oral zavegepant. 
Endpoint 
Various safety endpoints (i.e., adverse events, clinically significant laboratory 
abnormalities). 
Summary 
Frequency by treatment group of safety endpoints for the safety analysis set. 
Intercurrent 
Events 
Not applicable. 


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Analysis Sets, Treatment Groups, and Subgroups 
 
Analysis Sets 
Enrolled: The enrolled analysis set includes all subjects who sign the informed consent form (ICF) and 
are assigned a subject identification number by the IWRS. 
Full: The full analysis set includes enrolled subjects who receive a randomization treatment assignment 
from the IWRS. 
Safety: The safety analysis set includes subjects from the full analysis set who received at least 1 dose of 
study therapy. The safety analysis set will be used for all analyses of safety endpoints. Subjects will be 
analyzed according to the treatment actually received. 
Modified Intent-to-Treat (mITT): The mITT analysis set includes safety subjects (received at least 1 
dose of study therapy) that provided at least 1 non-missing post-baseline LAR assessment. Subjects will 
be analyzed according to randomized treatment assignment. 
Follow-up: Safety subjects whose last contact date is in the follow-up analysis period. This analysis set is 
used to assess follow-up safety. 
Treatment Groups 
The two treatment groups are zavegepant and placebo. The safety analysis set is assessed by as-treated 
treatment group, the full and mITT analysis sets are assessed by as-randomized treatment group, and 
the enrolled analysis set is assessed overall. 
If a subject receives ≥ 1 dose of planned randomized treatment then that subject is considered to have 
as-treated treatment group equal to as-randomized treatment group, and will be analyzed according to 
randomized treatment. 
Subgroups 
No subgroup analyses are planned. 


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General Aspects for Statistical Analysis 
 
All statistical analyses are performed using SAS statistical software (Version 9.4 or higher). 
 
General Methods 
Refer to the Core SAP for descriptive statistics, counting rules, rounding rules, dictionaries for coding 
AEs, medical history, and non-study medications. 
• Unless otherwise specified, summaries will be presented for each treatment group and overall. 
 
• Continuous variables will be summarized using the number of observations (n), mean, standard 
deviation (SD), median, minimum, and maximum. Categorical variables will be summarized using 
number of observations (n), frequency and percentages of subjects. 
• Unless otherwise specified, listings will be sorted by randomization status (randomized, not 
randomized), which is not displayed, subject ID, and visit and/or assessment date (and time) if 
applicable. 
• If multiple assessments are conducted at a given time point or visit, the non-missing value closest 
to the target date/time for the visit is used; in the case of a tie, the last value collected is used. All 
assessment results will be listed. 
Key Definitions 
• Baseline is the last non-missing observation prior to first administration of study drug unless 
otherwise specified. 
• Change from baseline will be calculated as post-baseline value minus baseline value. If either the 
baseline or post-baseline value is missing, the change from baseline is set to “missing”. 
• The Study Day is the day relative to the date of first administration of study drug, where Day -1 is 
the day before administration of zavegepant and Day 1 is the day of first administration of study 
drug. 
• Study day will be calculated as: 
 
o 
Study day = date of assessment – date of first administration of study drug +1 if the date of 
assessment is on or after the date of first study drug administration; Otherwise: Study day = 
date of assessment – date of first administration of study drug. 
• Follow-up day will be calculated from the study drug last date as: 
 
o 
Measurement date − study drug last date, if measurement date ≥ study drug last date + 1; 
otherwise: Measurement date − study drug last date − 1, if measurement date < study drug 
last date + 1. 


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Missing Data 
All analyses will be based on observed data unless otherwise specified. For the purposes of assessing 
treatment emergence for AEs or classifying medications into prior/concomitant, the algorithms described 
in Section 7.1.2.3 of the Core SAP will be used to impute partially and completely missing dates. 
Visit Windows 
All subjects are to adhere to the protocol-specified visit schedule in Table 2. Visits will be analyzed as 
captured in the database, no visit windows will be assigned. 


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Disposition, Demographic, Other Baseline Characteristics and 
Medication 
Analysis Sets 
The number of subject in each analysis set described in Section 5.1 is tabulated. 
 
A by-subject listing of analysis sets is provided for the enrolled analysis set, and an administrative listing 
of randomization scheme and codes is provided for all randomization numbers and block numbers, even 
those not assigned to a subject. Refer to the Core SAP for listing contents. 
Enrollment 
Enrollment by country and site is tabulated for the enrolled analysis set. Refer to the Core SAP for more 
details. 
Subject Disposition and Withdrawals 
Subject disposition is based on the “Eligibility Criteria,” “Informed Consent,” and “Subject Disposition” 
CRFs, unless otherwise noted. 
A by-subject listing of subject disposition will be provided for the enrolled analysis set based on the 
“Subject Disposition” and “Informed Consent” CRFs and includes the following: date informed consent 
was signed, protocol version, study completion status (yes, no, ongoing); reason for not completing the 
study, including specify text for “other” and AE preferred terms (PTs); study drug start date; and last 
contact date.This listing also identifies subjects who terminated the study prematurely due to COVID-19. 
Subject Disposition from Enrollment to Randomization 
Subject disposition from enrollment to randomization is tabulated for the enrolled analysis set as the 
number and percentage of subjects in the following categories: 
• 
Randomized 
• 
Not randomized 
o 
Reasons for discontinuation (i.e., not completing the study), including not reported. For 
subjects whose reason is screen failure due to inclusion/exclusion criteria, the reasons 
for screen failure are also included from the "Eligibility Criteria” CRF 
• 
Not randomized and terminated the study prematurely due to COVID-19. This has the same 
subcategories as “Not randomized.” 
Subject Disposition from Randomization to Treatment 
Subject disposition from randomization to treatment is tabulated for the randomized analysis set by as- 
randomized treatment group and overall as the number and percentage of subjects in the following 
categories: 
• 
Treated with study drug (identified as those with non-missing study drug start date) 
• 
Not treated with study drug (identified as those with missing study drug start date) 
o 
Reasons for discontinuation (i.e., not completing the study), including not reported 
• 
Not treated with study drug and terminated the study prematurely due to COVID-19. This has the 
same subcategories as “Not treated with study drug.” 


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Subject Disposition from Treatment to End of Study/Follow-up 
Subject disposition from treatment to end of study is tabulated for the safety analysis set by as-treated 
treatment group and overall as the number and percentage of treated subjects in the following categories: 
• 
Completed the study (identified as those with “yes” response to the question “Did the subject 
complete the study?”) 
• 
Did not complete the study (identified as those with “no” response to the question “Did the subject 
complete the study?”) 
o 
Reasons for not completing the study, including not reported 
• 
Terminated the study prematurely due to COVID-19. This has the same subcategories as “Did 
not complete the study.” 
Protocol Deviations 
 
A relevant protocol deviation is a deviation from the protocol which is programmed from the database and 
which could potentially affect the interpretability of the study results. This type of deviation includes but is 
not limited to: 
 
• 
Eligibility 
 
• 
Subject management 
The frequency table of relevant protocol deviations displays the number and percentage of subjects in 
deviation categories and subcategories by deviation type (e.g., eligibility, subject management) for the full 
analysis set. Results are displayed for all deviations, even those with 0 counts, unless otherwise 
specified. See Section 6.2.4.1 of the Core SAP for further details. 
A by-subject listing of relevant, programmable protocol deviations is provided for the enrolled analysis set. 
Relevant protocol deviations are outlined in Section 16 . 
A by-subject listing of significant protocol deviations is provided for the enrolled analysis set. This includes 
visit, type, and description, which are used as additional sorting variables. 
A Microsoft Excel file of protocol deviations is provided by the data management vendor from the clinical 
trial management system (CTMS). This file serves as the raw data source of protocol deviations, and 
classifies deviation severity as major, minor, or exclude. Significant protocol deviations are defined as 
those with major severity. A footnote describes the raw data source and how significant protocol 
deviations are identified, e.g., “Significant protocol deviations are those with major severity reported by 
the data management vendor in the clinical trial management system.” 
Demographic and Baseline Characteristics 
A summary of demographic and baseline characteristics will be presented by treatment group and overall 
using the safety analysis set. Descriptive statistics will be calculated for continuous variables (age, BMI, 
height, and weight) at baseline. Frequency counts and percentages will be tabulated for categorical 
variables (age category, gender, childbearing potential if female, ethnicity, race, country, BMI category). 
Demographic and baseline characteristics will also be listed by subject for the enrolled analysis set. 
Weight, height, and BMI will be listed with vital signs as detailed in Section 10.3. 
Alcohol Consumption and Smoking History 
Alcohol consumption and smoking history will be listed by subject for the enrolled analysis set. 


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Medical History and Concomitant Diseases 
Medical history as recorded at baseline will be summarized by treatment group and overall for the safety 
analysis set using the number and percentages of subjects reporting each system organ class (SOC) and 
preferred term (PT). Medical history will be sorted by descending overall total by SOC and PT within each 
SOC using the Medical Dictionary for Regulatory Activities (MedDRA) coding dictionary version 24 or later 
in the summary table. 
Medical history will be listed by subject for the enrolled analysis set. 
 
Non-Study Medications 
Non-study medications taken during the course of the study will be presented in tabular form for the 
safety analysis set using Anatomical Therapeutic Chemical (ATC) classification level 4 terms (ATC4) and 
preferred name via the World Health Organization (WHO) Drug Global B3 March 2021 or later for the 
following types: 
• 
Prior medications (previous, current) 
• 
Concomitant medications 
 
The definitions of medication types are in Section 6.2.6.3 of the Core SAP. Medications are displayed in 
descending order of overall frequency within therapeutic class and preferred name. Imputed medication 
start and stop dates are used to assign non-study medication type (previous, current, concomitant, follow- 
up) to all non-study medications. Refer to the Core SAP for non-study medication start and stop date 
imputation. Subjects will be counted only once for each ATC4 term in the event that they have multiple 
records of the same ATC level in the database. 
A by-subject listing of all non-study medications is provided for the enrolled analysis set. Refer to the 
Zavegepant Core SAP for listing contents. 
Prior Medications 
Prior medications will be summarized descriptively by treatment group and overall for the safety analysis 
set in two tables: one for prior medications (including both previous and current) and one for current 
medications. 
Concomitant Medications 
Concomitant medications will be summarized descriptively by treatment group and overall for the safety 
analysis set. 
Extent of Exposure 
Study drug is zavegepant 300 mg daily, i.e., six 25 mg softgel capsules twice daily, taken in the morning 
and the evening. Study drug is dispensed in a wallet-type blister pack with a unique wallet ID and 8 
wallets are placed into a subject specific kit with a unique kit ID. Each wallet covers 4 days of morning 
dosing (6 capsules) and evening dosing (6 capsules) dosing, for a total of 48 capsules. Sites will record 
the kit and wallet IDs dispensed to each subject on the Drug Accountability CRF. 
Subjects report study drug exposure in the eDiary, whereas sites report study drug accountability in the 
Drug Accountability CRF. 


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Study drug exposure is tabulated as continuous or categorical variables by treatment group and overall 
for the safety analysis set and includes the following parameters: 
• 
Time from study drug start to last contact (days), derived as: last contact date – study drug start 
date + 1 
• 
Time on study drug (days), derived as: study drug end date – study drug start date + 1 
• 
Time on study drug categories (weeks): 1, 2, 3, 4, or > 4 
• 
Cumulative study drug exposure (mg), derived by summing {number of capsules × 25} across 
records with complete study medication start dates 
• 
Average study drug exposure (mg per day), derived as cumulative study drug exposure/time on 
study drug (days) 
• 
Total study drug exposure (mg) summed across all subjects, derived by summing cumulative 
exposure across all subjects 
• 
Total study drug exposure (patient-years), derived by summing (study drug end date – study drug 
start date + 1)/365.25 across all subjects. 
 
Study drug accountability is tabulated by treatment group and overall for the safety analysis set that 
includes the number and percentage of subjects in the following category: 
• 
Study drug taken but subject not randomized 
• 
Kit dispensed and all 8 wallets returned 
• 
Kit dispensed and all 8 wallets not returned 
o 
Reason for wallets not being returned 
• 
Number of capsules returned 
• 
Number and percentage of subjects who took > 12 capsules on any 1 day 
• 
Any partial/missed doses 
• 
Compliance < 80%, derived as: (number of capsules dispensed – number of capsules 
returned)/(number of capsules expected to be taken) x 100% 
• 
No study drug taken for ≥ 3 days (not necessarily consecutive) in any 1 week 
• 
Incorrect study drug taken: all the time, or at least once 
 
Incorrect study drug at least once means subject is (1) randomized to placebo group but received >=1 
dose of study drug from study drug kit/container or (2) randomized to study drug group but received >=1 
dose of study drug from placebo kit/container. 
Incorrect study drug all the time means subject received incorrect study drug at least once (as defined 
above) and never received any randomized study drug. 
A by-subject listing of study drug accountability is provided for the safety analysis set. Additionally, a by- 
subject listing of study drug accountability for partial/missed doses is provided for the safety analysis set. 
An administrative listing of IP batch numbers is provided for the safety analysis set. Refer to the Core 
SAP for listing contents. 


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Efficacy 
 
Efficacy will be measured via spirometry and lung function assessments. These assessments will be 
performed after each study dose treatment at Visit 5, Visit 6, Visit 7, and Visit 8. Methacholine PC20 and 
airway inflammation will be assessed before and after study dose treatment, and allergen-induced 
methacholine PC20, allergen-induced bronchoconstriction, and allergen-induced airway inflammation will 
be assessed following allergen challenges. All efficacy assessments will be performed on the mITT 
analysis set. 
 
The methacholine inhalation test will be performed at Visit 2, Visit 4, Visit 5, Visit 6, and Visit 8. This test 
will measure FEV1 at 30 and 90 seconds after each inhalation and, if necessary, at 180 and 300 seconds 
and beyond until the lowest response is captured. The test is terminated when a fall in FEV1 of at least 
20% (lowest post diluent FEV1 versus lowest post methacholine concentration FEV1) occurs, and the 
methacholine PC20 is calculated. The PC20 assessment will be performed at the start of each treatment 
period, then 24 hours before and 24 hours following allergen challenge as a measure of AHR. 
The allergen inhalation challenge will be performed at Visit 3 and Visit 7. At Visit 3, doubling 
concentrations of allergen will be given until a 20% decline in FEV1 is measured 10 minutes post-allergen 
inhalation versus baseline FEV1. The FEV1 will then be measured at regular intervals: 10, 20, 30, 45, 60, 
90, 120 minutes, and 3, 4, 5, 6, and 7 hours after allergen inhalation to confirm both ≥20% fall in FEV1 
(EAR) and ≥15% fall in FEV1 (LAR). The same final 3 doses of allergen administered during the 
screening period are administered during the dosing period challenge. The EAR is taken to be the largest 
fall in FEV1 wihin 2 hours after allergen inhalation and the LAR is taken to be the largest fall in FEV1 
between 3 and 7 hours after allergen inhalation. The concentration of allergen that resulted in a 20% 
decline in FEV1 will be selected for the allergen challenges at Visit 7 and Visit 8. 
 
Sputum induction will be performed at Visit 2, Visit 3, Visit 4, Visit 5, Visit 6, Visit 7, and Visit 8. It will be 
performed 24 hours before allergen challenges and at 7 and 24 hours after allergen challenges, at the 
start of each treatment period, again at 24 hours before allergen challenges, and at 7 and 24 hours after 
allergen challenges. 
 
 
 
Allergy skin testing will be performed at Visit 1 or Visit 2. It will determine the allergen that is given to 
each patient in the inhalation allergen challenge. If an allergen provokes an allergic reaction, a raised 
itchy bump (wheal) and redness (flare) develops. The size of the wheal will be measured and recorded 
with a ruler in millimeters in the horizontal and vertical directions, perpendicular to each other after 
approximately 15 minutes. The size of the wheal for each antigen will be recorded. A reaction greater 
than 2 x 2 mm will be regarded as positive, provided that the positive and negative controls are 
appropriately positive (histamine) and negative (diluent), respectively. 
 
Allergy skin titration testing will be performed at Visit 1 and Visit 2. It will identify the lowest titration of 
allergen that causes a skin wheal at least 2 x 2 mm in size. The diameter of each wheal is measured in 2 
perpendicular directions after 10 minutes. The average wheal diameter for each dilution in the horizontal 
and vertical directions is recorded. The weakest dilution of allergen that produces an average wheal of at 
least 2 x 2 mm is the “skin test endpoint.” This measurement is used to calculate the starting allergen 
dose for inhalation. 
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Primary Efficacy Endpoint and Analysis 
Late Asthmatic Response 
The primary efficacy endpoint is allergen-induced LAR, as assessed by maximum percentage decrease 
in FEV1 between 3 and 7 hours post-allergen challenge at Visit 7, compared between zavegepant and 
placebo using analysis of covariance (ANCOVA). The maximum percentage decrease is the difference 
between the baseline (pre-allergen challenge) FEV1 at Visit 7 and lowest FEV1 between hours 3 and 7 at 
Visit 7 divided by the baseline value from Visit 7. An ANCOVA model based on the decrease in FEV1 
between 3 and 7 hours post-allergen challenge with treatment as a factor and baseline LAR as a 
covariate will be fitted. The point estimate and 95% CIs will be reported for the difference in LARs 
comparing zavegepant and placebo. 
The LAR will also be assessed by an area under the curve (AUC) for the percent decrease in FEV1 value 
between 3 to 7 hours. The AUC for percent decrease in FEV1 will be compared between zavegepant and 
placebo using ANCOVA. ANCOVA model based on the AUC for the percent decrease in FEV1 between 
3 and 7 hours at Visit 7 with treatment as a factor and baseline (pre-allergen challenge) FEV1 at Visit 7 as 
a covariate to adjust for AUC will be fitted. AUC will be calculated using the trapezoidal method to 
estimate the areas over the observation time. The point estimate and 95% CIs will be reported for the 
difference in AUCs comparing zavegepant and placebo. 
Additional supportive endpoints, including minimum absolute FEV1 value in 3 to 7 hours and AUC of the 
absolute FEV1 values in 3 to 7 hours at Visit 7 will also be analyzed. The minimum absolute FEV1 will be 
the lowest value between hours 3 and 7 post-allergen challenge at Visit 7 and AUC will be calculated as 
described above. Both endpoints will be compared between zavegepant and placebo using an ANCOVA 
model with treatment as a factor and baseline FEV1 at Visit 7 as a covariate. The baseline value is the 
measurement prior to dosing at Visit 7. The point estimate and 95% CIs will be reported for the difference 
in minimum absolute FEV1 or AUC when comparing zavegepant and placebo. 
The time-response curve of allergen-induced percentage decrease in FEV1 may be plotted for baseline 
(screening allergen challenge) and Visit 7. 
Secondary Efficacy Endpoints and Analyses 
The secondary efficacy endpoints are the allergen-induced EAR assessed as maximum percentage 
decrease in FEV1 between 0 and 2 hours after the administration of allergen inhalation challenge and 
allergen-induced change in AHR (methacholine PC20) at 24 hours post-allergen challenge. 
 
Early Asthmatic Response 
The maximum percentage decrease in FEV1 between 0 and 2 hours at Visit 7 will be compared 
between zavegepant and placebo using ANCOVA. The maximum percentage decrease is the 
difference between the baseline (pre-allergen challenge) FEV1 at Visit 7 and the lowest FEV1 
between 0 and 2 hours at Visit 7 divided by the baseline value from Visit 7. An ANCOVA model 
based on the decrease in FEV1 between 0 and 2 hours at Visit 7 with treatment as a factor and 
baseline FEV1 at Visit 7 as a covariate will be fitted. The baseline value is the measurement prior to 
dosing at Visit 7. The point estimate and 95% CIs will be reported for the difference in AUCs 
comparing zavegepant and placebo. 
Additionally, as a supportive analysis for the EAR, the AUC for percent decrease in FEV1 between 0 
and 2 hours at Visit 7 will be compared between zavegepant and placebo using ANCOVA. AUC will 


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be calculated as described in Section 8.1.1. An ANCOVA model based on the AUC for the percent 
decrease in FEV1 between 0 and 2 hours at Visit 7 with treatment as a factor and baseline (pre- 
allergen challenge) FEV1 at visit 7 as a covariate will be fitted. The baseline value is the pre-allergen 
challenge measurement at Visit 7. The point estimate and 95% CIs will be reported for the difference 
in AUCs comparing zavegepant and placebo. 
The minimum absolute FEV1 value in 0 to 2 hours and AUC of the absolute FEV1 values in 0 to 2 
hours at Visit 7 will also be analyzed. AUC will be calculated as described in Section 8.1.1. The 
minimum absolute FEV1 will be the lowest value between hours 0 and 2 post-allergen challenge at 
Visit 7. Both endpoints will be compared between zavegepant and placebo using an ANCOVA model 
with treatment as a factor and baseline FEV1 at Visit 7 as a covariate. The baseline value is the 
measurement prior to dosing at Visit 7. The point estimate and 95% CIs will be reported for the 
difference in minimum absolute FEV1 or AUC comparing zavegepant and placebo. 
Methacholine PC20 
The methacholine PC20 will first be normalized by log transformation. The shift will be measured as the 
difference in the concentration of methacholine required to cause a 20% decline in FEV1 pre- and post- 
allergen exposure. Specifically, shift in PC20 is calculated as post-allergen challenge – pre-allergen 
challenge (Visit 8 – Visit 6), and baseline shift in PC20 will be calculated as post – pre (Visit 4 – Visit 2). 
The pre- versus post-allergen shift in PC20 will be compared between zavegepant and placebo using 
ANCOVA. The ANCOVA model will include treatment as a factor and baseline shift as a covariate. Pre- 
and post-allergen challenge methacholine PC20 will be summarized descriptively with geometric mean 
and range. 
 
The methacholine PC20 geometric means may be presented graphically. 
CCI 
 


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Pharmacokinetics 
 
Not applicable. The PK data will not be analyzed for this CSR. 


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Safety 
 
All safety analyses will be performed using the safety analysis set. Safety will be assessed based on AEs, 
clinical laboratory data, spirometry, S-STS, physical examinations, vital signs. 
Analysis periods are pre-treatment, on-treatment, and follow-up. Refer to Core SAP about slotting safety 
parameters into analysis periods. 
Safety parameters are tabulated descriptively as continuous variables at baseline and each scheduled 
visit over time during the pre-treatment, on-treatment, and follow-up analysis periods. 
By-subject listings of safety parameters are described in subsections. 
 
Adverse Events 
All reported AEs will be coded using the MedDRA coding dictionary version 24.0 or later, andsummarized 
by System Organ Class (SOC) and Preferred Term (PT),. 
Refer to the Core SAP for AE start date imputation, AE counting rules, definition of AEs related to study 
drug, definition of AEs of special interest, and TLF contents. 
Tables present number and percentage of subjects experiencing AEs by SOC and PT, unless specified 
otherwise. AEs are tabulated in descending order of overall frequency within SOC and PT. 
A by-subject listing of AEs is provided for the enrolled analysis set. 
 
Deaths 
Deaths are identified from the following sources: 
• 
AE CRF: PT or reported term containing “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?”); or non-missing death date. 
• 
Subject Disposition CRF: study non-completion reason of death. 
A by-subject listing of deaths is provided for the enrolled analysis set. 
AE Overview 
An AE overview without SOC and PT presents the number and percentage of subjects with any of the 
following AEs: any AE, mild AE, moderate AE, severe AE, moderate or severe AE, AE related to study 
drug, AE leading to study drug discontinuation, SAE, SAE related to study drug, SAE leading to study 
drug discontinuation, potential drug abuse AE, hepatic-related AE, cardiovascular AE, and suicidality AE. 
 
An AE overview is produced for each analysis period (pre-treatment, on-treatment) for the safety analysis 
set. 
 
On-treatment AEs 
 
On-treatment AEs are tabulated for the safety analysis set by SOC and PT for the following endpoints: 
• 
AEs by intensity (total, mild, moderate, severe, moderate or severe, not reported) 
• 
AEs related tostudy drug by intensity 


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• 
AEs by relationship to study drug (related, possibly related, unlikely related, not related, not 
reported) 
• 
SAEs 
• 
AEs leading to study drug discontinuation 
Follow-up AEs 
 
Follow-up AEs are tabulated for the safety analysis set by SOC and PT for the following endpoints: 
• 
AEs by intensity (total, mild, moderate, severe, moderate or severe, not reported) 
• 
SAEs 
Laboratory Evaluations 
Laboratory parameters include, but are not limited to, assessments in Table 3. 
Table 3. Laboratory Parameters 
Hematology 
Serum Chemistry 
Urinalysis 
Full and differential blood 
count 
albumin 
ALT 
appearance 
pH 
Hct 
ALP 
protein 
Hb 
AST 
glucose 
MCH 
BUN or urea 
ketone bodies 
MCHC 
carbon dioxide 
specific gravity 
MCV 
creatinine 
urobilinogen 
Platelet count 
RBC count 
WBC count with differential 
eGFR 
creatine phosphokinase 
electrolytes (sodium, 
potassium, chloride, calcium, 
phosphorus) 
bilirubin 
occult blood 
nitrates 
leukocytes 
GGT 
glucose 
LDH 
total bilirubin 
direct and indirect bilirubin 
total cholesterol 
LDL 
HDL 
triglycerides 
Pregnancy test: A human chorionic gonadotropin (hCG) blood test will be conducted on all WOCBP at 
screening; an hCG urine test will be conducted at all subsequent visits according to Error! Reference 
source not found.. 
Urine drug screen: Drugs of abuse include, but are not limited to, amphetamines, barbiturates, 
benzodiazepines, tetrahydrocannabinol, cocaine, opiates, and PCP (see Error! Reference source not 
found. Assessments). Retesting for positive results that are exclusionary is not allowed. 
Sputum test: Refer to Section Error! Reference source not found. of protocol. 
Abbreviations: ALP=alkaline phosphatase; ALT=alanine aminotransferase; AST=aspartate 
aminotransferase; BUN=blood urea nitrogen; eGFR=estimated glomerular filtration rate; GGT=gamma- 
glutamyl transpeptidase; Hb=hemoglobin; HBV=hepatitis B; Hct= hematocrit; HDL=high-density 


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lipoproteins; LDH=lactate dehydrogenase; LDL=low-density lipoproteins; MCH=mean corpuscular 
hemoglobin; MCHC=mean corpuscular hemoglobin concentration; MCV=mean corpuscular volume; 
PCP=phencyclidine; pH=potential hydrogen; RBC=red blood cell; WBC=white blood cell; 
WOCBP=women of childbearing potential. 
 
Blood and urine samples will be analyzed at a central laboratory facility. Each subject will be assessed 
with the following laboratory tests and parameters: 
• 
Clinical laboratory samples will be collected Visit 1, Visit 5, Visit 8, and at Follow-Up. 
• 
Urinalysis samples will be collected at Visit 1, Visit 5, and Visit 8. 
• 
A serum pregnancy test will be conducted at Screening and urine pregnancy testing at Visit 5 and 
Visit 8. 
• 
Urine drug testing will be performed at Visit 1 only. 
 
Urine samples will be analyzed by dipstick, and a microscopic analysis will be performed if the results of 
dipstick indicate abnormalities to be further investigated. 
TLFs show data in the Systeme Internationale (SI) unit system, if applicable. Tables present results by 
treatment group and overall, and laboratory tests alphabetically within laboratory test group, as 
applicable. 
Clinically significant laboratory test abnormalities will be identified as Grade 3 to Grade 4 laboratory test 
results graded accordingly 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 AEs. If a subject has a laboratory test abnormality with 
different toxicity grades over time, then only the highest toxicity grade will be reported in the lab 
abnormality summary table. Refer to the Core SAP for laboratory tests of clinical interest for analyses, 
including identification of those with toxicity grades. 
Laboratory Test Abnormalities 
On-treatment laboratory test abnormalities are tabulated as the number and percentage of subjects in the 
safety analysis set in the following tables: 
• 
Worst (highest) on-treatment laboratory test abnormality for each graded laboratory test. 
• 
Laboratory test toxicity grade shift from baseline to the worst on-treatment toxicity grade for each 
graded laboratory test. 
Refer to the Core SAP for toxicity grade categories and additional details. 
Liver Function Test Elevations 
 
Refer to the Zavegepant Core SAP for LFT elevation categories and additional details. 
 
LFT Elevations: Cumulative, Mutually Exclusive, and Composite 
 
LFT elevations are based on fold changes above ULN. The number and percentage of subjects with 
prespecified LFT elevations are tabulated separately for each analysis period (pre-treatment, on- 
treatment) for the safety analysis set. 
LFT ULN Shifts from Baseline to Worst Elevation 


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LFT ULN shifts from baseline to the worst (highest) on-treatment LFT elevation are tabulated as the 
number and percentage of subjects in the safety analysis set in pre-specified elevation categories. 
 
LFT Plots 
 
An evaluation of drug-induced serious hepatotoxicity (eDISH) scatter plot displays the maximum TBL ratio 
of value to ULN on the y-axis versus the maximum ALT ratio of value to ULN on the x-axis by treatment 
group, where both maxima are on treatment but not necessarily concurrent. 
Laboratory Test Changes from Baseline 
Values and changes from baseline in hematology and serum chemistry laboratory tests are tabulated 
descriptively as continuous variables at baseline and each scheduled visit in the on-treatment and follow- 
up analysis periods. 
Laboratory Test Listings 
 
All laboratory test listings will be based on the enrolled analysis set. 
 
A by-subject listing of the following select laboratory tests is provided for subjects with at least one 
laboratory assessment of grade 3 or 4 abnormality or a positive pregnancy test result: hematology results, 
serum chemistry results, and urinalysis results. If there is a positive pregnancy test, defined as a serum or 
urine pregnancy test with either (1) “positive” character value, or (2) numeric value ≥ 25 U/L. the listing will 
also include all pregnancy test results over time. 
Refer to Section 6.4.2.6 of the Core SAP for listing contents as applicable to this study. 
A by-subject 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 Section 6.4.2.6 of the Core SAP for listing 
contents as applicable to this study. 
Vital Signs and Physical Measurements 
Vital signs will be taken at Visit 1, Visit 5, Visit 6, Visit 7, and Visit 8. 
 
The vital signs to be captured are systolic blood pressure, diastolic blood pressure, heart rate, respiratory 
rate, and temperature. Temperature will be presented in summaries and listings in Celsius (Temperature 
(in °C) = 5/9 (Temperature [in °F]-32)). 
Vital Sign and Physical Measurement Change from Baseline 
Values and changes from baseline in vital signs and physical measurements will be tabulated 
descriptively as continuous variables at baseline and each scheduled visit in the on-treatment analysis 
period. 
Vital Sign and Physical Measurement Abnormalities 
On-treatment vital sign and physical measurement abnormalities are tabulated as the number and 
percentage of subjects in the safety analysis set in categories specified in the Core SAP. 
Spirometry 
Spirometry will be measured at every visit during Part 1 (Screening) and after each study dose treatment 
at Visits 5 through 8. Spirometry is used to monitor baseline lung function and gauge the level of 
bronchoconstriction during methacholine and allergen challenges. Measurements include: forced vital 
capacity (FVC) in liters, FEV1 in liters, and the percentage of predicted FEV1 value. Results are tabulated 


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pre-treatment and on-treatment for the safety analysis set. On-treatment data will also include changes 
from baseline. 
S-STS 
The S-STS is a prospective, clinician-administered rating questionnaire with 16 patient-reported questions 
and 6 clinician-reported questions that tracks both treatment-emergent suicidal ideation and behaviors. 
The S-STS will be performed at Visit 1, Visit 5, and Visit 8. 
 
Refer to the Core SAP for calculation of the S-STS ideation subscale, behavior subscale, and total 
scores. 
Values and changes from baseline in the self-reported S-STS ideation subscale, behavior subscale, and 
total score are tabulated descriptively as continuous variables at baseline and the worst (highest) score in 
the analysis periods. The table also presents the number and percentage of subjects in the worst 
(highest) score change from baseline category (i.e., < -1, -1, no change, 1, >1) in analysis periods for the 
ideation subscale, behavior subscale, and total score. 
Results are tabulated on-treatment for the safety analysis set. 
 
Safety Narratives 
 
A by-subject listing of safety narrative subject identifiers is provided for the following select events and 
analysis sets as columns: 
• 
Deaths for the enrolled analysis set 
• 
On-treatment and follow-up SAEs for the safety analysis set, regardless of relationship to study drug 
• 
AEs leading to discontinuation of study drug across all analysis periods for the safety analysis set, 
regardless of relationship to study drug 
• 
On-treatment events of special interest for the 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 AEs, i.e., PTs containing cirrhosis, hepatic failure, hepatitis, jaundice, or 
liver failure 
o 
Cardiovascular AEs 
o 
Suicidality AEs 
Refer to the Core SAP for additional details. The listing flags subjects with select events. 
 
Should the criteria stated in the Biohaven Zavegepant Safety Narrative Scope conflict with the criteria 
above, the Biohaven Zavegepant Safety Narrative Scope will take precedence. 
 
 
COVID-19 Impact 
 
COVID-19 impact will not be analyzed for the CSR. 


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Conventions 
 
Derived Dates 
 
Derived dates for defining analysis periods are defined as follows: 
 
• 
Study drug start date: Date of first dose of study drug from Study Drug Accountability CRF. 
 
• 
Imputed study medication stop date: If the study medication stop date is (1) non-complete or (2) 
complete but before the study medication start date, then the imputed stop date is set to the study 
medication start date. Otherwise, the imputed stop date is set to the complete study medication stop 
date. Derived only for subject dosing diary 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 and (2) imputed study 
medication stop dates. Both (1) and (2) are from subject dosing diary records with number of 
capsules taken > 0. 
 
• 
Study drug last date: Study drug end date derived only for subjects with non-missing response to the 
question “Did the subject complete the study (including the follow-up visit)?” on the Subject 
Disposition CRF. Thus, in an interim analysis, all post-baseline data are included for a subject who is 
still on study. At the last database lock, the study drug last date is equal to the study drug end date. 
 
• 
COVID-19 visit date: (1) Complete visit date, if it exists; (2) otherwise, complete date the visit was 
planned to occur for a missed visit. 
 
• 
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 stop; COVID-19 visit for in-person or remote visits; 
ECG; informed consent; laboratory test collection; non-study medication start or stop; physical exam; 
physical measurement; procedure; questionnaire; study medication start or stop; vital sign; visit. 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: Last contact date derived only for subjects who died (see Section 11.1). 
 
No imputations are performed on these derived dates unless specified otherwise. Complete dates are 
those with valid, non-missing day, month, and year. 
Analysis Periods 
 
Analysis periods are defined as follows: 
 
• 
Pre-treatment: measurement date/time on or before the study drug start date. This period is used to 
derive baseline values and to assess safety endpoints. Note that all measurements are pre-treatment 
for subjects in the enrolled analysis set with missing study drug start date. Note that AEs with imputed 
start date equal to the study drug start date are NOT part of this period. 
 
o 
Pre-treatment will include Visits 1 – 5 / Study Days -29 – 1 
• 
On-treatment: measurement date/time after the study drug start date through the study drug last date 
+ 7 days or ending at the follow-up visit, whichever is earliest. This period is used to assess safety 
endpoints on treatment. Note that AEs with imputed start date equal to the study drug start date are 
part of this period. 


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o 
On-treatment will include Visits 6 – 8 / Study Days 1 – 28 
• 
Follow-up: measurement date after the study drug last date + 7 days or starting at the follow-up visit, 
whichever is earliest. This period is used to assess safety endpoints during follow-up. 
 
o 
Follow-up will include Visit 9 / Study Days 35 – 41 
See Section 11.1 for derived dates for determining analysis periods. If measurement time is missing, not 
collected, or not applicable for a parameter, then the measurement date is compared to the derived date. 


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Interim Analyses 
 
No interim analyses are planned for this study. 


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Changes from Analysis Planned in Protocol 
 
The Treated Population is defined in the study protocol. However, it has been renamed the Safety 
Population in the SAP. 
 
One additional study populations were added that are not defined in the study protocol, the Follow-up 
population. 


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Quality Control 
 
SAS programs are developed to produce output such as analysis data sets, summary tables, data 
listings, figures or statistical analyses. An overview of the development of programs is detailed in Syneos 
Health Developing Statistical Programs SOP (3907) . 
Syneos Health Developing Statistical Programs SOP (3907), Conducting the Transfer of Biostatistical 
Deliverables SOP (3908) and the SAS Programming and Validation Plan describes the quality control 
procedures that are performed for all SAS programs and output. Quality control is defined here as the 
operational techniques and activities undertaken to verify that the SAS programs produce the output by 
checking for their logic, efficiency and commenting and by review of the produced output. 


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Shells 
 
The TFL shells will be provided as a separate document. 


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Appendices 


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Appendix A Relevant Protocol Deviations 
 
Relevant eligibility protocol deviations include the following categories: 
• 
Respiratory disease other than mild intermittent asthma 
• 
Baseline FEV1 < 70% of predicted value 
• 
Score on the Sheehan-Suicidality Tracking Scale (S-STS) at screening > 0 
• 
Methacholine challenge (PC20 > 16 mg/mL) 
• 
History of liver disease or viral hepatitis 
• 
History of HIV 
• 
Use of tobacco products and/or vaping products within the previous 12 months or smoking history 
> 10 pack years. 
• 
Positive drug screen 
• 
Findings out of range, defined any as any of the following subcategories: 
o 
At any time during the study: 
 
Females with a positive pregnancy test 
o 
During pre-treatment period: 
 
ALT ≥ 1.5x ULN 
 
AST ≥ 1.5x ULN 
 
Direct bilirubin ≥ 1.5x ULN 
 
Indirect bilirubin ≥ 1.5x ULN 
 
Total bilirubin ≥ 1.5x ULN 
 
BMI ≥ 33 kg/m2 
 
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 
 
Systolic blood pressure > 150 mmHg 
 
Diastolic blood pressure > 100 mmHg 
 
 
Relevant subject management protocol deviations include the following categories: 
• 
Study drug dosing 
o 
< 80% compliance 
• 
Study drug dosing error, defined as any of the following subcategories: 
o 
Study drug taken but not randomized 
o 
Study drug actually received different from randomized treatment assignment 
• 
Missed study exit visit 
• 
Missed methacholine challenge, skin allergen challenge, allergen challenge 
• 
Washout period after methacholine challenge and sputum induction on Visit 4 other than 2-4 
weeks 
• 
Visit 5 methacholine challenge FEV1 < 90% of baseline for FEV1 
• 
Visit 9 (follow up onsite visit) conducted outside 7-10 day after last study treatment window 
• 
Use of any prohibited medications (refer to Table 9.1 in the protocol) on or after informed consent 
o 
CGRP targeting medications 
o 
Anti-IgE therapy 
o 
Allergy immunotherapy 
o 
Investigational drug 
o 
Systemic, inhaled, topical nasal steroids 
o 
Immunosuppressives 
o 
Anticoagulants 
o 
Theophylline 
o 
Nedocromil or cromoglycate 
o 
Modafinil 


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o 
St. John’s wort 
o 
Atypical antipsychotics such as aripiprazole, olanzapine, quetiapine, risperidone, 
ziprasidone 
o 
Mood stabilizers such as lithium, lamotrigine or divalproex/valproic acid/valproate 
o 
Strong cytochrome P450 3A4 (CYP3A4) inhibitors or inducers such as 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, 
apalutamide, carbamazepine, phenobarbital, phenytoin, rifampin, rifapentine, St. John’s 
wort 
o 
Potent P-glycoprotein (P-gp) inhibitors or inducers such as amiodarone, clarithromycin, 
cyclosporine, dronedarone, itraconazole, lapatinib, propafenone, quinidine, ritonavir, 
verapamil 
o 
Leukotriene modifiers 
o 
Long-acting beta agonists 
o 
Long-actine anticholinergics 
o 
Antimuscarinics 
o 
Non-steroidal anti-inflammatory drugs