BHV3500-203: Phase 2/3: Double-Blind, Randomized, Placebo Controlled, Safety and Efficacy Trial of Zavegepant (BHV-3500) Intranasal (IN) for Hospitalized Patients With COVID-19 Requiring Supplemental Oxygen
Phase: PHASE2
Conditions: COVID-19 Infection
Sponsor: Pfizer

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DRUG: 
Zavegepant 
 
 
STUDY NUMBER(S): 
BHV3500-203 
 
 
PROTOCOL TITLE: 
BHV3500-203: Phase 2/3: Double-Blind, 
Randomized, Placebo Controlled, Safety and Efficacy 
Trial of Zavegepant (BHV-3500) Intranasal (IN) for 
Hospitalized Patients with COVID-19 Requiring 
Supplemental Oxygen 
 
IND NUMBER: 
CCI  
 
 
 
EudraCT NUMBER: 
NA 
(if applicable) 
 
SPONSOR: 
Biohaven Pharmaceuticals, Inc. 
 
 
ORIGINAL PROTOCOL DATE: 
13 April 2020 
 
 
VERSION NUMBER: 
V 7.0 
 
 
VERSION DATE: 
11 May 2022 

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SUMMARY OF CHANGES 
 
Version Number 
Brief Description Summary of Changes 
Date 
Version 1.0 – Original 
Not Applicable 
13 April 2020 
Version 2.0 
• 
Incorporation of Administrative Letter #1: clarification 
of Visit Day vs. Calendar Day and addition of windows 
to Day 14, Day 15, and Day 16. 
• 
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• 
Clarification around dosing every 8 hours to allow for a 
window of +/- 2 hours 
• 
Clarification of Inclusion Criteria #6 to specify non- 
invasive supplemental oxygen 
• 
Clarification of Exclusion Criteria # 1to specify invasive 
mechanical ventilation. 
• 
Change to exclusion #8 to allow for 48 hours of 
supplemental oxygen prior to randomization 
• 
Clarification to exclusion criteria #9 to define severe 
COPD as exclusionary 
• 
Change to Exclusion Criteria #13 to allow for subjects 
with ALTs and ASTs up to 5x ULN to be allowed 
• 
Clarification of Secondary Objectives #2, 4, and 5 to 
specify invasive mechanical ventilation 
• 
Clarification of Secondary Objective #8 to specify 
SpO2/FiO2 ratio 
• 
Reordering of Secondary Objectives and Secondary 
Endpoints 
• 
Clarification throughout the protocol that creatinine 
clearance is assessed via measurement of eGFR 
• 
Removal of MDRD as the required calculation for 
eGFR 
• 
Update to Study Schematic Changes throughout the 
protocol to allow Clinical Safety labs, LFTs, urinalysis, 
NEWS2 assessments, Vitals, PE, SpO2, FiO2, ECG, 
and chest x-ray collected within 48 hours of signing 
Informed Consent to be used as Screening assessments. 
• 
Clarification throughout the protocol that clinically 
important clinical labs, urinalysis, LFTs, ECGs, and 
chest X-rays that are collected as per SOC on non- 
06 May 2020 

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protocol specified days should be collected in the eCRF 
from Days 1 through 29 
• 
Clarification throughout the protocol that SOFA is 
collected upon admission to the ICU and collected 
again, only if subject is still in ICU at Day 29 
• 
Clarifications to Schedule of Assessments 
• 
Clarification about collection of serum sample for 
SARS-CoV2 antibody analysis and sample for CGRP 
evaluation 
• 
Clarification of Day 60 Safety Follow-up visit 
• 
Clarification to early discontinuation from 
investigational product 
• 
Change to Early Discontinuation from the Study 
parameters to correct typo. 
• 
Clarifications to Dose and Administration to specify 
completing treatment as completing 42 doses of study 
drug 
• 
Change to Definition of Serious Adverse Event to 
include admission to the ICU as an SAE 
• 
Update to Collection and Reporting of Serious Adverse 
Events to provide email information for PVG vendor 
• 
The analysis of the primary endpoint was changed to 
use a Mixed Model for Repeated Measures. 
• 
Clarification made to Missing Data for the Mixed Model 
for Repeated Measures 
• 
Various typos have been corrected 
Version 3.0 
• 
Correction of minor typos throughout the document 
• 
Specification throughout the protocol that subjects 
whose eGFR declines to < 15 mL/min will be 
discontinued from study drug 
• 
Further clarification throughout the protocol that EOT is 
when the patient takes the last dose of study drug which 
may not necessarily be Day 15 and that if an EOT visit 
is performed prior to subject completing treatment, then 
Day 15 is a telephone visit 
• 
Change to Exclusion Criteria # 2 to exclude patients 
with eGFR < 30 mL/min from < 60 mL/min 
• 
The wording for objectives that involved “numbers of 
subjects” or “percentages of subjects” was harmonized 
to “proportion of subjects” 
• 
Clarification of wording for Secondary Objective # 24 
19 June 2020 

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• 
Minor changes to the study schematic 
• 
Inclusion of Section 1.3.3 to provide rationale to include 
patients with eGFR 2. 30 mL/min into the trial. Subjects 
whose eGFR drops to <15 mL/min while on study will 
be discontinued from study drug. 
• 
The wording of the primary endpoint was clarified to 
indicate the treatment groups will be compared based on 
their average difference on the 6 point severity scale. 
• 
The wording for endpoints that involved “numbers of 
subjects” or “percentages of subjects” was harmonized 
to “proportion of subjects” 
• 
Clarification of wording for Secondary Endpoint # 24 
• 
Clarification that Visit Days 22 and 29 have a window 
of +/- 2 days 
• 
Clarification of the Schedule of Assessments to specify 
AE and SAE collection periods, CCI 
 
and to specify urinalysis and 
safety labs that need to be collected in the table 
• 
Additional clarifications to descriptions in the Schedule 
of Assessments for chest x-ray collection, concomitant 
medication collection, and Telephone visits 
• 
Clarification of Sections 4.3.6.1 and 4.3.6.2 surrounding 
the timeframe for capturing of AEs and SAEs 
• 
Clarification to Section 4.3.7 about collection of SAEs 
• 
Update to Section 6.1 concerning labels for CGRP 
samples and clarification about the local laboratory 
collection 
• 
Clarification to Section 6.3.5 to specify that clinically 
significant laboratory abnormalities need to be collected 
out to Day 29 
• 
Clarification to Section 6.3.5.1 to match order of lab 
collection data in eCRF 
• 
 
• 
Clarification in Section 6.3.5.3 to indicate Syneos 
Laboratory Manual for PK sampling and to provide 
further clarification around the collection of PK 
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samples. 
• 
Clarification to Section 6.3.5.4 about the serum sample 
for SARS-CoV2 antibody testing 
• 
Change to section 6.6 to adjust requirement to 
discontinue subjects from study drug if eGFR drops to < 
15 ml/min 
• 
Clarification to Section 7.2 to specify that when 
possible, drug should be dispensed if subject is 
transferred to another acute care facility 
• 
Further clarification to Section 8.3.1 (Definition of 
Serious Adverse Event) to define situations which may 
be considered as SAEs. 
• 
Clarification for collecting SAEs made to Section 8.3.2 
• 
Moved SAE sections of Overdose, Pregnancy and DILI 
to from Section 8.4 to Section 8.3 for flow – no 
language changes made to those sections 
• 
Clarification to Section 8.4.1 regarding the time period 
for collection of AEs 
• 
Clarification to Section 8.4.2 regarding the time period 
for collecting lab abnormality AEs 
• 
Version 4.0 
• 
Incorporation of Administrative Letter #3: Change of 
Generic Name for BHV-3500 from “Vazegepant” to 
“Zavegepant”.The generic name of BHV-3500 was 
revised from “vazegepant” to “zavegepant” throughout 
the protocol. Since August 2019, "vazegepant" has been 
used for BHV-3500 after this non-proprietary name was 
approved for use in the U.S. by the United States 
Adopted Names (USAN) Council. In May 2020, the 
organization responsible for establishing non- 
proprietary names for international use (the World 
Health Organization (WHO) International 
Nonproprietary Names (INN) Expert Committee) 
revised the name to "zavegepant". This change has been 
subsequently accepted by the USAN Council for use in 
the U.S. and is pending formal adoption by the INN for 
international use. 
• 
The collection of concomitant procedures, which are 
captured from first dose of study drug through Day 29 
(except for the start of supplemental oxygen within 48 
hours of randomization) has been added throughout the 
protocol. 
12 August 2020 

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• 
Clarifications made to Secondary Objectives to define 
the population for analysis. 
• 
The Study Schematic has been updated to reflect 
concomitant procedures collection. 
• 
The Schedule of Assessments has been updated to 
include collection of concomitant procedures, 
identification that admission and discharge from the 
ICU should be captured on the AE eCRF, and 
clarification of the collection of the SOFA assessment. 
• 
eCRF sources were clearly defined for efficacy 
measures, thus, endpoint definitions were modified to 
all relevant sources 
• 
Clarification to collection of ECG data beyond 
screening if clinically significant and to collect all chest 
X-ray data if done as SOC beyond Day 15. 
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• 
Clarification to Section 8 to indicate that for this study, 
admission and discharge to the ICU needs to be 
captured on the Adverse Event eCRF. 
• 
Clarification that laboratory test data related to an SAE 
should be collected out to Day 60. 
• 
Clarifications made to the statistical methods Section 
9.3. 
Version 5.0 
(note Version 5.0 Protocol 
was completed and approved 
on 09 Nov 2020 but not 
submitted because an error in 
one of the figures was 
discovered.It is superseded 
by version 6.0) 
• 
Removal of the requirement for the specific Abbot IgG 
antibody test. 
• 
Specification that antibody test needs to be done no 
earlier than Day 15 and before Day 60. 
• 
Updates concerning antibody testing in the Study 
Schematic and Schedule of Assessments, 
• 
Punctuation corrections throughout the protocol. 
• 
Clarification of the wording in Section 9.3. Statistical 
Methods section. 
09 November 2020 
Version 6.0 
• 
Corrected Study Schematic – version for submissions 
10 Nov 2020 
Version 7.0 
• 
The headers were changed to reflect the new version 
number. 
• 
The cover page was updated to reflect the new version 
number and date. 
• 
Typos corrected in Exclusion Criteria #11 in the 
Synopsis and Section 5.3 
11 May 2022 

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• 
Section 3.2 was updated to describe the CRFs to be used 
to analyze secondary endpoints 
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• 
Section 9.3.3 was updated to reflect the changes of 
secondary endpoints to exploratory endpoints. 

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STUDY SUMMARY (SYNOPSIS) 
 
Title: 
BHV3500-203: Phase 2/3: Double-Blind, Randomized, Placebo 
Controlled, Safety and Efficacy Trial of Zavegepant (BHV-3500) 
Intranasal (IN) for Hospitalized Patients with COVID-19 Requiring 
Supplemental Oxygen 
Rationale: 
Zavegepant (BHV-3500) is a potent calcitonin gene-related peptide 
(CGRP) receptor antagonist. Acute lung injury induces upregulation of 
transient receptor potential (TRP) channels which activates CGRP leading 
to both acute lung injury (pulmonary edema with acute phase 
cytokine/mediator release, with immunologic milieu shift toward Type 17 
helper (Th17) cytokines) followed by chronic lung injury with hyaline 
membrane formation, fibrosis and reduced diffusion capacity. Acute 
respiratory distress syndrome (ARDS), which is a common pathway 
resulting from diverse types of lung injury is part of this pathogenic 
process. Because Coronavirus Disease 2019 (COVID-19), which is caused 
by infection with serious acute respiratory syndrome coronavirus-2 
(SARS-CoV-2), leads to an acute insult of pulmonary epithelia, we 
postulate that a CGRP receptor antagonist may potentially blunt the severe 
inflammatory response at the alveolar level, delaying or reversing the path 
towards oxygen desaturation, ARDS, requirement for supplemental 
oxygenation, artificial ventilation or death. 
The data from this study will allow characterization of the relative safety 
and efficacy of IN zavegepant versus placebo in the treatment of 
COVID-19 infection leading to hospitalization. 
Target 
Population: 
The study will recruit male and female subjects 18 years of age and older 
with polymerase chain reaction (PCR)-documented COVID-19 infection 
that necessitates supplemental oxygen at the time of hospitalization. 
Number of 
Subjects: 
Approximately 180 subjects will be screened to randomize approximately 
120 subjects. The subjects will be randomized in a 2:1 ratio to the 
zavegepant (80 subjects) or placebo (40 subjects) treatment groups. 
Randomization will be done through an IWRS, that will be accessed by the 
unblinded research pharmacists or their designees. The randomization 
scheme will be stratified by age ( <60; 2. 60). 
Objectives: 
Primary: To evaluate the safety and efficacy of zavegepant (BHV-3500) 
compared with placebo in subjects hospitalized with COVID-19 infection 
requiring supplemental oxygen. 

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Study 
Hypothesis: 
Zavegepant reduces and slows the progression of the disease and improves 
overall outcome of COVID-19 infection. 
Study 
Design: 
This is a double-blind, randomized, multicenter, inpatient (and post- 
discharge outpatient) evaluation of the safety and efficacy of zavegepant 
(BHV-3500) as compared to placebo in the treatment of COVID-19 
associated pulmonary disease. The study drug will be zavegepant 10 mg or 
matching placebo, given as an intranasal (IN) dose every 8 hours (+/- 2 
hours) for approximately 14 days (total of 42 doses). The study will 
randomize approximately 120 subjects in a 2:1 ratio across the two 
treatment groups (zavegepant or matching placebo). The randomization 
will be stratified by age (less than 60 years vs 60 years and older). 
After signing informed consent and meeting eligibility criteria, the subject 
may be immediately randomized and dosed with the double-blind study 
medication (10 mg or matching placebo) and continue dosing every 8 
hours (Q8h) for approximately 14 days (total of 42 doses). 
For the purposes of this protocol, the start of Visit Day 1 will start when 
the 1st dose of study drug is administered until 24 hours later. Therefore, 
depending on the time the 1st dose of study drug is administered, a visit day 
may spread over 2 calendar days. The last dose of study drug could be 
administered on Visit Day 14 but could actually occur on calendar day 15 
of the study. The EOT assessments should be completed after the last dose 
of study drug and before discharge from the hospital and the subjects 
should remain in the hospital for a full 24 hours after their last dose of drug 
if they are to be released. If subjects complete all 42 doses of study drug, 
the Day 15 in-person visit is the same as the EOT visit. Randomization 
will be done through an IWRS, that will be accessed by the unblinded 
research pharmacists or their designees. so that subjects can be dosed as 
soon as possible following consent and assessment of eligibility criteria. 
After completion of treatment, subjects will be followed out to Day 60 
during the post treatment phase. 
Inclusion 
Criteria 
1. Subjects must provide informed consent in accordance with 
requirements of the study center’s institutional review board (IRB) or 
ethics committee, prior to the initiation of any protocol-required 
procedures 
2. Subjects must agree to provide all requested demographic information 
(i.e. gender, race) 
3. Subjects must be able to read and understand English or Spanish 
4. Subjects must be over the age of 18 years 

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5. Subjects must have laboratory-confirmed SARS-CoV-2 infection as 
determined by PCR-based commercial or public health assay 
6. Subjects must have symptoms that require hospitalization with 
supplemental oxygen and or non-invasive ventilation as determined 
by the admitting physician. The maximum nasal cannula O2 
concentration should be determined by the treating clinician and the 
limitations of the specific equipment 
7. Subjects must be willing and able to comply with study-related 
procedures/assessments 
Exclusion 
Criteria 
1. Subjects in immediate need of invasive mechanical ventilation or 
extracorporeal membrane oxygenation (ECMO) 
2. Subjects with an estimated glomerular filtration rate (eGFR) of < 30 
mL/min, at the Screening Visit 
3. Prisoners or subjects who are involuntarily incarcerated 
4. Subjects who are participating in any other investigational clinical trial 
while participating in this clinical trial 
5. Subjects under the age of 18 years 
6. Subjects who are pregnant (all potential female enrollees to have 
negative pregnancy test prior to investigational product [IP] 
administration) 
7. Subjects with multi-organ failure 
8. Subjects who have received more than 48 hours of supplemental 
oxygen prior to randomization 
9. Subjects with prior significant pulmonary disease (e.g., severe chronic 
obstructive pulmonary disease [COPD]/ interstitial lung disease 
[ILD]/congestive heart failure [CHF]/idiopathic pulmonary fibrosis 
[IPF]) are excluded 
10. Subjects receiving investigational therapies as part of a formal clinical 
trial for the treatment of COVID-19. During the course of this study, 
investigational therapies that may become “standard of care” to treat 
COVID-19, but are not part of a clinical trial, are allowed 
11. Subjects who are on long-acting CGRP monoclonal antibodies 
including Aimovig® (erenumab), Emgality® (galcanezumab), Ajovy® 

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(fremanezumab), and Vyepti® (eptinezumab). Additionally, the 
investigational oral CGRP receptor antagonist, atogepant, that is taken 
daily is excluded. Oral CGRP receptor antagonists, Nurtec® ODT 
(rimegepant) and UbrelvyTM (ubrogepant) that are typically used PRN 
infrequently will not be excluded as long the subject was not taking 
them on a daily basis and does not take them during the current stud 
12. Subjects who are unlikely to survive for more than 48 hours from the 
Screening Visit 
13. Subjects with any of the following abnormal laboratory values at 
screening: aspartate aminotransferase (AST) or alanine 
aminotransferase (ALT) greater than 5x upper limit of normal (ULN) 
or bilirubin greater than 2x upper limit of normal 
14. Subjects with known active tuberculosis (TB), history of incompletely 
treated TB, suspected or known extrapulmonary TB 
15. Subjects with suspected or known systemic bacterial or fungal 
infections. However, empiric antibiotics are permitted 
16. Subjects who have participated in any clinical research study 
evaluating an IP or therapy within 3 months and less than 5 half-lives 
of IP prior to the screening visit 
17. Subjects with any physical examination findings and/or history of any 
illness that, in the opinion of the study investigator, might confound 
the results of the study or pose an additional risk to the subject by their 
participation in the study 
Primary 
Objective: 
To compare the efficacy of zavegepant (BHV-3500) to placebo, in 
subjects hospitalized with COVID-19 infection requiring supplemental 
oxygen, using a six-point rating scale at Day 15 
Secondary 
Objectives 
Key Secondary Objectives 
1. To compare zavegepant to placebo on the proportion of subjects alive 
and off of oxygen at Day 29 
2. To compare zavegepant to placebo on the proportion of subjects 
requiring initiation of invasive mechanical ventilation, non-invasive 
ventilation or use of high flow nasal cannula through Day 29 
3. To compare zavegepant to placebo on the proportion of subjects 
admitted into an intensive care unit (ICU) through Day 29 
Other Secondary Objectives 

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1. To examine the safety of zavegepant, relative to placebo, as reflected 
by the number of: deaths; SAEs; severe AEs; and Grade 3 or 4 
laboratory test abnormalities 
2. To examine the safety of zavegepant, relative to placebo, as reflected 
by the incidence of severe or life-threatening bacterial, invasive 
fungal, or opportunistic infections through Day 29 
3. To examine the safety of zavegepant, relative to placebo, as reflected 
by the incidence of intranasal administration reactions through Day 29 
4. To examine the safety of zavegepant, relative to placebo, as reflected 
by the proportion of subjects who develop a significant loss of renal 
function, defined as at least 50% reduction in eGFR from baseline 
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STUDY SCHEMATIC 
 
 
 
 
 
 
 

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TABLE OF CONTENTS 
SUMMARY OF CHANGES ......................................................................................................... 2 
CONFIDENTIALITY AND INVESTIGATOR STATEMENT ................................................ 8 
STUDY SUMMARY (SYNOPSIS) ............................................................................................... 9 
STUDY SCHEMATIC ................................................................................................................. 16 
TABLE OF CONTENTS ............................................................................................................. 17 
LIST OF TABLES ....................................................................................................................... 20 
LIST OF FIGURES ..................................................................................................................... 20 
LIST OF ABBREVIATIONS ...................................................................................................... 21 
1 
INTRODUCTION AND RATIONALE .............................................................................. 24 
1.1 
Therapeutic Area Background ........................................................................................ 24 
1.1.1 
CGRP Background ..................................................................................................... 24 
1.1.2 
Product Development Background ........................................................................... 25 
1.1.2.1 
Non-clinical Pharmacology, Pharmacokinetics, Pharmacodynamics 
and Toxicology ...................................................................................................... 25 
1.1.2.2 
Clinical Experience ............................................................................................... 25 
1.1.2.3 
Other Clinical/Non-Clinical Studies ................................................................... 26 
1.1.2.4 
Clinical Adverse Event Profile ............................................................................ 26 
1.2 
Study Rationale................................................................................................................. 27 
1.3 
Dosing Rationale ............................................................................................................... 28 
1.3.1 
Zavegepant Properties ............................................................................................... 28 
1.3.2 
Rationale for Dose Selection ...................................................................................... 29 
1.3.3 
Rationale for Including Patients with Renal Impairment ....................................... 30 
1.4 
Research Hypothesis ........................................................................................................ 30 
2 
STUDY OBJECTIVES ......................................................................................................... 31 
2.1 
Primary Objective ............................................................................................................ 31 
2.2 
Secondary Objectives ....................................................................................................... 31 
2.2.1 
Key Secondary Objectives ......................................................................................... 31 
2.2.2 
Other Secondary Objectives ...................................................................................... 31 
3 
STUDY ENDPOINTS ........................................................................................................... 33 
3.1 
Primary Endpoint ............................................................................................................ 33 
3.2 
Secondary Endpoints ....................................................................................................... 33 
3.2.1 
Key Secondary Endpoints .......................................................................................... 33 
3.2.2 
Other Secondary Endpoints ...................................................................................... 33 
4 
STUDY PLAN ....................................................................................................................... 35 
4.1 
Study Design and Duration .............................................................................................. 35 
4.2 
Study Schematic ............................................................................................................... 36 
4.3 
Schedule of Assessments .................................................................................................. 37 
4.3.1 
Screening Phase (Day -2 to Day 1) ............................................................................ 51 
4.3.2 
Baseline Visit / Randomization (Day 1) .................................................................... 51 
4.3.3 
Treatment Phase (Days 1 – 14 +/-1 day) ................................................................... 51 
4.3.3.1 
While Subjects are In the Hospital ..................................................................... 51 
4.3.3.2 
If Subjects are Discharged Prior to Day 15 ........................................................ 52 

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4.3.4 
Treatment Phase Day 5 (+/- 2 days) .......................................................................... 53 
4.3.5 
End of Treatment or Day 15 (+/- 1 day) ................................................................... 53 
4.3.6 
Post Treatment Phase (Days 16 +/- 1 day Through 29 +/- 2 days) ......................... 53 
4.3.6.1 
For Subjects Who Remain in the Hospital ......................................................... 53 
4.3.6.2 
For Subjects Discharged from the Hospital after Day15, but Prior to 
Day 22 .................................................................................................................... 53 
4.3.7 
60-Day Safety Follow-up Visit (+/- 15 Days) ............................................................ 54 
4.4 
Post Study Access to Therapy ......................................................................................... 54 
5 
POPULATION ...................................................................................................................... 55 
5.1 
Number of Subjects .......................................................................................................... 55 
5.2 
Inclusion Criteria.............................................................................................................. 55 
5.3 
Exclusion Criteria ............................................................................................................. 55 
5.4 
Prohibited and Restricted Concomitant Medications/Procedures ............................... 57 
5.5 
Women of Childbearing Potential .................................................................................. 57 
5.6 
Other Restrictions and Precautions ................................................................................ 58 
5.7 
Deviation from Inclusion/Exclusion Criteria .................................................................. 58 
6 
STUDY CONDUCT AND DESCRIPTION OF STUDY PROCEDURES ....................... 59 
6.1 
Study Materials ................................................................................................................. 59 
6.2 
Eligibility Assessments ..................................................................................................... 59 
6.3 
Safety Assessments ........................................................................................................... 60 
6.3.1 
Vital Signs and Physical Measurements (Height and Weight) ............................... 60 
6.3.2 
Electrocardiogram (ECG).......................................................................................... 60 
6.3.3 
Chest x-ray .................................................................................................................. 60 
6.3.4 
Physical Exam ............................................................................................................. 60 
6.3.5 
Laboratory Assessments ............................................................................................ 60 
6.3.5.1 
Safety Laboratory Testing ................................................................................... 61 
6.3.5.2 
Experimental Predictive Biomarkers ................................................................. 62 
6.3.5.3 
Pharmacokinetic (PK) Samples ........................................................................... 63 
6.3.5.4 
SARS-CoV-2 Antibody Testing ........................................................................... 63 
6.3.5.5 
Pregnancy Testing ................................................................................................ 63 
6.4 
Efficacy Assessments ........................................................................................................ 63 
6.4.1 
6-point ordinal scale ................................................................................................... 63 
6.5 
Other Assessments ............................................................................................................ 64 
6.5.1 
National Early Warning Score (NEWS2) ................................................................. 64 
6.5.2 
Sequential Organ Failure Assessment (SOFA) Score ............................................. 64 
6.5.3 
COVID-19 Characteristics and Outcomes ............................................................... 64 
6.6 
Early Discontinuation from Investigational Product .................................................... 65 
6.7 
Early Discontinuation from the Study ............................................................................ 65 
6.8 
Lost to Follow Up.............................................................................................................. 65 
7 
STUDY DRUG MANAGEMENT ....................................................................................... 67 
7.1 
Description of Study Drug ............................................................................................... 67 
7.1.1 
Investigational Product .............................................................................................. 67 
7.1.2 
Non-Investigational Product ..................................................................................... 67 
7.1.3 
Formulation ................................................................................................................ 67 
7.1.4 
Packaging, Shipment and Storage ............................................................................ 68 
7.2 
Dose and Administration ................................................................................................. 68 

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7.2.1 
Method of Assigning Subject Identification ............................................................. 68 
7.2.2 
Selection and Timing of Dose and Administration .................................................. 68 
7.3 
Blinding and Unblinding .................................................................................................. 69 
7.4 
Treatment Compliance .................................................................................................... 69 
7.5 
Destruction and Return of Study Drug ........................................................................... 69 
8 
ADVERSE EVENTS ............................................................................................................. 70 
8.1 
Definition of Terms Related to all Adverse Events (Serious and Non-serious) ......... 70 
8.2 
Assessment for Determining Relationship of AE to Study Drug .................................. 71 
8.3 
Serious Adverse Events .................................................................................................... 71 
8.3.1 
Definition of Serious Adverse Event (SAE) .............................................................. 71 
8.3.2 
Collection and Reporting Serious Adverse Events .................................................. 73 
8.3.3 
Overdose ...................................................................................................................... 74 
8.3.4 
Pregnancy .................................................................................................................... 74 
8.3.5 
Potential Drug Induced Liver Injury (DILI) ............................................................ 75 
8.4 
Non-serious Adverse Events ............................................................................................ 76 
8.4.1 
Collection and Reporting of Non-Serious Adverse Events ..................................... 76 
8.4.2 
Laboratory Test Abnormalities ................................................................................. 76 
8.5 
Adverse Events of Special Interest .................................................................................. 76 
9 
STATISTICS ......................................................................................................................... 77 
9.1 
Sample Size ....................................................................................................................... 77 
9.2 
Analysis Sets ...................................................................................................................... 78 
9.3 
Statistical Methods ........................................................................................................... 78 
9.3.1 
Demographic and Baseline Characteristics .............................................................. 78 
9.3.2 
Primary Endpoint ...................................................................................................... 78 
9.3.3 
Secondary Endpoints ................................................................................................. 79 
9.3.4 
Adjustment for Multiplicity ....................................................................................... 79 
9.3.5 
Missing Data ............................................................................................................... 79 
9.3.6 
Analysis of Safety ....................................................................................................... 79 
9.3.7 
Futility Analysis .......................................................................................................... 80 
9.4 
Schedule of Analyses ........................................................................................................ 80 
10 ETHICS AND RESPONSIBILITIES .................................................................................. 81 
10.1 
Good Clinical Practice ..................................................................................................... 81 
10.2 
Data Monitoring Committee (DMC) .............................................................................. 81 
10.3 
Steering Committee .......................................................................................................... 82 
10.4 
Institutional Review Board/Independent Ethics Committee ........................................ 82 
10.5 
Informed Consent ............................................................................................................. 82 
10.6 
Case Report Forms ........................................................................................................... 83 
11 RECORDS MANAGEMENT .............................................................................................. 84 
11.1 
Source Documentation ..................................................................................................... 84 
11.2 
Study Files and Record Retention ................................................................................... 85 
12 AMENDMENTS ................................................................................................................... 86 
13 STUDY REPORT AND PUBLICATIONS ......................................................................... 87 
14 STUDY DISCONTINUATION ............................................................................................ 88 
15 CONFIDENTIALITY ........................................................................................................... 89 
16 CLINICAL PROTOCOL APPROVAL FORM ................................................................. 90 
17 APPENDICES ....................................................................................................................... 91 
17.1 
APPENDIX I – Names of Study Personnel .................................................................... 91 

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18 REFERENCES ...................................................................................................................... 92 
 
LIST OF TABLES 
Table 1: 
Schedule of Assessments...................................................................................... 37 
Table 2: 
Distribution, number (N), and percent (%) of 300 subjects tested for 
COVID-19 ............................................................................................................ 77 
 
LIST OF FIGURES 
Figure 1: 
Simulated Steady State Zavegepant In Concentrations: 10 mg every 8 hours29 
Figure 2: 
BHV3500-203 Study Design ............................................................................... 36 

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LIST OF ABBREVIATIONS 
ABG 
Arterial Blood Gas 
AE 
Adverse Event 
ALI 
Acute Lung Injury 
ALT 
Alanine Aminotransferase 
AM 
Morning 
ARDS 
Acute respiratory distress syndrome 
AST 
Aspartate Aminotransferase 
AUC 
Area Under the Curve 
BHV-3500 
Zavegepant 
BP 
Blood Pressure 
BUN 
Blood Urea Nitrogen 
Ca2+ 
Calcium ion 
CGRP 
Calcitonin Gene-Related Peptide 
CHG 
Congestive heart failure 
Cmax 
Maximum Plasma Concentration 
COPD 
Chronic Obstructive Pulmonary Disease 
COVID-19 
 Coronavirus Disease 2019 
CRO 
Clinical Research Organization 
CRP 
C-Reactive Protein 
CTCAE 
Common Terminology Criteria for Adverse Events 
CYP 
Cytochrome P 
DILI 
Drug-Induced Liver Injury 
DMC 
Data Monitoring Committee 
ECG 
Electrocardiogram 
ECMO 
Extracorporeal Membrane Oxygenation 
eCRF 
Electronic Case Report Form 
eGFR 
Estimated Glomerular Filtration Rate 
EOT 
End of Treatment 
ER 
Emergency Room 
eTMF 
Electronic Trial Master File 

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FiO2 
Fraction of Inspired Oxygen 
FSH 
Follicular Stimulating Hormone 
GCP 
Good Clinical Practice 
GMP 
Good Manufacturing Practice 
h 
Hour(s) 
HbA1c 
Hemoglobin A1c 
HR 
Heart Rate 
HRT 
Hormone Replacement Therapy 
ICF 
Informed Consent Form 
IB 
Investigator’s Brochure 
ICH 
International Conference on Harmonization 
ICU 
Intensive Care Unit 
IEC 
Independent Ethics Committee 
IL 
Interleukin 
ILD 
Interstitial Lung Disease 
IMP 
Investigational Medicinal Product 
IN 
Intranasal 
IP 
Investigational Product 
IPF 
Idiopathic Pulmonary Fibrosis 
IRB 
Institutional Review Board 
i.v. 
Intravenous 
kg 
Kilogram 
L 
Liters 
LDH 
Lactate Dehydrogenase 
LFT 
Liver Function Test 
MedDRA 
Medical Dictionary for Regulatory Activities 
MERS-CoV 
 Middle East Respiratory Syndrome-Related Coronavirus 
mg 
Milligram 
min 
Minute 
MTD 
Maximum Tolerated Dose 
NEWS2 
 National Early Warning Score 2 
PCR 
Polymerase Chain Reaction 

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PE 
Physical Exam 
PID 
Patient Identification 
PK 
Pharmacokinetic 
PM 
Evening 
p.o. 
By Mouth, Orally 
PVG 
Pharmacovigilance 
Q8h 
Administered Every 8 Hours 
QD 
Once Daily 
RBC 
Red Blood Cell 
SAD 
Single Ascending Dose 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SARS-CoV 
 Severe Acute Respiratory Syndrome Coronavirus 
SARS-CoV-2 
 Severe Acute Respiratory Syndrome Coronavirus-2 
SOFA 
Sequential Organ Failure Assessment 
SOP 
Standard Operating Procedure 
SpO2 
Peripheral Capillary Oxygen Saturation Measured by Pulse Oximeter 
SpO2/FiO2 
 Ratio of Pulse Oximeter-Measured Oxygen Saturation to Fraction of 
Inspired Oxygen 
TB 
Tuberculosis 
TEAE 
Treatment-Emergent Adverse Event 
Th17 
Type 17 Helper 
TNF 
Tumor Necrosis Factor 
TRP 
Transient Receptor Potential 
ULN 
Upper Limit of Normal 
WBC 
White Blood Cell 
WHO 
World Health Organization 
WOCBP 
Women of Childbearing Potential 

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1 INTRODUCTION AND RATIONALE 
1.1 
Therapeutic Area Background 
 
Coronavirus Disease 2019 (COVID-19) infection presents with respiratory symptoms and fever 
in the majority of patients.1,2 Among patients requiring hospitalization, the majority develop 
pulmonary infiltrates. The virus that causes COVID-19, SARS-CoV-2, as with SARS-CoV and 
Middle East respiratory syndrome-related coronavirus (MERS-CoV), can induce an excessive 
and aberrant non-effective host immune responses that is associated with severe lung pathology, 
leading to death.2-4 Similar to patients with SARS-CoV and MERS-CoV, some patients with 
SARS-CoV-2 develop ARDS with characteristic pulmonary ground glass changes on imaging. In 
most patients who develop critical disease, SARS-CoV-2 infection is associated with a cytokine 
storm, with high levels of IL-6 and other proinflammatory cytokines being associated with poor 
outcomes.5,6 Similar cytokine storm pathology and outcomes has been described for SARS-CoV 
and MERS-CoV.7 A recent single arm study in 20 COVID-19 patients in China suggests that 
targeting IL6 with anti-IL-6 antibody may have clinical benefit,8 and several studies are initiating 
to study anti-IL-6 treatment in a controlled manner. 
 
In patients who develop acute lung injury (ALI)/ARDS due to coronavirus infection who go on 
to survive intensive care, the excessive immune response leads to long-term lung damage and 
fibrosis, causing functional disability and reduced quality of life.9,10 
An important downstream effect of CGRP release is upregulation and release of IL-6 from a 
variety of cell types in different diseases.11-18 CGRP also drives T-cell polarization towards a 
Th17 response.17,19-21 Consequently, the treatment of COVID-19 by an agent that blocks the 
CGRP receptor my provide therapeutic benefit in this disease state by inhibiting the downstream 
IL-6 and/or Th17 sequelae, and forms the basis of this proposal. 
 
1.1.1 
CGRP Background 
 
Calcitonin gene-related peptide, or CGRP, is a pleotropic neuropeptide that is primarily released 
in response to activation of TRP ion channels.22 Originally, TRP channel physiology focused on 
its fundamental meaning in sensory neuronal function. However, it is now known that activation 
of diverse TRP ion channels in multiple cell types results in neuropeptide release and 
consecutive neurogenic inflammation, with TRPV122 TRPV423 and TRPA12,24 known to be 
responsible for CGRP release. 
 
The TRP channel is a non-selective cation channel predominately permeable for calcium ion 
(Ca2+),25 and is directly activated by chemical, thermal (e.g. fever), and mechanical stimuli, 
including infectious disease stimuli.20,26-29 TRP channels are ubiquitously expressed in dinerent 
tissues and cell types and are a key player in the regulation of intracellular calcium. Viruses 
require Ca2+ for replication and respiratory viruses, including coronavirus, have been reported to 
increase the expression of these channels in sensory neurons and human bronchial epithelium 
cells25,30,31 to facilitate replication. 

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As a result of its connection to TRP channel activation, CGRP is released and is pleotropic 
effects involved in a variety of acute lung injuries diseases.32,33 CGRP receptor antagonists have 
been shown to reduce proximal airway necrosis by 40% and terminal bronchiole necrosis by 
50% in chemical acute lung injury.32 Blockade of TRPV4, or downstream CGRP, could be an 
important therapeutic approach in managing edema and acute lung injury in inflammatory lung 
diseases.34-36 
An important downstream effect of CGRP release is upregulation and release of IL-6 from a 
variety of cell types in different diseases.11-18 
CGRP regulates T-cell function via T-cells’ interaction with dendritic cells (DCs) and 
macrophages, both of which express the CGRP receptor.37,38 In various diseases in which CGRP 
signaling becomes dysfunctional, including those induced by aberrant TRP activation, CGRP 
drives T-cell polarization towards a Th17 response.17,19-21 In fact, deletion of a crucial subunit of 
the CGRP receptor has been shown to ameliorate Th17 autoimmunity.21 
1.1.2 
Product Development Background 
 
Details of the clinical and preclinical studies are provided in the most current version of the 
Investigator’s Brochure. 39A summary of the relevant data is presented below. 
1.1.2.1 
Non-clinical Pharmacology, Pharmacokinetics, Pharmacodynamics and 
Toxicology 
 
A series of in vitro and in vivo pharmacokinetic (PK) and metabolism studies were conducted 
with zavegepant in rats, dogs, rabbits, mice and monkeys. Safety studies in were also performed 
in rat and monkey to determine tolerability, potential for local irritation, and to assess systemic 
toxicity. The details of these studies can be found in the Zavegepant (BHV-3500) Investigator 
Brochure (IB).39 
1.1.2.2 
Clinical Experience 
CCI 
 
 

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1.1.2.3 
Other Clinical/Non-Clinical Studies 
A series of in vitro studies have been performed to investigate CYP-mediated drug interactions. 
Zavegepant has been examined for effects in a transporter study.40 The details of these studies 
can be found in the Zavegepant (BHV-3500) IB.39 
1.1.2.4 
Clinical Adverse Event Profile 
 
1.1.2.4.1 
Phase 2/3 Dose Ranging Study (BHV3500-201) 
 
BHV3500-201 is a concluded, pivotal, Phase 2/3, double-blind, randomized, placebo-controlled, 
dose-ranging study conducted to evaluate the safety and efficacy of zavegepant (5 mg, 10 mg, or 
20 mg) of a single dose of zavegepant IN versus placebo in the acute treatment of migraine. 
 
No deaths were reported, and no treatment-related SAEs were reported. SAEs were reported on- 
treatment in two subjects including post-traumatic thrombosis reported in one subject in the 
zavegepant 10 mg group, and vestibular migraine reported in one subject in the placebo group. 
Both events were moderate in intensity and judged by the investigator as not related to study 
drug. 
 
The overall incidence of AEs was 26.2% (311 of 1,185 subjects) in the zavegepant groups and 
15.4% (62 of 403 subjects) in the placebo group. The incidence of AEs in the zavegepant groups 
were as follows: 22.7% (88 of 388 subjects) in the 5 mg group, 24.6% (97 of 394 subjects) in the 
10 mg group, and 31.3% (126 of 403 subjects) in the 20 mg group. The majority of AEs were 
mild in intensity. The table below presents the most frequently reported (2. 1% in any zavegepant 
group) AEs in the zavegepant groups. 
CCI 

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BHV3500-201 Most Frequently (೦1%) Reported AEs 
No. Treated 
(N=388) 
(N=394) 
(N=403) 
(N=1185) 
(N=403) 
Adverse Event 
5 mg 
10 mg 
20 mg 
Overall 
zavegepant 
Placebo 
Dysgeusia 
13.9% 
13.5% 
16.1% 
14.5% 
3.5% 
Nausea 
2.6% 
4.1% 
2.7% 
3.1% 
0.5% 
Nasal Discomfort 
1.3% 
1.3% 
5.2% 
2.6% 
0.2% 
Throat Irritation 
1.0% 
1.0% 
2.2% 
1.4% 
0.0% 
Vomiting 
0.3% 
1.8% 
1.7% 
1.3% 
0.2% 
UTI 
0.8% 
1.0% 
2.0% 
1.3% 
1.2% 
 
Nasal inspection conducted at screening, baseline and end of treatment showed no clinical 
evidence of nasal mucosal injury. No subject had AST or ALT > 3x ULN or bilirubin > 2x ULN 
in any treatment group. 
 
The first-generation small molecule CGRP antagonists (e.g. telcagepant and MK-3207), have 
shown effects on elevated transaminases and hypertension. The liver effects of these compounds 
were thought to be related to the chemical structures and off-target effects of antagonizing CGRP 
receptors41. 
Additional information with next generation monoclonal antibodies targeting CGRP receptors 
(e.g. Aiomivig) and other small molecules (e.g. Ubrelvy and Nurtec ODT) have not shown 
similar liver safety issues. Zavegepant is a third-generation CGRP receptor antagonist that is 
structurally unrelated to the first-generation small molecule CGRP receptor antagonists. Liver 
effects have not been observed with zavegepant; however, liver safety and blood pressure will be 
monitored in this study. 
 
1.2 
Study Rationale 
 
There is an urgent need to assess both antiviral mechanisms but also host innate mechanisms to 
combat the COVID-19 pandemic.5,42 Given the urgent need to test novel mechanisms to combat 
COVID-19 infection, the pleotropic function of CGRP as a key mediator of the neuro-immune 
system warrants assessment of the potential for CGRP-antagonism in mitigating the hyper- 
immune disease characteristic of serious COVID-19 infection. This study will assess the 
hypothesis that antagonizing CGRP receptors in a variety of neural and immune cells within the 
respiratory tract in the setting of COVID-19 infection will decrease both acute inflammation and 
edema formation and reduce the subsequent risk of developing interstitial lung diseases 
(ALI/ARDS) resulting from a hyper-inflammation immune response. 

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1.3 
Dosing Rationale 
 
1.3.1 
Zavegepant Properties 
 
Zavegepant has multiple properties which render it an ideal molecule for near-term treatment of 
COVID-19, including (as detailed below), high CGRP receptor affinity, clinical proof-of-concept 
in migraine for 10 mg intranasal dose, ~6 hour half-life, hospital- and patient-friendly Aptar 
device usable in ventilation patients, clinical safety with up to 14 days of dosing, Good 
Manufacturing Practice (GMP) clinical supplies available now, and high aqueous solubility with 
potential for alternate (i.v., p.o.) formulations: 
 
• 
Ultra-high affinity for the human CGRP receptor (Ki = 0.023 nM) that can displace CGRP 
from the receptor and blocks the effects of ongoing CGRP release 
 
• 
Clinical efficacy already demonstrated with 10 mg intranasal dose in the acute treatment of 
migraine; showing ability block a human disease state associated with high CGRP release 
 
• 
Short half-life of ~6 hours allows it to be withdrawn and quickly cleared if needed, while 
also providing durable CGRP receptor occupancy with 8 hour dosing (see Section 1.3.2 
Rationale for Dose Selection) 
 
• 
Intranasal route of delivery that’s usable even in patients on ventilation or nasal cannula 
respiratory support 
 
• 
The device is familiar, simple to use, disposable, Aptar nasal spray single-shot technology 
that’s already used in hospital settings to treat opioid overdose (Narcan™) 
 
• 
Safety and tolerability of nasal zavegepant have already been demonstrated in humans with 
multiple doses up to 40 mg daily for 8 days and 20 mg daily for 14 days. The selected 
zavegepant dose of 10 mg IN every 8 hours is expected to produce a geometric mean Cmax 
of 13 ng/mL and AUC over 24 h of 92.7 ng-h/mL (extrapolating from 14 days of dosing up 
to 10 mg IN once daily (QD) in Study 3500-102). The highest geometric mean Cmax and 
AUC over 24 h obtained in Study 3500-102 after dosing 20-40 mg IN for up to 14 days were 
24.6-40.9 ng/mL and 87.9 to 94.2 ng-h/mL, respectively. Thus, zavegepant 10 mg every 8 
hours IN is expected to produce a Cmax at least 2-3 fold lower and an AUC over 24 hours 
similar to that produced by the highest doses given to humans for up to14 days. 
 
• 
GMP clinical supplies are currently on-hand and available (diverting units from our planned 
second Phase 3 migraine study) 
 
• 
High aqueous solubility (> 300 mg/mL) provides for multiple routes of administration; upon 
successful proof-of-concept can be readily reformulated as intravenous, subcutaneous or oral 
agent to provide dosing options for inside and outside the hospital setting 

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CCI 
 
CCI  
 
 
CCI 
 
1.3.2 
Rationale for Dose Selection 
 
Zavegepant 10 mg IN delivered every 8 hours provides durable coverage for CGRP receptor 
occupancy to test the effect on COVID-19: 
 
• 
Human PK data were used to conduct steady state simulations 
• 
 
 
• 
 
 
• 
The clinical safety and tolerability of nasal zavegepant have already been demonstrated in 
humans with multiple doses up to 40 mg daily for 8 days and 20 mg daily for 14 days. The 
selected zavegepant dose of 10 mg IN every 8 hours is expected to produce a Cmax at least 2 
to 3-fold lower than, and an AUC over 24 hours similar to, that produced by the highest 
doses given to humans over 14 days (see details in Section 1.3.1). 
CCI 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
. 
CCI 
CCI 

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1.3.3 
Rationale for Including Patients with Renal Impairment 
 
Zavegepant is metabolically stable and primarily excreted unchanged as parent compound. A 
recently completed rat ADME study where [14C]-BHV-3500 was intravenously administered to 
rats44 showed that the majority (~85% dose) of radioactivity was recovered during the first 48 
hours with feces (64%) as the major route of elimination and a more minor contribution via renal 
(24%) elimination. 
 
Consistent with these results, in the human zavegepant MAD and SAD studies,39 there was no 
evidence of renal injury. 
 
Subjects with estimated creatinine clearance 2. 30 mL/min will be allowed into the study. 
Subjects who develop eGFR <15 mL/min while on study should be discontinued from the study 
drug. 
 
1.4 
Research Hypothesis 
 
Zavegepant reduces and slows the progression of the disease and improves overall outcome of 
COVID-19 infection. 

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2 STUDY OBJECTIVES 
2.1 
Primary Objective 
 
To compare the efficacy of zavegepant (BHV-3500) to placebo, in subjects hospitalized with 
COVID-19 infection requiring supplemental oxygen, using a six-point rating scale at Day 15. 
 
2.2 
Secondary Objectives 
 
2.2.1 
Key Secondary Objectives 
1. To compare zavegepant to placebo on the proportion of subjects alive and off of oxygen at 
Day 29. 
2. To compare zavegepant to placebo on the proportion of subjects requiring initiation of 
invasive mechanical ventilation, non-invasive ventilation or use of high flow nasal cannula 
through Day 29. 
3. To compare zavegepant to placebo on the proportion of subjects admitted into an intensive 
care unit (ICU) through Day 29. 
 
2.2.2 
Other Secondary Objectives 
1. To examine the safety of zavegepant, relative to placebo, as reflected by the number of: 
deaths; SAEs; severe AEs; and Grade 3 or 4 laboratory test abnormalities. 
2. To examine the safety of zavegepant, relative to placebo, as reflected by the incidence of 
severe or life-threatening bacterial, invasive fungal, or opportunistic infections through Day 
29. 
3. To examine the safety of zavegepant, relative to placebo, as reflected by the incidence of 
intranasal administration reactions through Day 29. 
4. To examine the safety of zavegepant, relative to placebo, as reflected by the proportion of 
subjects who develop a significant loss of renal function, defined as at least 50% reduction in 
eGFR from baseline. 
 
 
 
 

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3 STUDY ENDPOINTS 
3.1 
Primary Endpoint 
 
Efficacy will be measured by the difference between treatment groups in the mean 6-point 
severity rating at Day 15. The severity ratings are: 
 
1. Death 
 
2. Hospitalized, on invasive mechanical ventilation or ECMO 
 
3. Hospitalized, on non-invasive ventilation or high flow oxygen devices 
 
4. Hospitalized, requiring supplemental oxygen 
 
5. Hospitalized, not requiring supplemental oxygen 
 
6. Not hospitalized 
 
Six point severity ratings are from the 6-point ordinal rating scale eCRFs. Deaths through Day 
15 from AE/SAE and subject disposition CRFs are also taken into account. 
 
3.2 
Secondary Endpoints 
 
Procedures are from concomitant procedures eCRFs. Deaths are determined from the following 
eCRFs: 6-point ordinal severity rating scale; AE/SAE; and subject disposition. 
 
3.2.1 
Key Secondary Endpoints 
 
1. Proportion of subjects who have a 6-point severity rating of 5 or 6, are alive, and do not use 
supplemental oxygen as a procedure at Day 29. 
 
2. Proportion of subjects who have a 6-point severity rating of 2 or 3, or use any ventilation or 
high-flow nasal cannula as procedures, on any day through Day 29. 
 
3. Proportion of subjects admitted into an ICU on any day through Day 29 from AE/SAE 
eCRFs. 
 
3.2.2 
Other Secondary Endpoints 
 
1. Number of subjects with deaths, SAEs, severe AEs, and Grade 3 or 4 laboratory test 
abnormalities at any time on study. All AEs are from AE/SAE eCRFs. Grade 3 or 4 
laboratory test abnormalities are determined from laboratory test values graded using 
standardized criteria defined in the SAP (e.g., CTCAE) from laboratory test eCRFs. 
 
2. Number and percentage of subjects with severe or life-threatening bacterial, invasive fungal, 
or opportunistic infections at any time through Day 29 from AE/SAE eCRFs. 

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3. Number and percentage of subjects with intranasal administration reactions at any time 
through Day 29 from AE/SAE eCRFs. 
4. Proportion of subjects with 250% reduction in eGFR from baseline at any time on study 
from laboratory test eCRFs. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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4 STUDY PLAN 
4.1 
Study Design and Duration 
 
This is a double-blind, randomized, multicenter, inpatient (and post-discharge outpatient) 
evaluation of the safety and efficacy of zavegepant (BHV-3500) as compared to placebo in the 
treatment of COVID-19-associated pulmonary disease. The study drug will be zavegepant or 
matching placebo, given as 10 mg IN dose every 8 hours (+/- 2 hours) for approximately 14 days 
(42 doses). The study will randomize approximately 120 subjects in a 2:1 ratio across the two 
treatment groups (zavegepant or matching placebo). The randomization will be stratified by age 
(less than 60 years vs 60 years and older). 
 
After signing informed consent and meeting eligibility criteria, the subject may be immediately 
randomized and dosed with the double-blind study medication (10 mg or matching placebo) and 
continue dosing every 8 hours (Q8h +/- 2 hours) up to approximately 14 days (42 doses). 
 
For the purposes of this protocol, the start of Visit Day 1 will start when the 1st dose of study 
drug is administered until 24 hours later. Therefore, depending on the time when the 1st dose of 
study drug is administered, a visit day may spread over 2 calendar days. The last dose of study 
drug could be administered on Visit Day 14 but could actually occur on calendar day 15 of the 
study. The EOT or Day 15 assessments (depending on when subject stops study drug) should be 
completed after the last dose of study drug, and the subjects should remain in the hospital for a 
full 24 hours after their last dose of drug if they are to be released. 
 
Randomization will be done through an IWRS that will be accessed by the unblinded research 
pharmacists or their designees. so that subjects can be dosed as soon as possible following 
consent and assessment of eligibility criteria. After completion of treatment, subjects will be 
followed out to Day 60 (+/- 15 days) during the post treatment phase. 
 
This study has a duration approximately 8 weeks from time of Screening and obtaining consent 
through the Post-Dose Follow-up Visit (Day 60 +/- 15 days). 

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4.2 
Study Schematic 
 
Figure 2: 
BHV3500-203 Study Design 
 

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4.3 
Schedule of Assessments 
 
Table 1: 
Schedule of Assessments 
 
Post- 
Treatment 
Phase 
Procedure 
Screening 
Visit 
Day -2 to 
Day 1 
Baseline 
Visit 
(Randomiza 
tion) 
Day 1 
Days 2 
through 14 
(+/- 1 day)1 
End of 
Treatment 
(EOT) Visit 
or Day 15 
(+/- 1 day)2 
Days 16 (+/- 
1 day) 
through 
Day 293 (+/- 
2 days) 
Day 60 
(+/- 15 days) 
Comments 
Informed 
Consent 
X 
X 
Inclusion / 
Exclusion 
Eligibility 
X 
COVID-19 test should be positive by 
PCR test prior to study entry. 
Criteria 
 
 
1 If subjects are planned for release from the hospital prior to Day 15, they should discontinue drug for at least 24 hours and receive the End of Treatment 
assessments prior to discharge. They will be discontinued from study drug but continue in the study. All early discontinuations should be discussed with the 
Medical Monitor prior to planned release. Subjects will have follow-up phone calls on Days 15, 22, and 29 to assess 6-point ordinal scale, AEs/SAEs, and 
concomitant medications & procedures unless they are able to return for in-person visits. Subjects will need to return for at least 1 in-person visit on or before 
Day 60 to have the complete set of Day 29 assessments completed. 
2 EOT assessments should be completed after the last dose of study drug is administered and prior to hospital discharge. If the subject remains in the hospital and 
completes treatment (42 doses), Day 15 assessments are the same as EOT assessments. If the subject has EOT assessments completed prior to Day 15, then the 
Day 15 visit is a telephone visit. 
3 After the Treatment Phase, if subjects remain in the hospital or are moved to a recovery facility, subjects should be evaluated daily for NEWS2, vitals, 
concomitant medications, AE/SAE, and SpO2 and FiO2 out to Day 29 with clinical labs collected per protocol on Days 22 and 29. Any clinical safety labs, 
urinalysis, LFTs, ECGs, or chest x-rays collected as per SOC should be entered into the eCRF in unscheduled visit pages for that assessment if not a per protocol 
assessment. If subjects are released from the hospital prior to Day 22, they should return for in-person visits on Day 22 (+/- 2 days) and Day 29 (+/- 2 days), if 
possible, and have a follow-up telephone visit at Day 60. If subjects are unable to return, then follow-up phone calls should be made on Days 22 (+/- 2 days) and 
29 (+/- 2 days) to assess 6-point ordinal scale, AEs/SAEs, and concomitant medications and procedures. Subjects will need to return for at least 1 in-person visit 
on or before Day 60 to have the complete set of Day 29 in-person assessments completed. 

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Procedure 
Screening 
Visit 
Day -2 to 
Day 1 
Baseline 
Visit 
(Randomiza 
tion) 
Day 1 
Days 2 
through 14 
(+/- 1 day)1 
End of 
Treatment 
(EOT) Visit 
or Day 15 
(+/- 1 day)2 
Post- 
Treatment 
Phase 
Days 16 (+/- 
1 day) 
through 
Day 293 (+/- 
 
2 days) 
Day 60 
(+/- 15 days) 
Comments 
Medical History 
X 
COVID-19 symptoms should be 
entered into medical history. 
Physical 
Examination 
(PE) 
X 
X 
X 
Full Physical exam at screening and 
EOT. If a full PE is collected as per 
SOC within 48 hours prior to signing 
Informed Consent, this can be used as 
the Screening assessment. Directed PE 
on Day 29 (only). 
X 
Urinalysis 
(pH, specific 
gravity, ketones, 
nitrites, 
urobilinogen, 
leukocyte 
esterase, protein, 
glucose and 
blood) 
Urinalysis will be collected per 
protocol at the Screening Visit. 
Urinalysis values collected within 48 
hours of signing Informed Consent 
may be used as the Screening 
assessments. 
If urinalysis is collected as per SOC 
on any other days from Day 1 through 
Day 29 and clinically significant, these 
values should be entered into the 
eCRF on Unscheduled Visit 
Urinalysis pages. 

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Procedure 
Screening 
Visit 
Day -2 to 
Day 1 
Baseline 
Visit 
(Randomiza 
tion) 
Day 1 
Days 2 
through 14 
(+/- 1 day)1 
End of 
Treatment 
(EOT) Visit 
or Day 15 
(+/- 1 day)2 
Post- 
Treatment 
Phase 
Days 16 (+/- 
1 day) 
through 
Day 293 (+/- 
 
2 days) 
Day 60 
(+/- 15 days) 
Comments 
Clinical Safety 
Laboratory 
X 
X 
X 
X 
X 
Clinical safety labs collected within 48 
hours of signing Informed Consent may be 
used as the Screening assessments. 
Testing 
(Hematology: 
Hemoglobin, 
hematocrit, RBC 
count, WBC 
count with 
differentials, and 
platelets 
HbA1c 
Clinical safety labs will be collected per 
protocol on Days 1, 2, 5, 10, 15, 22, and 
29. If clinical safety labs are collected as 
per SOC on any other days and are 
clinically significant, these values should 
be entered into the eCRF on Unscheduled 
Visit Clinical Safety Labs pages. 
After hospital discharge, clinical 
safety labs should be done at in-person 
visits on Days 22, 29, and 60 (if this is 
an in-person visit). 
Chemistry: 
Sodium, 
potassium, 
chloride, 
bicarbonate, 
calcium; glucose, 
BUN, serum 
creatinine, total 
protein, albumin, 
uric acid, LDH, 
and CK 
Abnormal laboratory test values 
related to an SAE should continue to 
be recorded out to Day 60. 

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Procedure 
Screening 
Visit 
Day -2 to 
Day 1 
Baseline 
Visit 
(Randomiza 
tion) 
Day 1 
Days 2 
through 14 
(+/- 1 day)1 
End of 
Treatment 
(EOT) Visit 
or Day 15 
(+/- 1 day)2 
Post- 
Treatment 
Phase 
Days 16 (+/- 
1 day) 
through 
Day 293 (+/- 
 
2 days) 
Day 60 
(+/- 15 days) 
Comments 
eGFR) 
Electrocardiogra 
m (ECG) 
X 
ECG will be collected per protocol at 
the Screening Visit. If an ECG is 
collected as SOC within 48 hours of 
signing Informed Consent, it may be 
used as the Screening ECG. If ECGs 
are collected as per SOC on any other 
days from Day 1 through Day 29 and 
are clinically significant, these values 
should be entered into the eCRF on 
Unscheduled Visit ECG pages. 
Physical 
Measurements 
X 
X 
Screening, Day 22 (+/- 2 days) and 
Day 29 (+/- 2 days) only. Physical 
measurements collected within 48 
hours of signing Informed Consent 
may be used as the Screening 
assessments. Height collected at 
screening only. 
Sequential Organ 
Failure 
X 
X 
X 
This is completed only if the subject is 
admitted to the ICU. It should only be 

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Procedure 
Screening 
Visit 
Day -2 to 
Day 1 
Baseline 
Visit 
(Randomiza 
tion) 
Day 1 
Days 2 
through 14 
(+/- 1 day)1 
End of 
Treatment 
(EOT) Visit 
or Day 15 
(+/- 1 day)2 
Post- 
Treatment 
Phase 
Days 16 (+/- 
1 day) 
through 
Day 293 (+/- 
 
2 days) 
Day 60 
(+/- 15 days) 
Comments 
Assessment 
(SOFA)4 
completed upon ICU admission and at 
Day 29 if the patient is still in the ICU. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
4 The Sequential Organ Failure Assessment Score (SOFA) will be completed as a supplemental assessment (not part of a scheduled visit) if the subject is 
admitted to the ICU during the course of the study. The Glascow Coma scale is part of the SOFA assessment and should be completed along with the SOFA 
assessment. 

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Procedure 
Screening 
Visit 
Day -2 to 
Day 1 
Baseline 
Visit 
(Randomiza 
tion) 
Day 1 
Days 2 
through 14 
(+/- 1 day)1 
End of 
Treatment 
(EOT) Visit 
or Day 15 
(+/- 1 day)2 
Post- 
Treatment 
Phase 
Days 16 (+/- 
1 day) 
through 
Day 293 (+/- 
 
2 days) 
Day 60 
(+/- 15 days) 
Comments 
National Early 
Warning Score 
(NEWS2) 
assessment 
X 
X 
X 
X 
X 
NEWS2 assessments collected as per 
SOC within 48 hours of signing 
Informed Consent may be used as the 
Screening assessments. NEWS2 
assessments will be collected daily 
while subject is in the hospital. This 
assessment may be assessed in the AM 
or PM but around the same time every 
collection day within 3 hours and 
entered on the eCRF. NEWS2 is a 
collection of ongoing vitals related to: 
respiration (breaths/min), SpO2 
Oxygen saturation (%), BP, pulse, 
consciousness, temperature to provide 
a total NEWS2 score. The timing of 
the NEWS2 for the purpose of the 
eCRF in the study should also 
correlate timing with the collection of 
the SpO2 and FiO2. 
After hospital discharge, NEWS2 
should be collected at in-person visits 
on Days 22, 29, and 60 (if this is an 
in-person visit). 
Vital Signs 
X 
X 
X 
X 
X 
X 
Vital signs collected as per SOC 

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Procedure 
Screening 
Visit 
Day -2 to 
Day 1 
Baseline 
Visit 
(Randomiza 
tion) 
Day 1 
Days 2 
through 14 
(+/- 1 day)1 
End of 
Treatment 
(EOT) Visit 
or Day 15 
(+/- 1 day)2 
Post- 
Treatment 
Phase 
Days 16 (+/- 
1 day) 
through 
Day 293 (+/- 
 
2 days) 
Day 60 
(+/- 15 days) 
Comments 
within 48 hours of signing Informed 
Consent may be used as the Screening 
assessment. While subjects are in the 
hospital, vital signs will be collected 
once daily in the AM or PM but 
around the same time every day within 
3 hours and entered on the eCRF. 
After hospital discharge, vital signs 
should be collected at in-person visits 
on Days 22, 29, and 60 (if this is an 
in-person visit). 
SpO2 and FiO2 
X 
X 
X 
X 
X 
X 
SpO2 and FiO2 collected as part of 
SOC within 48 hours of signing 
Informed Consent may be used as the 
Screening assessments. While the 
subject is in the hospital, this is 
collected in the eCRF once daily and 
should correlate (AM or PM) with the 
time the vital signs and the NEWS2 
are collected. 
After hospital discharge, SpO2 and 
FiO2 should be collected at any in- 
person visits on Days 22, 29, and 60 
(if this is an in-person visit). 

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Procedure 
Screening 
Visit 
Day -2 to 
Day 1 
Baseline 
Visit 
(Randomiza 
tion) 
Day 1 
Days 2 
through 14 
(+/- 1 day)1 
End of 
Treatment 
(EOT) Visit 
or Day 15 
(+/- 1 day)2 
Post- 
Treatment 
Phase 
Days 16 (+/- 
1 day) 
through 
Day 293 (+/- 
 
2 days) 
Day 60 
(+/- 15 days) 
Comments 
Arterial Blood 
Gas (ABG) 
Arterial Blood Gas (ABG) is not a 
required assessment for the protocol. 
However, if it is collected as per SOC 
within 48 hours from signing 
Informed Consent through Day 29, 
this data should be entered in the 
eCRF in Unscheduled Visit ABG 
pages. 
6-point ordinal 
scale 
X 
X 
X 
X 
X 
X 
While in the hospital, this is collected 
once daily. This may be collected in 
the AM or PM at the discretion of the 
Investigator or staff but should be 
collect around the same time (within 3 
hours) every day. If subjects are 
discharged from the hospital and 
unable to return for in-person visits, 
this scale should be assessed by phone 
on Days 15, 22, and 29. 
After hospital discharge, this 
assessment should be collected at in- 
person visits on Days 22, 29, and 60 
(if an in-person visit). 

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Procedure 
Screening 
Visit 
Day -2 to 
Day 1 
Baseline 
Visit 
(Randomiza 
tion) 
Day 1 
Days 2 
through 14 
(+/- 1 day)1 
End of 
Treatment 
(EOT) Visit 
or Day 15 
(+/- 1 day)2 
Post- 
Treatment 
Phase 
Days 16 (+/- 
1 day) 
through 
Day 293 (+/- 
 
2 days) 
Day 60 
(+/- 15 days) 
Comments 
Chest x-ray 
X 
X 
Chest x-ray required at screening and 
End of Treatment or Day 15 (if subject 
is in the hospital on Day 15). If a 
chest x-ray is collected within 48 
hours of signing Informed Consent, 
this may be used as the Screening 
chest x-ray assessment. If a chest x- 
ray is collected as per SOC after Day 
15 until Day 29, these data should be 
entered into the eCRF on Unscheduled 
Visit Chest x-ray pages. 
Serum antibody 
test for SARS- 
CoV2 virus 
X 
X 
The serum antibody test should be 
done no earlier than Day 15 and 
before Day 60 
CCI 
 
 
 
 
 

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Procedure 
Screening 
Visit 
Day -2 to 
Day 1 
Baseline 
Visit 
(Randomiza 
tion) 
Day 1 
Days 2 
through 14 
(+/- 1 day)1 
End of 
Treatment 
(EOT) Visit 
or Day 15 
(+/- 1 day)2 
Post- 
Treatment 
Phase 
Days 16 (+/- 
1 day) 
through 
Day 293 (+/- 
 
2 days) 
Day 60 
(+/- 15 days) 
Comments 
Screening Visit 
Liver function 
tests (LFTs) 
(AST, ALT, 
alkaline 
phosphatase, and 
bilirubin -Total, 
Direct, Indirect) 
X 
X 
LFTs will be collected per protocol at the 
Screening Visit and on Day 15. If LFTs 
are collected as per SOC within 48 hours 
of signing Informed Consent, these may 
be used as the Screening values. If 
additional LFTs are collected as per SOC 
on any other days from Day 1 through 29 
and are clinically significant, these values 
should be entered into the eCRF on 
Unscheduled Visit LFT pages. 
Pregnancy Test 
for women of 
childbearing 
potential 
(WOCBP) 
X 
X 
X 
Day 29 
only 
X 
Urine test is recommended, but serum 
may also be done if preferred by 
Investigator/Staff. WOCBP must 
have a negative pregnancy test at the 
Screening Visit before being 
randomized and treated with IP. 
If a WOCBP is discharged from the 
hospital prior to Day 22, a urine 
pregnancy test should be collected at 
in-person visits on Days 22 (+/- 2 
days), 29 (+/- 2 days), and 60 (+/- 15 
days) (if an in-person visit). 

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Post- 
Treatment 
Phase 
Procedure 
Screening 
Visit 
Day -2 to 
Day 1 
Baseline 
Visit 
(Randomiza 
tion) 
Day 1 
Days 2 
through 14 
(+/- 1 day)1 
End of 
Treatment 
(EOT) Visit 
or Day 15 
(+/- 1 day)2 
Days 16 (+/- 
1 day) 
through 
Day 293 (+/- 
 
2 days) 
Day 60 
(+/- 15 days) 
Comments 
Sparse PK 
sampling 
X 
Day 5 (+/- 
2 days) 
PK sampling should be obtained on 
Day 5 (+/- 2 days). PK may include 
samples collected at Pre-dose, 0.5, 1, 
2.5 and 5h (all samples collected 
within +/-0.5h). 
Concomitant 
Medication 
Collection 
X 
X 
X 
X 
X 
Concomitant medications are captured 
from first dose of study drug through 
Day 29. 
Concomitant 
Procedures 
Collection 
X 
X 
X 
X 
X 
Concomitant procedures are captured 
from first dose of study drug through 
Day 29 except for the start of 
supplemental oxygen which could 
start within 48 hours of 
randomization. This data should be 
captured on the concomitant 
procedures page. 
AE Assessment 
X 
X 
X 
X 
Non-serious AEs are captured from 
first dose of study drug through Day 
29. Non-serious adverse events 
should be followed until conclusion or 
stabilization or reported as SAEs if 
they become serious. Follow-up is 
also required for non-serious AEs that 

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Procedure 
Screening 
Visit 
Day -2 to 
Day 1 
Baseline 
Visit 
(Randomiza 
tion) 
Day 1 
Days 2 
through 14 
(+/- 1 day)1 
End of 
Treatment 
(EOT) Visit 
or Day 15 
(+/- 1 day)2 
Post- 
Treatment 
Phase 
Days 16 (+/- 
1 day) 
through 
Day 293 (+/- 
 
2 days) 
Day 60 
(+/- 15 days) 
Comments 
cause interruption or discontinuation 
of study drug or those that are present 
at Day 29. Note: For this study, 
admission and discharge to the ICU 
should be captured on the Adverse 
Event eCRF. 
SAE assessment 
X 
X 
X 
X 
X 
X 
SAEs are captured any time after 
signing consent through the Day 60 
visit. 
All SAEs should be followed until 
resolution or stabilization. 
Administer study 
drug 
X 
X 
IP is dispensed every 8 hours (+/- 2 
hours) during the Treatment Phase for 
a total of 42 doses. 
If subjects are discharged from the 
hospital to home prior to Day 15 they 
will be discontinued from study drug 
but continue in the study. Please note 
that due to the potential for rebound 
from withdrawal of an 
immunomodulating agent, subjects 
who are planning to be discharged 
should be off of study drug for at least 

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Procedure 
Screening 
Visit 
Day -2 to 
Day 1 
Baseline 
Visit 
(Randomiza 
tion) 
Day 1 
Days 2 
through 14 
(+/- 1 day)1 
End of 
Treatment 
(EOT) Visit 
or Day 15 
(+/- 1 day)2 
Post- 
Treatment 
Phase 
Days 16 (+/- 
1 day) 
through 
Day 293 (+/- 
 
2 days) 
Day 60 
(+/- 15 days) 
Comments 
24 hours before release from the 
hospital. 
If the subject is discharged to a step- 
down or satellite care facility where 
they can be monitored for safety, they 
should continue receiving study drug 
until completing 42 doses. 
Telephone Visits 
X 
X 
X 
If subjects are released from the 
hospital prior to Day 15 , and an EOT 
visit was conducted, a follow-up 
phone call should be made on Days 
15, 22, and 29 to assess 6-point 
ordinal scale, AEs/SAEs, and 
concomitant medications and 
procedures. If the subject remains in 
the hospital on Days 15, 22, or 29, 
telephone visits are not required, but 
in-person visits should be conducted. 

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Procedure 
Screening 
Visit 
Day -2 to 
Day 1 
Baseline 
Visit 
(Randomiza 
tion) 
Day 1 
Days 2 
through 14 
(+/- 1 day)1 
End of 
Treatment 
(EOT) Visit 
or Day 15 
(+/- 1 day)2 
Post- 
Treatment 
Phase 
Days 16 (+/- 
1 day) 
through 
Day 293 (+/- 
 
2 days) 
Day 60 
(+/- 15 days) 
Comments 
Safety Follow-up 
Visit (Day 60) 
X 
If subjects have not had an in-person 
visit from the time of hospital 
discharge prior to Day 60, the Day 60 
visit should be an in-person visit, and 
the same assessments that would have 
been collected on Day 29 should be 
performed. 
If subjects have been able to have an 
in-patient or an in-person visit on Day 
29, then the Day 60 visit will be done 
by telephone to collect 6-point ordinal 
scale, status of any AEs/SAEs 
ongoing at time of discharge, any new 
SAEs, and to confirm subject 
mortality. 
 
 
 
 
 
 
 
 
 
 
 

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4.3.1 
Screening Phase (Day -2 to Day 1) 
 
Approximately 180 subjects will be screened in this study. 
 
Subjects with PCR-documented COVID-19 infection that necessitates hospitalization with 
supplemental oxygen will be considered for this study. The screening phase is 48 hours. Before 
any study procedures are performed, subjects must sign Informed Consent. However, any 
clinical labs, urinalysis, LFTs, PE, Vitals, SpO2, FiO2 , NEWS2 assessments, ECG, or chest x- 
ray collected as per SOC within 48 hours of signing Informed Consent may be used as the 
Screening assessments. 
 
Concomitant procedures are captured from first dose of study drug through Day 29 except for the 
start of supplemental oxygen which could start within 48 hours of randomization. This data 
should be captured on the concomitant procedures page. 
 
After Informed Consent has been signed, subjects will be assessed for eligibility and should be 
immediately randomized once eligibility is confirmed. Subjects will also undergo all screening 
procedures prior to randomization, including the collection of Experimental Predictive 
Biomarkers as detailed in Table 1 and Section 6.3.5.2. If the screening laboratory test results or 
any eligibility criteria are determined to be unacceptable per protocol, the subject is considered a 
screen failure and will not be allowed to re-screen for the study. 
 
4.3.2 
Baseline Visit / Randomization (Day 1) 
 
The Baseline Visit should occur as quickly as eligibility is confirmed after consent form is 
signed (and no greater than 48 hours later). An unblinded research pharmacist will be required 
to dispense medication to the research staff. Screening procedures should be completed as 
quickly as possible so that the patient is randomized within 48 hours from the start of non- 
invasive supplemental oxygen. All Baseline Visit procedures are outlined in Table 1. 
 
4.3.3 
Treatment Phase (Days 1 – 14 +/-1 day) 
 
Approximately 180 subjects will be screened to randomize approximately 120 subjects. The 
subjects will be randomized in a 2:1 ratio to the zavegepant (80 subjects) or placebo (40 subjects) 
treatment groups. Subjects will receive 10 mg IN zavegepant or placebo every 8 hours (+/- 2 
hours) for approximately 14 days (42 doses). Subjects whose renal function declines to an eGFR 
of < 15 mL/min will be discontinued from study drug. 
 
4.3.3.1 
While Subjects are In the Hospital 
 
During the Treatment Phase, while subjects are inpatient, SpO2, FiO2 and ongoing vitals will be 
collected each day. Although these procedures may be collected throughout the day as part of 
standard of care, for the purpose of data collection for this study, vitals, SpO2, and FiO2 will be 
collected in the eCRF one time daily. This data may be collected in the morning (AM) or 
evening (PM) but should be around the same time every day (within 3 hours) and entered on the 
eCRF. Arterial Blood Gas (ABG) is not a required assessment per protocol. However, if ABG 

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is collected as per SOC at any time within 48 hours prior to signing Informed Consent through 
Day 29, this data should be entered in the eCRF whenever it is collected on Unscheduled Visit 
ABG pages. 
 
NEWS2 is a collection of ongoing vitals related to: respiration (breaths/min), SpO2 oxygen 
saturation (%), blood pressure (BP), pulse, consciousness, and temperature to provide a total 
NEWS2 score. While subjects are inpatient, NEWS2 should be assessed daily. The timing of the 
NEWS2 for the purpose of the data collection for the study should also correlate with the timing 
of the collection of the SpO2 and FiO2, and entered in the eCRF. 
 
Subjects will have SAE/AEs monitored as well as concomitant medications and procedures 
daily. 
 
Clinical safety labs, urinalysis, LFTs, ECGs, and chest x-rays will be collected as specified in 
Table 1. 
If the subject is admitted to the ICU, then SOFA2 will be collected upon admission to the ICU, 
and will be collected again if subject is still in the ICU at Day 29. 
 
If during the treatment period, subjects are transferred to another care facility, they should 
continue on study drug with the expectation that the Investigator and Staff will coordinate with 
the treating facility to obtain, at minimum, safety and primary endpoint data and allow the 
subject to complete the trial as per protocol. 
 
For the purpose of the 6-point ordinal primary endpoint scale, item number 6 (Not Hospitalized) 
means discharged from acute care. Transferring a subject to another acute care facility due to 
COVID-19 challenges does not qualify as a 6 on the ordinal scale. Any operational questions 
about logistics of a transferred subject should be addressed with the Biohaven Medical Monitor 
or designee. 
 
If local administration site irritation develops, the PI should call the medical monitor to discuss 
the dosing plan. 
 
4.3.3.2 
If Subjects are Discharged Prior to Day 15 
 
If a subject is planned to be discharged from the hospital prior to completing treatment, they will 
be discontinued from study drug. The Investigator should discuss the discharge plan with the 
Medical Monitor. 
Note: Due to the potential for rebound from withdrawal of an immunomodulating agent, if 
a subject is withdrawn from drug, they need to be monitored in the hospital for at least 24 
hours before release. All End of Treatment (EOT) assessments (see Section 4.3.5) should be 
collected after the patient’s last dose of study drug and prior to discharge. Although subjects will 
be discontinued from the study drug, they will remain in the study. If possible, subjects should 
continue with in-person visits as per Table 1. If this is not possible due to COVID-19 
restrictions, a phone call should be made to the subject on Days 15, 22, and 29 to collect these 
assessments: 6-point ordinal scale, AEs/SAEs, and concomitant medications and procedures. If 

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the subject is unable to return for in-person visits on Days 22 and 29 due to quarantine, subjects 
will need to return for at least 1 in-person visit on or before Day 60 to have the Day 29 in-person 
assessments completed. 
4.3.4 
Treatment Phase Day 5 (+/- 2 days) 
In addition to what is collected daily during the Treatment Phase as per Table 1, whenever 
possible, sparse PK will be collected on Day 5 (+/- 2 days). Additionally, experimental 
predictive biomarkers will be collected on Day 5 (+/- 2 days), with the exception of troponin 
which is only collected at Screening as per Table 1. 
4.3.5 
End of Treatment or Day 15 (+/- 1 day) 
Subjects will complete the End of Treatment (EOT) Visit after their last dose of study drug (if 
they discontinue drug prior to Day 15) or on Day 15 +/- 1 day after the subject has received 42 
doses of study drug as per Table 1. If possible, the subject should return for Post-Dose Follow-up 
visits on Day 22 (+/- 2 days) and Day 29 (+/- 2 days). If a subject has an EOT visit prior to Day 
15, then the Day 15 visit should be done as a telephone visit. 
Subjects need to have a SARS CoV-2 antibody test completed no earlier than Day 15, but no 
later than Day 60 (see Section 6.3.5.4). 
 
4.3.6 
Post Treatment Phase (Days 16 +/- 1 day Through 29 +/- 2 days) 
 
4.3.6.1 
For Subjects Who Remain in the Hospital 
After administration with the study medication ends, the 6-point ordinal scale assessment, daily 
vital signs, SpO2, FiO2, concomitant medications and procedures, and NEWS2 will continue to 
be collected daily while the patient is in the hospital (Table 1). AEs/SAEs, should be captured 
and followed to resolution or stabilization. Clinical safety labs will be collected per protocol on 
Days 22 (+/- 2 days) and 29 (+/- 2 days). If clinical safety labs, urinalysis, LFTs, and ECGs are 
collected as per SOC on any days out to Day 29, data that are clinically significant should be 
entered into the eCRF on Unscheduled Visit assessment pages. Any chest x-rays collected as per 
SOC from Day 16 through 29 should be entered into the eCRF on Unscheduled Visit Chest x-ray 
pages. 
If the subject is admitted to the ICU, then SOFA2 will be collected upon admission to the ICU 
and on Day 29 if the subject is still in the ICU. Subjects need to have a SARS CoV-2 antibody 
test completed no earlier than Day 15, but no later than Day 60 (see Section 6.3.5.4). 
 
4.3.6.2 
For Subjects Discharged from the Hospital after Day15, but Prior to Day 
22 
If a subject is discharged from the hospital prior to Day 22, when possible, they should return to 
the site on Day 22 (+/- 2 days) and Day 29 (+/- 2 days) to have the assessments indicated in 
Table 1 and should receive a follow-up phone visit on Day 60. 

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If the subject is unable to return for in-person visits on Days 22 and 29 due to COVID-19 
restrictions, a phone call should be made to the subject to collect these assessments: 6-point 
ordinal scale, AEs/SAEs, and concomitant medications and procedures on those visit days (+/- 2 
days). Subjects will need to return for at least 1 in-person visit on or before Day 60 to have the 
Day 29 assessments completed. Subjects need to have a SARS CoV-2 antibody test completed 
no earlier than Day 15, but no later than Day 60 (see Section 6.3.5.4). 
4.3.7 
60-Day Safety Follow-up Visit (+/- 15 Days) 
If subjects have been able to return for an in-person visit on Day 29, this will be a follow-up 
safety phone visit. During this contact, the staff will collect the 6-point ordinal scale, collect any 
new SAEs, update the status of any AE/SAEs that were ongoing since the last visit, and confirm 
subject mortality status. 
If subject has been unable to complete an in-person visit from the time of hospital discharge prior 
to Day 60, this Day 60 visit should be an in-person visit, and the same assessments that would 
have been collected at Day 29 should be performed. 
4.4 
Post Study Access to Therapy 
Not Applicable. 

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5 POPULATION 
Individuals entered in this trial will be male and female subjects 18 years of age and older with 
PCR-documented COVID-19 infection that necessitates hospitalization with supplemental 
oxygen. The treatment setting for these subjects will include hospitals or institutions where 
subjects will be treated for symptoms related to COVID-19. Subjects may be recruited through a 
variety of sources, including referrals from physicians and other health care professionals. 
 
5.1 
Number of Subjects 
 
Up to approximately 180 subjects will be screened and up to approximately 120 subjects will be 
treated with study drug in this study. It is anticipated that enrollment will occur at approximately 
2-5 sites in the United States over a period of approximately 4 months. 
 
5.2 
Inclusion Criteria 
 
1. Subjects must provide informed consent in accordance with requirements of the study 
center’s IRB or ethics committee, prior to the initiation of any protocol-required procedures. 
 
2. Subjects must agree to provide all requested demographic information (i.e. gender, race). 
 
3. Subjects must be able to read and understand English or Spanish. 
 
4. Subjects must be over the age of 18 years. 
 
5. Subjects must have laboratory-confirmed SARS-CoV-2 infection as determined by PCR- 
based commercial or public health assay. 
 
6. Subjects must have symptoms that require hospitalization with supplemental oxygen and/or 
non-invasive ventilation as determined by the admitting physician. The maximum nasal 
cannula O2 concentration should be determined by the treating clinician and the limitations of 
the specific equipment. 
 
7. Subjects must be willing and able to comply with study-related procedures/assessments. 
 
5.3 
Exclusion Criteria 
 
1. Subjects in immediate need of invasive mechanical ventilation or extracorporeal membrane 
oxygenation (ECMO). 
2. Subjects with an eGFR of < 30 mL/min, at the Screening Visit 
 
3. Prisoners or subjects who are involuntarily incarcerated 
 
4. Subjects who are participating in any other investigational clinical trial while participating in 
this clinical trial 

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5. Subjects who are under the age of 18 years 
 
6. Subjects who are pregnant (all potential female enrollees need to have a negative pregnancy 
test prior to IP administration) 
 
7. Subjects with multi-organ failure 
 
8. Subjects who have received more than 48 hours of supplemental oxygen prior to 
randomization 
 
9. Subjects with prior significant pulmonary disease (e.g., severe COPD/ILD/CHF/IPF) are 
excluded 
 
10. Subjects receiving investigational therapies as part of a formal clinical trial for the treatment 
of COVID-19. During the course of this study, investigational therapies that may become 
“standard of care” to treat COVID-19, but are not part of a clinical trial, are allowed. 
 
11. Subjects who are on long-acting CGRP monoclonal antibodies will be excluded including 
Aimovig® (erenumab), Emgality® (galcanezumab), Ajovy® (fremanezumab), and Vyepti® 
(eptinezumab). Additionally, the investigational oral CGRP receptor antagonist, atogepant, 
that is taken daily will also be excluded. Oral CGRP receptor antagonists, Nurtec® ODT 
(rimegepant) and UbrelvyTM (ubrogepant) that are typically used PRN infrequently will not 
be excluded as long the subject was not taking them on a daily basis and does not take them 
during the current study 
 
12. Subjects who are unlikely to survive for more than 48 hours from the Screening Visit 
 
13. Subjects with any of the following abnormal laboratory values at screening: aspartate AST or 
ALT greater than 5x ULN or bilirubin greater than 2x ULN 
14. Subjects with known active TB, history of incompletely treated TB, suspected or known 
extrapulmonary TB 
 
15. Subjects with suspected or known systemic bacterial or fungal infections. However, empiric 
antibiotics are permitted 
 
16. Subjects who have participated in any clinical research study evaluating an IP or therapy 
within 3 months and less than 5 half-lives of IP prior to the screening visit 
17. Subjects with any physical examination findings and/or history of any illness that, in the 
opinion of the study investigator, might confound the results of the study or pose an 
additional risk to the subject by their participation in the study 
 
Please see Section 5.4 for prohibited medications during the course of the study. 

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5.4 
Prohibited and Restricted Concomitant Medications/Procedures 
 
Investigational therapies as part of a formal clinical trial for the treatment of COVID-19 are 
prohibited during the course of this study. However, if during the course of this study 
investigational therapies become “standard of care” to treat COVID-19, they are allowed. 
 
Long-acting CGRP monoclonal antibodies Aimovig (erenumab), Emgality (galcanezumab), 
Ajovy (fremanezumab), and Vyepti (eptinezumab) are not allowed in the trial. A minimum 30- 
day washout period for these drugs is appropriate, prior to randomization. Additionally, the 
investigational oral CGRP receptor antagonist, atogepant, that is taken daily will also be 
excluded. Oral CGRP receptor antagonists, Nurtec ODT (rimegepant) and Ubelvy (ubrogepant) 
that are typically used PRN infrequently will not be excluded as long the subject was not taking 
them on a daily basis and does not take them during the current study. 
 
Prior to the Baseline Visit (randomization), if a subject has been on non-invasive supplemental 
oxygen for more than 48 hours, they should not be randomized. However, if a subject progresses 
to requiring mechanical ventilation (invasive or non-invasive) after randomization, they will 
remain on the study, per the Investigator’s judgement. 
 
Subjects with renal impairment who have an eGFR2. 30mL/min are allowed into the study. 
Subjects who develop an eGFR< 15mL/min while on the study should be discontinued from the 
study drug. 
 
5.5 
Women of Childbearing Potential 
 
Women of childbearing potential (WOCBP) includes any female who has experienced menarche 
and who has not undergone successful surgical sterilization (hysterectomy, bilateral tubal 
ligation, or bilateral oophorectomy) or is not postmenopausal. Menopause is defined as: 
 
• 
Amenorrhea greater than or equal to 12 consecutive months without another cause and a 
documented serum follicle stimulating hormone (FSH) level > 35mIU/mL 
 
Or 
 
• 
Woman with irregular menstrual periods and a documented serum FSH level > 35mIU/mL 
Or 
NOTE: FSH level testing is not required for women greater than or equal to 62 years old with 
amenorrhea of greater than or equal to one year 
 
• 
Woman on hormone replacement therapy (HRT) 
For the purpose of this study, subjects who are WOCBP, MUST have a negative pregnancy test 
prior to randomization and administration of study medication. If during the course of the trial 
the subject is discharged for the remainder of the study, the subject should be abstinent and/or 

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use an acceptable method of birth control if they become sexually active. Acceptable methods of 
birth control are listed below. 
 
• 
WOCBP and all men must use acceptable methods of contraception to avoid pregnancy 
throughout the study and for 90 days after the last dose of investigational product in such a 
manner that risk of pregnancy is minimized. The requisite drug interaction studies to 
determine the interaction of zavegepant with oral contraceptives have not been performed to 
date. It is, therefore, not possible to determine the efficacy of oral contraceptives as an 
effective method of contraception for WOCBP or men with partners who are WOCBP who 
are participating this study. Oral estrogen and progestin hormonal contraceptives as a sole 
method of contraception are therefore prohibited. 
 
• 
It is required that all WOCBP use two methods of contraception to prevent pregnancy, for the 
duration of the study (i.e. this study begins with signed consent form through 90 days after 
last dose of study drug). The two methods should include one barrier method (ex. condom 
with spermicidal gel, intrauterine devices, cervical cap etc.) and one other method. The other 
method could include hormonal contraceptives (e.g. oral contraceptives, injectable 
contraceptives, patch, or contraceptive implant) used since at least 4 weeks prior to sexual 
intercourse or another barrier method. 
 
• 
Subjects who report abstinence, or who report exclusively being in same-sex relationships 
are still required to comply with the contraception requirements in this study to prevent 
pregnancy. These subjects must still be counseled on the requirement to avoid pregnancy 
throughout the study and for 90 days after the last dose of study medication, as well as 
acceptable methods of contraception to use during the study. 
 
• 
All WOCBP must complete the pregnancy test schedule (Table 1). 
• 
Male subjects must be willing not to donate sperm until 90 days following the last study drug 
administration. 
 
5.6 
Other Restrictions and Precautions 
 
Not Applicable. 
 
5.7 
Deviation from Inclusion/Exclusion Criteria 
 
Any significant event that does not comply with the inclusion/exclusion criteria, study conduct, 
or study procedures will be documented as a deviation. Deviations will be documented and 
reported through the clinical monitoring of the trial. Deviations will be reported to the IRB/EC at 
the frequency required by your IRB/EC. Prospective approval of protocol deviations to 
recruitment and enrollment criteria, also known as protocol waivers or exemptions, is not 
permitted. 

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6 STUDY CONDUCT AND DESCRIPTION OF STUDY PROCEDURES 
6.1 
Study Materials 
 
The following study materials will be provided to the site: 
 
• 
Investigator File/Study Binder 
• 
Drug Accountability Logs (blinded and unblinded) 
• 
IB 
• 
eCRF Completion Instructions 
o eCRFs will be prepared for all data collection fields 
 
• 
Drug Administration Instructions 
• 
Laboratory manual, laboratory kits for PK and labels for CGRP samples will be provided. 
PK samples and CGRP samples will be shipped to a central laboratory for analysis 
 
• 
Local laboratory collection will be used for this study and performed via hospital procedures 
for all labs with the exception of any experimental biomarkers that local labs are not able to 
perform (see Section 6.3.5.2) 
 
• 
Experimental Predictive Biomarkers Collection and Processing Instructions. For 
experimental biomarkers that cannot be done at the local lab, instructions have been provided 
to order tests through a central laboratory for analysis and reporting. 
 
• 
SAE Forms and SAE instructions 
• 
Pregnancy surveillance forms and reporting instructions 
• 
Instructions for NEWS2 and SOFA assessments for data entry 
6.2 
Eligibility Assessments 
 
Informed consent, inclusion/exclusion criteria including medical history, concomitant 
medications and procedures, and laboratory assessments should be completed as outlined in 
Table 1. Any eligibility assessments completed within 48 hours of signing Informed Consent 
may be used as the Screening assessments. The start of non-invasive supplemental oxygen 
should be captured on the concomitant procedures page. 

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6.3 
Safety Assessments 
 
6.3.1 
Vital Signs and Physical Measurements (Height and Weight) 
 
Body weight and height will be recorded at the scheduled visits as outlined in Table 1. While in 
the hospital, vital signs and SpO2, and FiO2 will be collected daily and entered into the eCRF. 
The site staff should collect this around the same time every day within 3 hours, and the 
collection for the purpose of data entry into the eCRF should correlate to the time the NEWS2 is 
collected (AM or PM). Vital signs, SpO2 and FiO2, and NEWS2 assessments should be done at 
any in-patient or in-person visit up to Day 60. Although not a required protocol assessment, If 
ABG is collected from Screening through Day 29 as per SOC, this data should be entered in the 
eCRF in Unscheduled Visit ABG pages whenever it is collected. 
 
6.3.2 
Electrocardiogram (ECG) 
A standard 12-lead ECG will be collected per protocol at the Screening Visit. If an ECG is 
collected as per SOC within 48 hours of signing Informed Consent, this may be used as the 
Screening ECG. If ECGs are collected as per SOC on Days 1 through 29, these values should be 
entered into the eCRF in Unscheduled Visit ECG pages if they are determined to be clinically 
significant. The Investigator will determine if any abnormalities are of clinical significance. 
 
6.3.3 
Chest x-ray 
A standard chest x-ray will be recorded at the screening visit and at the EOT or Day 15 visit as 
per Table 1. A chest x-ray collected within 48 hours of signing Informed Consent may be used 
as the Screening chest x-ray. If a chest-x-ray is collected as per SOC after Day 15 out to Day 29, 
the data should be collected in the eCRF in Unscheduled Visit Chest x-ray pages. The 
Investigator will determine if any abnormalities are of clinical significance. 
 
6.3.4 
Physical Exam 
 
Subjects will undergo a physical examination (PE) at the scheduled visits as outlined in (Table 
1). If a full PE is performed within 48 hours of signing Informed Consent, it may be used as the 
Screening PE. The directed physical exam should be guided by the subject’s signs and 
symptoms. 
 
6.3.5 
Laboratory Assessments 
 
The investigator must review all laboratory reports, document this review, and record any 
clinically significant relevant changes occurring during the study in the AE section of the eCRF 
(see guidance in Section 8.4.2). The laboratory reports must be filed with the source documents. 
Clinically significant abnormal laboratory test findings are those which are not associated with 
the underlying disease, unless judged by the investigator to be more severe than expected for the 
subject's condition. 

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All laboratory tests with abnormal values collected through Day 29 considered to be clinically 
significant by the Investigator should be reported as adverse events and repeated and recorded in 
the eCRF until the values return to normal or baseline or are no longer considered clinically 
significant by the investigator or medical monitor. Abnormal laboratory test values related to an 
SAE should continue to be recorded out to Day 60. 
 
If such values do not return to normal/baseline within a reasonable period of time judged by the 
investigator, the etiology should be identified, and the sponsor notified. 
All protocol-required laboratory assessments must be conducted in accordance with Table 1. 
 
If laboratory values from non-protocol specified laboratory assessments performed as per SOC 
require a change in subject management or are considered clinically significant by the 
investigator (e.g., SAE or AE), then the results must be recorded in the eCRF. 
 
6.3.5.1 
Safety Laboratory Testing 
 
Blood and urine samples will be obtained as outlined in Table 1 for clinical laboratory 
evaluations. If clinical labs are collected within 48 hours of signing Informed Consent, they may 
be used as the Screening labs. Laboratory samples will be collected and processed via 
hospital/site standard operating procedure (SOP). 
 
Clinical Safety Labs: 
 
• 
Hematology: red blood cell (RBC) count, hemoglobin, hematocrit, platelets, white blood 
cell (WBC) count, and differentials (neutrophils, basophils, eosinophils, lymphocytes, 
monocytes, bands) 
 
• 
HbA1c 
• 
Chemistry: albumin, calcium, creatinine kinase (CK), serum glucose, LDH, total protein, 
potassium, sodium, uric acid, blood urea nitrogen (BUN), serum creatinine, chloride, and 
bicarbonate 
 
• 
eGFR and method of calculation 
LFTs: 
• 
AST, ALT, alkaline phosphatase, total bilirubin, direct bilirubin, and indirect bilirubin 
Urinalysis: 
 
• 
pH, specific gravity, ketones, nitrites, urobilinogen, leukocyte esterase, urine protein, urine 
glucose, and blood 

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6.3.5.4 
SARS-CoV-2 Antibody Testing 
 
The serum antibody test should be done no earlier than Day 15 and before Day 60. The test 
should be performed by the hospital local lab or can be sent to a Central Lab if an account has 
been set-up by the Sponsor for the site. 
 
6.3.5.5 
Pregnancy Testing 
 
Pregnancy tests will be conducted (serum or urine), when appropriate and as outlined in Table 1. 
 
6.4 
Efficacy Assessments 
 
6.4.1 
6-point ordinal scale 
 
A 6-point ordinal scale will be collected for the Primary and secondary endpoints. The scale 
consists of the following anchor points: 
 
1. Death 
 
2. Hospitalized, on invasive mechanical ventilation or ECMO 
 
3. Hospitalized, on non-invasive ventilation or high flow oxygen devices 
 
4. Hospitalized, requiring supplemental oxygen 
 
5. Hospitalized, not requiring supplemental oxygen 
 
6. Not hospitalized 
 
The 6-point ordinal scale will be collected each day the subject is in the hospital and at all in- 
person or telephone visits. 

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6.5 
Other Assessments 
6.5.1 
National Early Warning Score (NEWS2) 
 
The NEWS2 is a validated tool for assessing physiological risk in deteriorating subjects and is 
based on a simple aggregate scoring system in which a score is allocated to physiological 
measurements, already recorded in routine practice, when subjects present to, or are being 
monitored in the hospital.45 Six simple physiological parameters form the basis of the scoring 
system: 1) respiration rate; 2) oxygen saturation; 3) systolic blood pressure; 4) pulse rate; 5) level 
of consciousness or new confusion; and, 6) temperature. 
6.5.2 
Sequential Organ Failure Assessment (SOFA) Score 
 
The (SOFA score, previously known as the sepsis-related organ failure assessment score, is used 
to track a person's status during the stay in an ICU to determine the extent of a person's organ 
function or rate of failure8,46-51. The score is based on six different scores, one each for the 
respiratory, cardiovascular, hepatic, coagulation, renal and neurological systems. The higher the 
SOFA score, the higher the likely mortality. 
6.5.3 
COVID-19 Characteristics and Outcomes 
 
Biohaven will collect several data points to better understand the current COVID-19 
characteristics and outcomes with regard to how hospitals are managing in the current 
environment secondary to this disease. The datapoints will include (but not limited to) the 
following: 
• 
When collecting SAEs with an outcome of death, collect whether the death occurred after 
withdrawal of care, and if so the reason for withdrawal of care 
• 
Supportive measures received by subjects who progress to ARDS within the study (e.g., 
proning, paralytics etc.) 
• 
Data collection on clinical decision-making that guides removal of a subject from mechanical 
ventilation in relation to their clinical deterioration or lack of clinical response (e.g., change 
in status to comfort measures, poor prognosis for recovery, allocation of resources in a 
pandemic setting etc.) 
• 
Collection upon study entry of reason for hospital admission, standard of care followed for 
each subject at a site and if care decisions are made based on resource limitation 
• 
Collection of any new infection that occurs during the study, (i.e., viral or non-viral), 
including the site of infection and source of culture (BAL, Tracheal aspirate, sputum, blood, 
urine etc.) 
• 
Collect the number of days between onset of symptoms and initiation of treatment with 
zavegepant 

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6.6 
Early Discontinuation from Investigational Product 
 
Subjects must discontinue investigational product for any of the following reasons: 
 
• 
Withdrawal of informed consent (subject’s decision to withdraw for any reason) 
• 
Subject’s eGFR decreases to < 15 mL/min 
• 
Subjects who are discharged from the hospital prior to completing the treatment period 
All subjects who discontinue treatment should still comply with remaining study visits and 
procedures as outlined in Table 1. 
6.7 
Early Discontinuation from the Study 
 
Subjects must discontinue investigational product and withdraw from the study for any of the 
following reasons: 
• 
Withdrawal of informed consent (subject’s decision to withdraw for any reason) 
• 
Loss of ability to freely provide consent through imprisonment or involuntary incarceration 
• 
Any clinical AE, laboratory abnormality or intercurrent illness which, in the opinion of the 
investigator or sponsor, indicates that continued participation in the study is not in the best 
interest of the subject 
• 
Pregnancy 
• 
Termination of the study by Biohaven Pharmaceuticals 
All subjects who terminate early (e.g., AE discontinuation) should still comply with remaining 
study visits and procedures as outlined in Table 1, and Section 4.3.6.2. The only exception to this 
requirement is when a subject withdraws consent for all study procedures or loses the ability to 
consent freely (as defined above). 
6.8 
Lost to Follow Up 
 
A participant will be considered lost to follow-up if he or she repeatedly fails to return for 
scheduled visits and is unable to be contacted by the study site. 
 
The following actions must be taken if a participant fails to return to the clinic for a required 
study visit: 
• 
The site must attempt to contact the participant and reschedule the missed visit as soon as 
possible and counsel the participant on the importance of maintaining the assigned visit 
schedule and ascertain whether or not the participant wishes to and/or should continue in the 
study. 

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• 
Before a participant is deemed lost to follow up, the investigator or designee must make 
every effort to regain contact with the participant (where possible, 3 telephone calls and, if 
necessary, a certified letter to the participant’s last known mailing address or local equivalent 
methods). These contact attempts should be documented in the participant’s medical record. 
• 
Should the participant continue to be unreachable, he/she will be considered to have 
withdrawn from the study. 

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7 STUDY DRUG MANAGEMENT 
7.1 
Description of Study Drug 
 
7.1.1 
Investigational Product 
An IP is defined as follows: 
 
• 
A pharmaceutical form of an active substance or placebo being tested or used as a reference 
in a clinical study, including products already with a marketing authorization but used or 
assembled (formulated or packaged) in a way different from the authorized form, or used for 
an unauthorized indication, or when used to gain further information about the authorized 
form. 
 
The IP should be stored in a secure area according to local regulations. It is the responsibility of 
the investigator to ensure that IP is only dispensed to study subjects. The IP must be dispensed 
only from official study sites by authorized personnel according to local regulations. 
 
In this protocol, IP is/are: 
 
• 
Zavegepant 10 mg IN and will be provided as single use disposable Aptar UDS devices fully 
prepared and ready for administration 
 
• 
Matching placebo IN devices provided as single use disposable Aptar UDS devices fully 
prepared and ready for administration 
 
7.1.2 
Non-Investigational Product 
Other medications used as support or rescue medication for preventative, diagnostic, or 
therapeutic reasons, as components of the standard of care for a given diagnosis, may be 
considered as non-investigational products. 
 
In this protocol, non-investigational product(s) is/are: 
 
Not Applicable 
 
7.1.3 
Formulation 
 
Zavegepant (BHV-3500), is formulated as 10 mg IN for intranasal single dose administration 
using an Aptar Unit Dose System (UDS) liquid spray device 

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7.1.4 
Packaging, Shipment and Storage 
 
The product storage manager should ensure that the study drug is stored in accordance with the 
environmental conditions (temperature, light, and humidity) as determined by the sponsor. Please 
see the IB for specific conditions. If concerns regarding the quality or appearance of the study 
drug arise, do not dispense the study drug and contact the Sponsor/Clinical Research 
Organization (CRO) immediately. 
 
7.2 
Dose and Administration 
 
Subjects who are hospitalized will be administered three doses (IN devices) per day of blinded IP 
(10 mg or matching placebo) to be dosed approximately 8 hours (+/- 2 hours) apart, for up to 14 
days (42 doses) of treatment. When possible, if subjects are discharged from the hospital to 
another acute care medical facility prior to completing treatment, they will be provided with 
enough of their blinded IP and dosing instructions to continue their Q8h regimen until 42 doses 
have been completed. 
 
Subjects who are discharged to home prior to completing treatment will be discontinued from 
study drug. Procedures indicated in Section 4.3.3.2 should be followed. 
 
7.2.1 
Method of Assigning Subject Identification 
 
Randomization will be done through an IWRS, that will be accessed by the unblinded research 
pharmacists or their designees. The randomization scheme will be stratified by age ( <60, 2. 60). 
 
Initially, after informed consent is obtained at the Screening Visit, the Investigator or designee 
will enter the subject into the study and assign a patient ID (PID). The PIDs will be sequentially 
assigned within each site, and will have the format XXX-YYYY, where XXX is the 3 digit site 
number and YYYY is the sequential subject number. 
 
Sites will be responsible for recording the container 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. 
 
7.2.2 
Selection and Timing of Dose and Administration 
 
Subjects, study staff, or hospital floor staff will be instructed to administer one spray from a 
single device three times per day at approximately 8 hours (+/- 2 hours) apart between doses. If 
possible, alternate nostrils should be used for each subsequent dose. Dosing will continue for up 
to 14 days (42 doses). For the purposes of this protocol, the start of Visit Day 1 will start when 
the 1st dose of study drug is administered until 24 hours later. Therefore, depending on what 
time the 1st dose of study drug is administered, a visit day may spread over 2 calendar days. The 
last dose of study drug could be administered on Visit Day 14 but could actually occur on 
calendar day 15 of the study. 

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7.3 
Blinding and Unblinding 
Blinding is critical to the integrity of this clinical study. However, in the event of a medical 
emergency or pregnancy in an individual subject, in which knowledge of the investigational 
product is critical to the subject’s management, the blind for that subject may be broken by the 
treating physician. 
Before breaking the blind of an individual subject’s treatment, the Investigator should have 
determined that the information is necessary, (i.e., that it will alter the subject’s immediate 
management). In many cases, particularly when the emergency is clearly not investigational 
product related, the problem may be properly managed by assuming that the subject is receiving 
active product without the need for unblinding. 
A pharmacokineticist, unblinded site monitor, unblinded site pharmacist, Biohaven Drug Supply 
Coordinator and pharmacovigilance designees may be unblinded before data are unblinded for 
the primary endpoint and all subjects complete the study. Except as noted above, other members 
of the BHV research team will remain blinded. For purposes of the DMC, periodic analysis will 
be carried out by the unblinded safety biostatistics team independent and firewalled from the 
team directly involved with the design and primary analysis of the trial. A report will be 
prepared for the DMC as outlined in the DMC charter. 
In cases of accidental unblinding, contact the Medical Monitor and ensure every attempt is made 
to preserve the blind for remaining site personnel. 
7.4 
Treatment Compliance 
Responsible study personnel or hospital floor staff will dispense the study drug to the study 
subjects. Accountability and compliance verification should be documented in the subject’s 
study records. For subjects discharged to another care facility, treatment compliance and drug 
accountability should be continued. 
 
Missed doses should be documented in the subject source/medical record. Since this study is 
intended to take place in the hospital setting, it is imperative that missed doses are correctly 
accounted for in addition to any intentional or unintentional dosing errors. 
7.5 
Destruction and Return of Study Drug 
All unused study drug can be sent back to the drug depot for destruction only after being 
inspected and reconciled by the responsible Study monitor or the sponsor’s designee. If it is site 
policy to destroy study drug on site, it is the Investigator’s responsibility to ensure that 
arrangements have been made for the disposal, procedures for proper disposal have been 
established according to the applicable regulations, guidelines and institutional procedures, and 
appropriate records of the disposal have been documented. The unused study drugs can only be 
destroyed after being inspected and reconciled by the responsible Study Monitor or the 
Sponsor’s designee. 

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8 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 
investigational product, whether or not considered related to the investigational product. 
 
Adverse events can be spontaneously reported or elicited during an open-ended questioning, 
examination, or evaluation of a subject. In order to prevent reporting bias, subjects should not be 
questioned regarding the specific occurrence of one or more AEs. 
 
If a specific diagnosis or syndrome is identified by the Investigator, this should be recorded as 
the AE, rather than recording (as separate AEs) the individual signs/symptoms or clinically 
significant laboratory test abnormalities known to be associated with and considered by the 
Investigator to be a component of the disease/syndrome. 
 
Note: For this study, all admissions and discharges to and from the ICU need to be 
captured on the Adverse Event eCRF. 
 
8.1 
Definition of Terms Related to all Adverse Events (Serious and Non- 
serious) 
 
Mild: Is usually transient and may require only minimal treatment or therapeutic intervention. 
The event does not generally interfere with usual activities of daily living. 
Moderate: Is usually alleviated with additional specific therapeutic intervention. The event 
interferes with usual activities of daily living, causing discomfort but poses no significant or 
permanent risk of harm to the subject. 
 
Severe: Interrupts usual activities of daily living, significantly affects clinical status, or may 
require intensive therapeutic intervention. 
 
Life threatening: An AE is life threatening if the subject was at immediate risk of death from the 
event as it occurred; i.e., it does not include a reaction that if it had occurred in a more serious 
form might have caused death. For example, drug induced hepatitis that resolved without 
evidence of hepatic failure would not be considered life threatening even though drug induced 
hepatitis can be fatal. 
 
Hospitalization: AEs requiring hospitalization should be considered SAEs. Hospitalization for 
elective surgery or routine clinical procedures that are not the result of AE (e.g., elective surgery 
for a pre-existing condition that has not worsened) need not be considered AEs or SAEs. If 
anything, untoward is reported during the procedure, that occurrence must be reported as an AE, 
either 'serious' or 'non-serious' according to the usual criteria. 

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8.2 
Assessment for Determining Relationship of AE to Study Drug 
 
The relatedness of each AE to study drug must be classified based on medical judgement and 
according to the following categories. The definitions are as follows: 
 
Related: This category applies to AEs that are considered, with a high degree of certainty, to be 
related to the study drug. An AE may be considered related when it follows a temporal sequence 
from the administration of study drug, it cannot reasonably be explained by the known 
characteristics of the subject’s clinical state, environment, or toxic factors, or other modes of 
therapy administered to the subject. An AE may be considered related when it follows a known 
pattern of response to the study drug, or if the AE reappears upon re-challenge. 
 
Possibly related (non-serious AEs only): This category applies to AEs that are considered to have 
an unlikely connection to study drug, but a relationship cannot be ruled out with certainty. 
Unlikely related (non-serious AEs only): This category applies to AEs that do not follow a 
reasonable temporal sequence from the administration of the study drug. The AE may readily 
have been produced by the subject’s clinical state, environmental or toxic factors, or other modes 
of therapy administered to the subject. 
 
Unrelated: This category applies to AEs that are considered with a high degree of certainty to be 
due only to extraneous causes (e.g. subject’s clinical state, environment, toxic factors, disease 
under study, etc.) and does not meet the criteria of other categories above. 
 
There are two types of adverse events, Serious Adverse Events (SAE) and Non-Serious Adverse 
Events (AEs). 
 
8.3 
Serious Adverse Events 
 
8.3.1 
Definition of Serious Adverse Event (SAE) 
 
In general, an SAE is any event that meets any of the following criteria listed below regardless of 
the relationship to study drug: 
 
• 
Death 
• 
Life-threatening 
• 
Prolongation of existing hospitalization 
• 
Persistent or significant disability/incapacity 
• 
Congenital anomaly/birth defect in the offspring of a subject who received zavegepant 
• 
Other: Important medical events such as admission to ICU because of worsening of subject’s 
condition, intubation or other medical procedures performed because of worsening of 
subject’s condition, etc. 

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• 
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 8.3.5) 
 
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 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 8.3.3 
 
In general, hospitalization signifies that the subject has been detained (usually involving at least 
an overnight stay) at the hospital or emergency ward for observation and/or treatment that would 
not have been appropriate in the physician's office or outpatient setting. When in doubt as to 
whether 'hospitalization' occurred or was necessary, the AE should be considered serious. 
 
The following hospitalizations are not considered SAEs in Biohaven clinical studies (but may be 
considered non-serious AEs): 
 
• 
A visit to the emergency room or other hospital department <24 hours that does not result in 
an admission (unless considered “important medical event” or event that is life threatening); 
 
• 
Elective surgery planned prior to signing consent; 
• 
Admissions as per protocol for a planned medical/surgical procedure; 
• 
Routine health assessment requiring admission (i.e., routine colonoscopy); 
• 
Admission encountered for another life circumstance that carries no bearing on health and 
requires no medical intervention (i.e., lack of housing, care-giver respite, family 
circumstances). 

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Disability/incapacitating: An AE is incapacitating or disabling if the experience results in a 
substantial and/or permanent disruption of the subject's ability to carry out normal life functions. 
 
8.3.2 
Collection and Reporting Serious Adverse Events 
Following the subject’s written consent to participate in the study, all SAEs, whether related or 
not related to study drug, must be collected, including those thought to be associated with 
protocol-specific procedures. All SAEs must be collected that occur from signing consent and 
throughout the course of the study up to and including the Post-dose Follow-up Visit Day 60. 
 
All SAEs should be followed to resolution or stabilization. 
 
An SAE report should be completed for any event where doubt exists regarding its status of 
seriousness. 
 
If the investigator believes that an SAE is not related to the study drug but is potentially related 
to the conditions of the study (such as a withdrawal of previous therapy or a complication related 
to study procedure), the relationship should be specified in the narrative section of the SAE 
Report Form. 
 
SAEs, whether related or not related to study drug, overdose (see Section 8.3.3), potential drug 
induced liver injury (see Section 8.3.3) and pregnancies (see Section 8.3.4) 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 as per the IRB’s reporting requirements. 
Additionally, the Investigator, or designated staff, is responsible for entering the SAE 
information into the eCRF and/or system (i.e., event term, start/stop dates, causality, and 
severity). 
 
Any serious adverse event must be reported immediately or no later than 24 hours after 
awareness of the event to PPD Pharmacovigilance (PVG). A written description of any serious 
adverse event, using the PPD SAE report form, must be sent to PPD PVG by facsimile (fax), 
within 24 hours after awareness of the event: 
 
• 
North America: 1-888-488-9697 
• 
EU EMEA: +44 1223 374 102 
Due to COVID-19 restrictions for sites, SAE reports may be sent via encrypted email to PPD at: 
wilsafety@ppdi.com. The subject line of the email must include “Biohaven Protocol 
BHV3500-203.” 
 
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 
• 
EU EMEA: +44 1223 374 240 

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If only limited information is initially available, follow-up reports are required. If an ongoing 
SAE changes in its intensity or relationship to study drug or if new information becomes 
available, a follow-up SAE report should be sent within 24 hours of the Investigator becoming 
aware of the updated information using the same procedure used for the transmission of the 
initial SAE and the same event term should be used. 
 
The minimum information required for an initial SAE report is: 
 
• 
Sender of report (Site number, Investigator name) 
• 
Subject identification (subject number) 
• 
Protocol number 
• 
SAE term (if an SAE is being reported) 
8.3.3 
Overdose 
 
An overdose is defined as the accidental or intentional administration of any dose of a product 
that is considered both excessive and medically important. 
 
All occurrences of medically significant overdose (suspected or confirmed and irrespective of 
whether it involved zavegepant) 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 two tablets instead of prescribed dose of 
one tablet in one calendar day) should be reported as deviations. 
 
8.3.4 
Pregnancy 
If, following the baseline visit, it is subsequently discovered that a study subject is pregnant or 
may have been pregnant at the time of the investigational product exposure, including during at 
least 6 half-lives after the product administration, the investigational product will be permanently 
discontinued in an appropriate manner (i.e., dose tapering if necessary for subject safety). 
Protocol-required procedures for study discontinuation and follow-up must be performed on the 
subject unless contraindicated by the pregnancy (i.e., x-ray studies). Other appropriate 
pregnancy follow-up procedures should be considered if indicated. 
 
Sites should instruct subjects to contact the Investigator if they become pregnant during the 
course of the study. The investigator must immediately notify the Biohaven (or designee) 
Medical Monitor and PPD of the event and complete the Pregnancy Form in accordance with 
SAE reporting procedures as described in Section 8.3.2. The pregnancy should be reported using 
paper forms, which should be faxed to PPD PVG by facsimile (fax), within 24 hours after 
Investigator/site awareness of the event: 

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• 
North America - 1-888-488-9697 
• 
EU EMEA: +44 1223 374 102 
Due to COVID-19 restrictions for sites, SAE reports may be sent via encrypted email to PPD at: 
wilsafety@ppdi.com. The subject line of the email must include “Biohaven Protocol 
BHV3500-203.” 
 
Or if the form cannot be faxed or emailed it should be reported via phone to the PPD Safety 
Hotline at North America: 1-800-201-8725 or EU EMEA: +44 1223 374 240. 
 
Once the paper form is available, the data must be reported per standard procedures. 
 
Follow-up information regarding the course of the pregnancy, including perinatal and neonatal 
outcome and, where applicable offspring information must also be reported on a Pregnancy 
Report Form. 
 
Any pregnancy that occurs in a female partner of a male study participant should be reported to 
the sponsor/PPD. Information on this pregnancy will be collected on the Pregnancy Report 
Form, as appropriate. 
 
8.3.5 
Potential Drug Induced Liver Injury (DILI) 
 
Wherever possible, timely confirmation of the initial liver-related laboratory abnormalities 
should occur prior to the reporting of a potential DILI event. All occurrences of potential DILIs, 
meeting the defined criteria, must be reported as SAEs as per Section 8.3.2. 
 
Potential drug induced liver injury is defined as: 
 
1. ALT or AST elevation > 3 times the upper limit of normal (ULN) 
 
AND 
 
2. Total bilirubin > 2 times ULN, without initial findings of cholestasis (elevated serum 
alkaline phosphatase) 
 
AND 
3. No other immediately apparent possible causes of ALT or AST elevation and 
hyperbilirubinemia, including but not limited to, viral hepatitis, pre-existing chronic or 
acute liver disease, or the administration of other drug(s) known to be hepatotoxic. 
 
If any potential DILI is identified and meets the criteria above, the Biohaven Medical Monitor 
(or designee) should immediately be contacted for further instruction and whether the subject 
must discontinue from the trial and appropriate follow up requirements. 

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8.4 
Non-serious Adverse Events 
 
A non-serious adverse event is an AE not classified as serious. 
 
8.4.1 
Collection and Reporting of Non-Serious Adverse Events 
 
The collection of non-serious AE information should begin at the initiation of study drug through 
Day 29. 
Non-serious adverse events should be followed until conclusion or stabilization or reported as 
SAEs if they become serious. Follow-up is also required for non-serious AEs that cause 
interruption or discontinuation of study drug or those that are present at Day 29. 
 
8.4.2 
Laboratory Test Abnormalities 
 
The following laboratory test abnormalities should be captured on the non-serious AE eCRF 
page (out to Day 29) or SAE Report Form (paper or electronic) as appropriate: 
 
• 
Any laboratory test result that is determined to be clinically significant or meets the 
definition of an SAE; 
 
• 
Any laboratory test abnormality that requires the subject to have the study drug discontinued 
or interrupted; 
 
• 
Any laboratory test abnormality that requires the subject to receive specific corrective 
therapy. 
 
8.5 
Adverse Events of Special Interest 
 
Not Applicable. 

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9 STATISTICS 
Complete details on the statistical methods for this study may be found in the Statistical Analysis 
Plan (SAP). 
9.1 
Sample Size 
 
This study will randomize 120 subjects in a 2 to 1 ratio, to zavegepant and placebo, respectively. 
 
Since our understanding of the course of the disease as measured by the primary endpoint, and 
the ability of the drug to alter that course, are limited, the sample size for this study was 
primarily based on what is typical for a phase II study. Based on a limited set of encountered 
data, presented below, we believe the study may have roughly 90% power to detect an average 
improvement of 1 unit on the primary endpoint. 
 
Just prior to the creation of this protocol, some epidemiological data was informally gathered by 
Biohaven from local hospitals. For 300 subjects tested for COVID-19, the distribution on the 
primary endpoint was estimated to be as shown in Table 2. 
 
Table 2: 
Distribution, number (N), and percent (%) of 300 subjects tested for 
COVID-19 
 
Category 
Description 
N 
% 
1 
Death 
4 
1.3% 
2 
Hospitalized, on invasive mechanical ventilation or ECMO 
34 
11.3% 
3 
Hospitalized, on non-invasive ventilation or high flow 
oxygen devices 
30 
10.0% 
4 
Hospitalized, requiring supplemental oxygen 
20 
6.7% 
5 
Hospitalized, not requiring supplemental oxygen 
14 
4.7% 
6 
Not hospitalized 
198 
66.0% 
 
The table shows the distribution at the time of initial testing for a broad range of subjects. In this 
study, the subjects will have tested positive for COVID-19, have been admitted to a hospital, and 
will generally be in category 4 (hospitalized, requiring supplemental oxygen). The distribution 
of subjects after 14 days of treatment with either zavegepant or placebo is a matter of 
speculation. However, it does seem reasonable to discount the large number of subjects in 
category 6 (not hospitalized). These subjects, who were tested and sent home, would not be 
admitted into this study. If the category 6 subjects are not included in the calculations, then the 
distribution of the remaining data can be described as having a mean of 3.1 and a standard 
deviation of 1.1. 

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Based on the table, we speculate that after 14 days of treatment the distribution of subjects on 
placebo might have a standard deviation as high as 1.5 units. If zavegepant improves the 
response of subjects by an average of 1 unit over placebo, then this study will have roughly 90% 
power. This calculation is based on a t-test, with sample sizes of 80 and 40 per group, and alpha 
level of 0.05 and a common standard deviation of 1.5 units. 
 
9.2 
Analysis Sets 
 
The following analysis sets will be used in this this study: 
 
• 
Enrolled: Subjects who sign informed consent and are assigned a subject identification 
number 
 
• 
Randomized: Subjects in the enrolled analysis set who receive a randomized treatment group 
assignment (zavegepant or placebo) 
 
• 
Safety: Subjects in the enrolled analysis set who receive at least one dose of study drug 
(zavegepant or placebo) 
 
• 
Efficacy: Subjects in the randomized analysis set who are randomized only once, and receive 
at least one dose of study drug. 
 
9.3 
Statistical Methods 
 
Categorical variables are tabulated with counts and percentages. Continuous variables are 
summarized with univariate statistics (e.g., n, mean, standard error, median, minimum and 
maximum). 
 
For the calculation of descriptive statistics of observed data, subjects must have a baseline value 
to be evaluable for endpoints based on values and changes from baseline over time. 
 
Tabulations of the following endpoints present the number of unique subjects with an event: 
protocol deviations; non-study medications; AEs; and laboratory test abnormalities. Thus, for 
these endpoints, multiple occurrences of the same event are counted only once per subject. 
 
9.3.1 
Demographic and Baseline Characteristics 
 
Tabulations of demographic and baseline characteristics are made for the efficacy and safety 
analysis sets. 
 
9.3.2 
Primary Endpoint 
 
The primary endpoint will be analyzed using a Mixed Model for Repeated Measures (MMRM) 
with treatment group, visit, visit-by-treatment group interaction, and randomization stratum age 
group as fixed effects, baseline SpO2/FiO2 ratio as a covariate, and subject as a random effect. 
Visit will be a categorical variable based on analysis visit windows for Days 5, 10, 15, 22, and 

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CCI 
 
29. The primary endpoint will be tested by comparing zavegepant to placebo at Day 15 at an 
alpha level of 0.05. Descriptive statistics will be provided for each treatment group that show the 
number and percentage of subjects in each category. Analyses are based on the efficacy analysis 
set. 
 
9.3.3 
Secondary Endpoints 
 
If the primary endpoint is significant at alpha :S 0.05, then the key secondary endpoints will be 
tested at an alpha level of 0.05 using the Holmes procedure. 
 
Analyses are based on the efficacy analysis set. 
 
9.3.4 
Adjustment for Multiplicity 
 
Multiplicity is addressed in this study using a gatekeeping procedure (see Section 9.3.3). 
 
9.3.5 
Missing Data 
 
Since this study is expected to be conducted in a hospital setting, we expect little or no missing 
data for the primary endpoint. Every effort will be made to contact subjects that are released 
from the hospital before Day 15 by telephone and determine their status for the primary 
endpoint. The statistical model for the primary endpoint will include all subjects, and is valid 
under the assumption of Missing At Random (MAR). Sensitivity analyses will assess the model 
under other assumptions regarding missingness. 
 
9.3.6 
Analysis of Safety 
The investigators determine the intensity of AEs and the relationship of AEs to study therapy. 
The investigators’ terms are coded and grouped by system organ class using the latest version of 
the Medical Dictionary for Regulatory Activities (MedDRA) available. AEs are presented by 
system organ class and preferred term in descending order of overall frequency of events. If a 
subject had an AE with different intensities over time, then only the greatest intensity is reported. 
 
Deaths, all AEs, and SAEs are listed for the enrolled analysis set. 
 
The frequencies of the following safety events on study are summarized by treatment group and 
overall for the safety analysis set: SAEs; AEs by intensity and overall; treatment-emergent AEs 
by intensity and overall; AEs leading to study drug discontinuation; and treatment-emergent AEs 
by relationship to study drug. 
 
Clinically significant laboratory test abnormalities on study will be identified as Grade 3 to 4 
laboratory test results graded according to numeric laboratory test criteria in CTCAE Version 5.0 
(2017), if available. Otherwise, if CTCAE grades are not available, then results will be graded 

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according to numeric laboratory test criteria in Division of AIDS (DAIDS) Table for Grading the 
Severity of Adult and Pediatric Adverse Events Corrected Version 2.1 (2017). If a subject has a 
laboratory test abnormality with different toxicity grades over time, then only the highest toxicity 
grade will be reported. 
 
Further safety analyses will be described in the SAP. 
 
9.3.7 
Futility Analysis 
 
A formal futility analysis will be performed by the DMC statistician after approximately 50% of 
subjects complete the 14-day treatment period. 
 
The DMC will test for futility stopping only. This test will not be counted against the alpha 
spend for the study. In particular, zavegepant will be tested for inferiority to placebo, on the 
primary endpoint (the six point, ordinal, severity scale). This will be done using a Wilcoxon rank 
sum test at a one-sided alpha level of 0.05. 
 
9.4 
Schedule of Analyses 
 
A futility analysis will be conducted by the DMC statistician after approximately half of the 
subjects have reached Day 15. 
The first planned analysis for this study may be executed after the last subject has reached Day 
29 of the study, and the database has been locked. The last planned analysis will occur after the 
last subject has completed the Day 60 safety follow up. 
 
Additional unplanned analyses may be executed as needed to protect subject safety and as 
requested by regulatory agencies. 

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10 ETHICS AND RESPONSIBILITIES 
10.1 Good Clinical Practice 
 
This study will be conducted in compliance with the protocol, Good Clinical Practice (GCP), 
Good Laboratory Practice (GLP), International Conference on Harmonization (ICH) guidelines, 
and all applicable regulations, including the Federal Food, Drug and Cosmetic Act, U.S. 
applicable Code of Federal Regulations (title 21), any Independent Ethics Committee (IEC) 
requirements relative to clinical studies. The study will also be conducted in compliance with the 
recommendations laid down in the most recent version of the Declaration of Helsinki, with the 
exception that registration of such Phase 1 trials in a publicly accessible database is not 
mandatory. 
 
This study will be conducted in compliance with the protocol. The protocol and any amendments 
and the subject informed consent will receive IRB/IEC approval/favorable opinion prior to 
initiation of the study. 
 
All serious breaches must be reported to Biohaven (or designee) immediately. A Serious breach 
is a breach of the conditions and principles of GCP in connection with the study or protocol, 
which is likely to affect, to a significant degree, the safety or physical or mental integrity of the 
subjects of the study or the scientific value of the study. 
 
Study personnel involved in conducting this study will be qualified by education, training, and 
experience to perform their respective task(s). 
 
This study will not use the services of study personnel where sanctions have been invoked or 
where there has been scientific misconduct or fraud (e.g., loss of medical licensure, debarment). 
 
The Principal investigator and the Sponsor’s representative must sign the protocol and its 
amendments (if any) before initiating the study. 
 
It is the Sponsor’s responsibility to submit the protocol and its amendments (if any), and the 
Informed Consent Forms (ICFs) to regulatory authorities when necessary. 
 
10.2 Data Monitoring Committee (DMC) 
 
An independent DMC will be utilized for this study. The DMC will review the safety of all 
subjects enrolled in trials on a regular basis. 
 
The DMC will review the protocol and will identify the data parameters and format of the 
information to be regularly reported. The DMC will meet in person or by conference call 
according to the schedule specified in the DMC charter. The DMC will typically receive reports 
with data by treatment group (e.g. blinded group A, group B etc.) or, if requested by the DMC, 
completely unblinded. 

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Based on the review of safety data, the DMC will make recommendations regarding the conduct 
of the study to the clinical team. These may include continuing the study as designed, amending 
safety monitoring procedures, modifying the protocol or the informed consent form, or 
recommending the termination of the study. In addition, the DMC statistician will conduct a 
futility analysis using the primary endpoint, after approximately half of the subjects have reached 
Day 15. 
 
For purposes of the DMC, data analysis will be carried out by the unblinded safety biostatistics 
team independent and firewalled from the team directly involved with the study design and 
primary analyses, and a report will be prepared for the DMC. 
 
For further details please refer to the DMC charter. 
 
10.3 Steering Committee 
 
Not Applicable. 
 
10.4 Institutional Review Board/Independent Ethics Committee 
 
The Investigators agree to provide the IRB/IEC with all appropriate documents, including a copy 
of the protocol/amendments, ICFs, advertising text (if any), IB (if any) and any other written 
information provided to study subjects. The trial will not begin until the Investigators have 
obtained the IRB/IEC favorable written approvals for the above-mentioned study documents. 
 
In the event that the protocol is amended, the revised protocol must be approved by the IRB/IEC 
prior to its implementation, unless the changes involve only logistical or administrative aspects 
of the trial. 
 
10.5 Informed Consent 
 
Investigators must ensure that subjects, or, in those situations where consent cannot be given by 
subjects, their legally acceptable representatives, are clearly and fully informed about the 
purpose, potential risks, and other critical issues regarding clinical studies in which they 
volunteer to participate. 
 
Biohaven (or designee) will provide the investigator with an appropriate (i.e., Global or Local) 
sample informed consent form which will include all elements required by ICH, GCP and 
applicable regulatory requirements. The sample informed consent form will adhere to the ethical 
principles that have their origin in the Declaration of Helsinki. 
 
Before the potential subject has undergone any study-related screening procedures, the nature of 
the study and the potential risks associated with it will be explained to the subject, and the 
subject will be given an opportunity to ask questions to his or her satisfaction. After the 
questions are answered, but before proceeding further, when possible, the subject must read, sign 
and date an IRB/IEC approved written informed consent form for study. The signed and dated 
ICF will be retained at the Investigator’s site, with a copy provided to the study subject and date 
will be entered in his or her eCRF or appropriate system. Because this study involves 

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hospitalized subjects with an infectious disease, alternative consenting procedures as described in 
recent FDA guidance52 may be used when necessary. 
The IRB/IEC must review and approve all protocol versions and informed consent form versions 
and a copy of each version of the IRB/IEC approved protocol and informed consent form is to be 
retained in the Study Master file. Any revisions to the protocol or ICF will be reviewed and 
approved by the IRB/IEC and subjects will be informed of ICF changes and document 
continuing consent by signing and dating the revised version of the ICF. 
 
If a revised ICF is introduced during the study, each subject’s further consent must be obtained. 
The new version of the ICF must be approved by the IRB/IEC, prior to subsequently obtaining 
each subject’s consent. 
 
If informed consent is initially given by a subject’s legal guardian or legally acceptable 
representative, and the subject subsequently becomes capable of making and communicating 
their informed consent during the study, then the consent must additionally be obtained from the 
subject. 
 
The informed consent form must also include a statement that Biohaven and its representatives 
and regulatory authorities may have direct access to subject records. 
 
10.6 Case Report Forms 
 
An investigator is required to prepare and maintain adequate and accurate case histories designed 
to record all observations and other data pertinent to the investigation of each study subject. Data 
reported on the eCRF that are derived from source documents must be consistent with the source 
documents or the discrepancies must be explained. 
 
Electronic CRFs will be prepared for all data collection fields when EDC is being used. 
 
The confidentiality of records that could identify subjects must be protected, respecting the 
privacy and confidentiality rules in accordance with the applicable regulatory requirement(s). 
 
The investigator must retain a copy of the eCRFs including records of changes and corrections. 
If EDC is being used, signatures will be obtained electronically and a copy of the electronic 
eCRFs will be provided (or the data from the eCRFs) for future reference. 

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11 RECORDS MANAGEMENT 
In accordance with the principles of GCP and GLP, the study may be inspected by regulatory 
authorities, the Sponsor and CRO. The Sponsor is entitled to access information about the status 
of the study and to review the original documents of the study. 
 
The investigator must retain all study records and source documents for the maximum time 
period required by the applicable regulations and guidelines, or institution procedures or for the 
period of time specified by the sponsor, whichever is longer. The investigator must contact the 
Sponsor prior to destroying any records associated with this study. 
 
Biohaven will notify the investigators when the study files for this study are no longer needed. 
 
If the investigator withdraws from the study (i.e., retirement, relocation), the records shall be 
transferred to a mutually agreed upon designee. Notice of such transfer will be given in writing 
to Biohaven. 
 
It is the responsibility of the investigator to ensure that the current disposition record of 
investigational product (may be supplied by the sponsor) is maintained at each study site where 
the study drug is inventoried and dispensed. Records or logs must comply with applicable 
regulations and guidelines and should include: 
 
11.1 Source Documentation 
 
An Investigator is required to prepare and maintain adequate and accurate case histories designed 
to record all observations and other data pertinent for all subjects on study. 
 
If source documents are created to support the collection of study information, this must be 
retained with the other pertinent medical records for each subject for verification of data points, 
unless otherwise instructed by the Sponsor or designee to enter data directly on the eCRF. 
 
Study monitors will perform ongoing source data verification to confirm that data entered into 
the eCRF by authorized site personnel are accurate, complete, and verifiable from source 
documents; that the safety and rights of participants are being protected; and that the study is 
being conducted in accordance with the currently approved protocol and any other study 
agreements, ICH GCP, and all applicable regulatory requirements. 
 
The investigator must permit study-related monitoring, audits, IRB/IEC review, and regulatory 
agency inspections and provide direct access to source data documents. 

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11.2 Study Files and Record Retention 
 
The Sponsor does not require original documents that have already been scanned and entered 
into the electronic Trial Master File (eTMF) system to be forwarded to the Sponsor. Any original 
documents (i.e. 1572, signed financial disclosure, signed ICF, etc.) will be retained in the 
regulatory binder at the study site. The CRO will conduct a final eTMF reconciliation to ensure 
all study files and regulatory documents have been correctly uploaded to the eTMF prior to the 
close or termination of the study. Any materials or documents to support the clinical trial outside 
of the eTMF (i.e. rater training tapes) should be maintained by the CRO. The Sponsor will be 
contacted to determine whether the study documents/materials that are retained outside of the 
eTMF will be forwarded to the Sponsor, destroyed or kept at the CRO or at another facility for a 
longer period of time at the Sponsor's expense. 
 
The CRO will maintain adequate study records after completion or termination of study. After 
that period, the Sponsor will be contacted to determine whether the study records will be 
forwarded to the Sponsor, destroyed or kept at CRO or at another facility for a longer period of 
time at the Sponsor's expense. 

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

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13 STUDY REPORT AND PUBLICATIONS 
Biohaven (or specified designee) is responsible for preparing and providing the appropriate 
regulatory authorities with clinical study reports according to the applicable regulatory 
requirements. 
 
The publication policy of Biohaven is discussed in the investigator's Clinical Research 
Agreement. 

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14 STUDY DISCONTINUATION 
Both Biohaven and the Principal Investigator reserve the right to terminate the study at the 
investigator’s site at any time. Should this be necessary, Biohaven or a specified designee will 
inform the appropriate regulatory authorities of the termination of the study and the reasons for 
its termination, and the Principal Investigator will inform the IRB/IEC of the same. In 
terminating the study, Biohaven and the Principal Investigator will assure that adequate 
consideration is given to the protection of the subjects’ interests. 

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15 CONFIDENTIALITY 
All information generated in this study is considered highly confidential and must not be 
disclosed to any person or entity not directly involved with the study unless prior written consent 
is gained from Biohaven. However, authorized regulatory officials, IRB/IEC personnel, 
Biohaven and its authorized representatives are allowed full access to the records. 
 
Identification of subjects and eCRFs shall be by initials (when allowed), screening and treatment 
numbers only. If required, the subject's full name may be made known to an authorized 
regulatory agency or other authorized official. 
 
The Sponsor may approve the sharing of de-identified data from this study to be made available 
to researchers for the purpose of advancing the understanding the pathogenesis of COVID-19 
disease or trial methodology. In any publication of this data, confidentiality of individual 
subjects will be protected. 

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Protocol Title: BHV3500-203: Phase 2/3: Double-Blind, Randomized, Placebo Controlled, Safety and 
Efficacy Trial of Zavegepant (BHV-3500) Intranasal (IN) Hospitalized Patients with COVID-19 
Requiring Supplemental Oxygen 
Study No: BHV3500-203 
Original Protocol Date: 13 April 2020 
Protocol Version No: V 7.0 
Protocol Version Date: 11 May 2022 
Author: 
, Clinical Operations 
Clinical Operations: 
, Clinical Operations 
PPD 
 
PPD 
 PPD  , Ph.D. 
 
 
 
Medical Lead: 
Digitally signed by PPD 
PP 
, MD 
D 
 
PPD 
Regulatory Affairs: 
Regulatory Affairs 
PPD 
 
Digitally signed by PPD 
 
Reason: I am approving this 
document 
PPD 
PPD  
Biometrics: 
PPD 
 
Biostatistics 
 
PPD 
 
PPD 
Date 
Signature Approval 
Name and Title 
PPD 
PPD 
PPD 
PPD 
PPD 
PPD 
 
16 CLINICAL PROTOCOL APPROVAL FORM 
 
 
• 
The current risk-benefit evaluation of the investigational product. 
• 
The moral, ethical and scientific principles governing clinical research as set out in the 
Declaration of Helsinki, and principles of GCP as described in 21 CFR parts 50, 54, 56 and 
312 and according to applicable local requirements. 
 
The Investigator will be supplied with details of any significant or new findings, including 
adverse events, relating to treatment with the investigational product. 
 
 

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17 APPENDICES 
17.1 APPENDIX I – Names of Study Personnel 
 
 
Sponsor: 
Biohaven Pharmaceuticals 
Refer to contact list in study binder for contact information 
Medical Monitor: 
PPD 
, MD PPD 
 
 
PPD 
 
 
Clinical Research 
Organizations: 
Cognitive Research Corporation 
Refer to contact list in study binder for contact information 
Pharmacovigilance: 
PPD 
Refer to SAE, Pregnancy Surveillance Forms and study 
binder for contact information. 

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