Clinical trial NCT06137703
Conditions: Biological Availability
Sponsor: Pfizer
Start date: 2022-08-24; Completion date: 2022-12-07
Enrollment: 52 participants; Allocation: RANDOMIZED; Intervention model: CROSSOVER

Brief summary:
This trial is designed to compare the rate and extent of absorption of four different formulations of zavegepant. 52 healthy male and female volunteers will receive a single dose of each formulation at least 7 days apart over a period of about 7 weeks and the amount of drug in their blood will be assessed over the 24 hour period after each dose.

Detailed description:
This is a Phase 1, single centre, open-label, single dose, 4-period, crossover study designed to compare the pharmacokinetics (PK) of zavegepant from three Test products and a Reference product (treatment D).

52 male and female healthy volunteers will be randomly assigned to one of 4 treatment sequences: ACBD, CDAB, BADC, and DBCA.

In each period, subjects will receive one of the following: Treatment A, B, C, or D on Day 1, followed by 24 hours of PK and safety assessments. On Day 2 subjects will be discharged from the clinical site and instructed to return after at least a 7 day washout time has passed for subsequent periods of treatment.

The study will include a screening visit from Day -28 to Day -2. Eligible subjects will be admitted to the clinical site on Day -1 and will be confined until completion of the assessments on Day 2. There will be a washout period of at least 7 days between doses. Study Exit procedures will be performed after the last assessment on the morning of Day 2 of Period 4. Study Exit procedures will be performed as soon as possible in case of Early Termination.

The total duration of study participation for each subject from Screening through Study Exit is anticipated to be approximately 6.5 weeks.

Arms: arm 1: Period 1 - Single zavegepant 100mg non-enteric coated soft gel capsule (Treatment A) followed by at least 7 days washout; Period 2 - Two zavegepant 100mg immediate release tablets (Treatment C) followed by at least 7 days washout; Period 3 - Single zavegepant 100mg immediate release tablet (Treatment B) followed by at least 7 days washout; Period 4 - Four zavegepant 25mg enteric coated soft gel capsule (Treatment D). arm 2: Period 1 - Two zavegepant 100mg immediate release tablets (Treatment C) followed by at least 7 days washout; Period 2 - Four zavegepant 25mg enteric coated soft gel capsule (Treatment D) followed by at least 7 days washout; Period 3 - Single zavegepant 100mg non-enteric coated soft gel capsule (Treatment A) followed by at least 7 days washout; Period 4 - Single zavegepant 100mg immediate release tablet (Treatment B). arm 3: Period 1 - Single zavegepant 100mg immediate release tablet (Treatment B) followed by at least 7 days washout; Period 2 - Single zavegepant 100mg non-enteric coated soft gel capsule (Treatment A) followed by at least 7 days washout; Period 3 - Four zavegepant 25mg enteric coated soft gel capsule (Treatment D) followed by at least 7 days washout; Period 4 - Two zavegepant 100mg immediate release tablets (Treatment C). arm 4: Period 1 - Four zavegepant 25mg enteric coated soft gel capsule (Treatment D) followed by at least 7 days washout; Period 2 - Single zavegepant 100mg immediate release tablet (Treatment B) followed by at least 7 days washout; Period 3 - Two zavegepant 100mg immediate release tablets (Treatment C) followed by at least 7 days washout; Period 4 - Single zavegepant 100mg non-enteric coated soft gel capsule (Treatment A).
Interventions: intervention 1: Zavegepant 100mg non-enteric coated soft gel capsule intervention 2: Zavegepant 100mg immediate release tablet intervention 3: Zavegepant 2 x 100mg immediate release tablets intervention 4: Zavegepant 4 x 25mg enteric coated soft gel capsule
Intervention descriptions: intervention 1: Zavegepant (PF-07930207/BHV3500) 100mg non-enteric coated soft gel capsule intervention 2: Zavegepant (PF-07930207/BHV3500) 100mg dodecylmaltoside dosage form immediate release tablet intervention 3: 2 x Zavegepant (PF-07930207/BHV3500) 100mg dodecylmaltoside dosage form immediate release tablets - total dose 200mg intervention 4: Zavegepant (PF-07930207/BHV3500) 25 mg enteric coated soft gel capsules - total dose 100mg

Protocol documents:
Prot_000.pdf: 
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PROTOCOL BHV3500-113
Syneos Health Project Number: Number: 222025
IND Number: 
A PHASE 1, OPEN-LABEL, RANDOMIZED, 4-PERIOD, 4-WAY CROSSOVER, 
COMPARATIVEBIOAVAILABILITY STUDY OF ZAVEGEPANT (BHV-3500) ORAL 
FORMULATIONS UNDER FASTING CONDITIONS
Sponsor:
Biohaven PharmaceuticalsHolding Company Limited
215 Church Street
New Haven,CT
USA06510
Tel.: 203-404-0410
Contract Research 
Organization:
Protocol Version:
Amendment 01
Date:
16-AUG-2022
CONFIDENTIAL
This document is strictly confidential. It was developed forBiohaven PharmaceuticalsHolding Company Limited, 
by Syneos Health.The information in this document may be disclosed only to persons involved in the study, ethics 
committees, regulatory agencies and study audit personnel. This document is copyrighted in favor of Syneos Health
and cannot be reproduced, modified, or adapted, in part or in total, without prior written approval by Syneos Health.
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PROTOCOL HISTORICAL FILE
Version
Brief description/summary of changes
Date
Final
Version submitted to the Independent Ethics 
Committee (IEC).
21-JUL-2022
Version 2.0(Amendment 01) Correction to IND number
16-AUG-2022


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SPONSORSIGNATURE PAGE
Biohaven PharmaceuticalsHolding Company Limited
215 Church Street
New Haven CT
USA 06510
Tel.: 203-404-0410
Sponsor’s representative:
18 August 2022
______________________
Date
PPD


19-Aug-2022
PPD
PPD


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TABLE OF CONTENTS
PROTOCOL HISTORICAL FILE..........................................................................................2
SPONSORSIGNATURE PAGE..............................................................................................3
INVESTIGATOR SIGNATURE PAGE..................................................................................4
TABLE OF CONTENTS..........................................................................................................5
LIST OF TABLES....................................................................................................................7
LIST OF ABBREVIATIONS...................................................................................................8
SYNOPSIS OF PROTOCOL.................................................................................................11
SCHEDULE OF ASSESSMENTS.........................................................................................17
1 INTRODUCTION............................................................................................................19
1.1
Background Information.............................................................................................19
1.2
Summary of Clinical Experience with Zavegepant....................................................19
1.3
Rationale for Study Design..........................................................................................20
1.4
Benefit/Risk Assessment..............................................................................................21
2 OBJECTIVES..................................................................................................................22
3 STUDY DESIGN..............................................................................................................22
4
STUDY POPULATION...................................................................................................22
4.1
Number of Subjects.....................................................................................................22
4.2
Inclusion Criteria.........................................................................................................22
4.3
Exclusion Criteria........................................................................................................24
4.4
Subject Withdrawal a nd Replacement.......................................................................27
5
STUDY TREATMENTS..................................................................................................28
5.1
Drug Supplies and Accountability..............................................................................28
5.2
Identification of Treatments........................................................................................28
5.3
Randomization and Blinding......................................................................................29
5.4
Study Drug Administration.........................................................................................29
6 STUDY RESTRICTIONS...............................................................................................29
6.1
Concomitant Medications............................................................................................29
6.2
Drugs, Nicotine, and Alcohol.......................................................................................30
6.3
Diet...............................................................................................................................30
6.4
Posture and Physical Activity......................................................................................30
7 STUDY PROCEDURES..................................................................................................31
7.1
Pharmacokinetic Assessments.....................................................................................31
7.2
Safety and Tolerability Assessments...........................................................................32
7.3
Adverse Events............................................................................................................35
7.4
Pregnancy....................................................................................................................40
7.5
Premature Termination of the Study..........................................................................41
8 STATISTICAL ANALYSES...........................................................................................41
8.1
Determination of Sample Size.....................................................................................41
8.2
Analysis Populations....................................................................................................41
8.3
Pharmacokinetic Parameters......................................................................................42
8.4
Pharmacokinetic Statistical Analysis..........................................................................42
8.5
Safety and Tolerability Analysis.................................................................................43
9
DATA COLLECTION.....................................................................................................44


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10 REGULATORY CONSIDERATIONS AND QUALITY ASSURANCE......................44
10.1 IEC/IRB Approval of Protocol and Other Study Documents....................................44
10.2 Compliance..................................................................................................................44
10.3 Quality Assurance and Monitoring.............................................................................45
10.4 Confidentiality and Retention of Study Records........................................................45
11 REFERENCES.................................................................................................................46


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LIST OF TABLES
Table 1
Schedule of Assessments..................................................................................17
Table 2
Time Tolerance Windows for PK Blood Samples ...........................................32
Table 3
Laboratory Assessments..................................................................................34
Table 4
Description of Severity of Adverse Events......................................................36


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LIST OF ABBREVIATIONS
AE
adverse event
ALT
alanine aminotransferase
ALP
alkaline phosphatase
ANOVA
analysis of variance
aPTT
activated partial thromboplastin time
AST
aspartate aminotransferase
AUC0-inf
area under the concentration-time curve from time zero to infinity 
(extrapolated)
AUC0-t
area under the concentration-time curve from time zero until the last 
observed concentration
BA
bioavailability
BMI
body mass index
BP
blood pressure
BUN
blood urea nitrogen
CGRP
calcitonin gene-related peptide 
Cl/F
apparent clearance
Cmax
maximal observed concentration
CPK
creatine phosphokinase
CRF
case report form
CTCAE
Common Technical Criteria for Adverse Events
DAIDS
Division of Aquired Imunodeficiency Syndrome
DDM
Dodecylmaltoside
DMP
Data Management Plan
ECG
electrocardiogram
eGFR
estimated glomerular filtration rate
ET
early termination
FDA
Food and Drug Administration
FSH
follicle-stimulating hormone
GCP
Good Clinical Practice
GGT
gamma-glutamyl transferase
GMP
Good Manufacturing Practice
HBsAg
hepatitis B surface antigen
HCG
human chorionic gonadotrophin
HCV
hepatitis C virus


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HEENT
head, eyes, ears, nose, and throat
HIV
human immunodeficiency virus
HR
heart rate
IB
Investigator’s Brochure
ICF
Informed Consent Form
ICH
International Council for Harmonisation of Technical Requirements 
for Pharmaceuticals for Human Use
IEC
Independent Ethics Committee
INR
International Normalized Ratio
IR
immediate release
IRB
Institutional Review Board
IV
intravenous
Kel
terminal elimination rate constant
LFT
liver function test
LLN
lower limit of normal
MAOI
monoamine oxidase inhibitor
Max
maximum
MDMA
3,4-methylenedioxymethamphetamine
MDRD
Modification of Diet in Renal Disease
MedDRA
Medical Dictionary for Regulatory Activities
Min
minimum
NOL
No Objection Letter
ODT
orally disintegrating tablet
OT
oral temperature
OTC
over-the-counter
PCP
phencyclidine
PK
pharmacokinetic(s)
PR
PR interval
PT
prothrombin time
PVG
pharmacovigilance
QA
quality assurance
QC
quality control
QRS
QRS interval of the ECG
QT
QT interval
QTcF
Fridericia’s corrected QT interval


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QI
Qualified Investigator
RBC
red blood cell
RR
respiratory rate
SAE
serious adverse event(s)
SAP
statistical analysis plan
SAS
Statistical Analysis System
SD
standard deviation
SGC
soft gel capsule
SOP
standard operation procedure
S-STS
Sheehan suicidality tracking scale
SUSAR
suspected, unexpected, serious adverse reaction
T½ el
terminal elimination half-life
TEAE
treatment-emergent adverse event
THC
tetrahydrocannabinol
Tmax
time when the maximal concentration is observed
ULN
upper limit of normal
Vz/F
apparent volume of distribution
WBC
white blood cell


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SYNOPSIS OF PROTOCOL
Project Number:
Biohaven PharmaceuticalsHolding Company Limitedstudy number: BHV3500-113
Syneos Health Protocol Number: 222025
IND Number: 
Title:
A PHASE 1, OPEN-LABEL, RANDOMIZED, 4-PERIOD, 4-WAY CROSSOVER, 
COMPARATIVEBIOAVAILABILITY STUDY OF ZAVEGEPANT (BHV-3500) 
ORAL FORMULATIONS UNDER FASTING CONDITIONS
Study Drug:
Zavegepant (BHV-3500) 100 mg non-enteric coated soft gel capsule (SGC), oral 
administration: Test 1 (Treatment A).
Zavegepant (BHV-3500) 100 mg immediaterelease (IR) tablet + Dodecylmaltoside 
(DDM)dosage form, oral administration: Test 2 (Treatment B).
Zavegepant (BHV-3500) 200 mg IR tablet + DDM dosage form, oral administration: 
Test 3 (Treatment C).The dose for Treatment C may instead be administered as 2 x 100 
mg IR tablets + DDM dosage form for a total zavegepant dose of 200 mg.
Zavegepant (BHV-3500) 25 mg enteric coated SGC, oral administration: Reference 
(Treatment D).
Study Phase and 
Type:
Phase 1 –Comparative Bioavailability (BA) study
Objective:
The objective of this study is to compare the rate and extent of absorption of zavegepant 
100mg oral non-enteric coated SGC (Test 1), zavegepant 100mg IR oral tablet + DDM 
dosage form (Test 2),zavegepant 1x 200 mg IR oral tablet + DDM dosage form or
zavegepant 2x 100 mg IR tablets+ DDM dosage form (Test 3), and zavegepant 4 x 
25mg enteric coated oral SGC (Reference), under fasting conditions.
Study Design:
This will be a Phase 1, single center, open-label, single dose, 4-period, comparative 
bioavailability study design. The study may be dosed in more than 1 Group.
The 4 sequences will be: ACBD, CDAB, BADC, and DBCA.
Study Population:
Approximately 52healthy male and female subjects, non-smoker (no use of tobacco 
products within 3months prior to Screening), ≥ 18 and ≤ 55 years of age, with body 
mass index (BMI)>18.5 and <30.0 kg/m2and body weight ≥50.0kg for males and 
≥45.0kg for females.
InclusionCriteria:
All of the following criteria must be met in order to be considered for inclusion into the 
study:
1. Subjects must sign and date IEC/Institutional Review Board (IRB)-approved 
Informed Consent Form (ICF) obtained prior to the conduct of anystudy activities.
2. Male or female ≥ 18 and ≤ 55 years of age, non-smoker (no use of tobacco or 
nicotine products within 3 months prior to Screening), with BMI >18.5 and <30.0 
kg/m2 and body weight ≥50.0 kg for males and ≥45.0 kg for females. 
3. Healthy as defined by:
a. The absence of clinically significant illness and surgery within 4 weeks prior to 
dosing. Subjects vomiting within 24 hours pre-dose will be carefully evaluated 
for upcoming illness/disease. Inclusion pre-dosing is at the discretion of the 
Investigator;
CCI


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b. The absenceof clinically significant history of neurological, endocrine, 
cardiovascular,respiratory, hematological, immunological, psychiatric, 
gastrointestinal, renal, hepatic, and metabolic disease in the estimation of the 
Investigator.
4. Subject’s score on the Sheehan Suicidality Tracking Scale (S-STS)at Screening 
must be 0 (lifetime lookback).
5. Females must not be breastfeeding or lactating.
6. All females must have a negative urine pregnancy test (minimum sensitivity 25 
IU/L or equivalent units of human chorionic gonadotropin [HCG]) at Screening. 
Women of childbearing potential must have negative serum pregnancy test at 
admission (Day -1).
7. Females of childbearing potential (defined as premenopausal females capable of 
becoming pregnant [all fertile women]) who are sexually active with a non-sterile 
male partner (sterile male partners are defined as men vasectomized at least 6 
months prior to Screening) must be willing to use one of the following acceptable 
contraceptive methods throughout the study and for 30 days after the last study drug 
administration:
a. Simultaneous use of non-hormonal intra-uterine contraceptive device placed at 
least 4 weeks prior to first study drug administration, and condom for the male 
partner;
b. Simultaneous use of hormonal contraceptives, started at least 4 weeks prior to 
study drug administration and must agree to use the same hormonal 
contraceptive throughout the study, and condom for the male partner;
c. Simultaneous use of diaphragm or cervical cap with intravaginally applied 
spermicide and male condom for the male partner, starting at least 21 days prior 
to the first study drug administration.
8. For females of non-childbearing potential: must have undergone one of the 
following sterilization procedures at least 6 months prior to dosing:
a. Hysteroscopic sterilization;
b. Bilateral tubal ligation or bilateral salpingectomy;
c. Hysterectomy;
d. Bilateral oophorectomy;
e. Or be post-menopausal with spontaneous amenorrhea for at least 
12consecutive months prior to dosing and follicle-stimulating hormone (FSH) 
serum levels 40mIU/mL consistent with post-menopausal status.
9. Male subjects who are not vasectomized for at least 6 months prior to Screening, 
and who are sexually active with a female partner of childbearing potential 
(childbearing potential females are defined as women that are neither post-
menopausal nor surgically sterile) must be willing to use one of the following 
acceptable contraceptive methods from the first study drug administration until at 
least 90 days after the last study drug administration:
a. Simultaneous use of a male condom and, for the female partner, hormonal 
contraceptives used since at least 4 weeks prior to the first study drug 
administration or intra-uterine contraceptive device placed since at least 4 
weeks prior to the first study drug administration;


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b. Simultaneous use of a male condom with spermicide and, for the female 
partner, a diaphragm or cervical cap with intravaginally applied spermicide.
10.Male subjects (including men who have had a vasectomy) with a pregnant partner 
must agree to use a condom from the first dosing and for 90 days after the last study 
drug administration.
11.Male subjects must be willing not to donate sperm for at least 90 days after the last 
study drug administration.
12.Subjects must be able to understand the nature of the study, agree to comply with 
the prescribed dosage regimens, and communicate to study personnel about AEs and 
concomitant medication use, as applicable.
Exclusion Criteria:
Subjects to whom any of the following applies will be excluded from the study:
Medical History and Concurrent Diseases
1. Current diagnosis of viral hepatitis or a history of liver disease.
2. Any history of seizuredisorder (e.g., epilepsy) other than a single childhood febrile 
seizure.
3. Current or recent (within 3 months of the first study drug administration) 
gastrointestinal disease that may interfere with drug absorption.
4. Subjects with prior gastrointestinal surgery that interferes with absorption and 
motility (e.g., gastric bypass, duodenectomy or gastric banding). 
5. Use of medication for the timeframes specified below and throughoutthe study, 
with the exception of medications exempted by the Investigator on a case-by-case 
basis if they are judged unlikely to affect the PK profile of the study drug or subject 
safety, and occasional use of ibuprofen:
a. Prescription medication within 30 days or 5 half-lives (whichever is longer) 
days prior to the first dosing;
b. Use of any over-the-counter (OTC) medications including acetaminophen-
containing products within at least 14 daysor 5 half-lives (whichever is longer)
prior to the first dosing except for the occasional use of ibuprofen;
c. Use of any natural health products (including herbal remedies such as Butterbur 
root extracts, homeopathic and traditional medicines, probiotics, food 
supplements such as vitamins [ascorbic acid is not allowed], minerals, amino 
acids, essential fatty acids, and protein supplements used in sports) within 
14days or 5 half-lives (whichever is longer) prior to the first dosing;
d. Use of any drug known to induce or inhibit hepatic drug metabolism, including 
St. John’s wort, from 30 days prior to the first dosinguntil after the last 
pharmacokinetic (PK)blood sample for the study is obtained; 
e. A depot injection or an implant of any drug within 3 months prior to the first 
dosing;
f. Small moleculecalcitonin gene-related peptide (CGRP)receptor antagonists 
within 1 month prior to the first dosing;
g. Biologic CGRP receptor antagonist within 6 months prior to the first dosing;
h. Receipt of any vaccination, including COVID-19 vaccine, within 30 days prior 
to first dosing.


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i. Monoamine oxidase inhibitors (MAOI) within 30 days prior to the first dosing.
6. History of significant alcohol abuse or regular use within 6 months prior to 
Screening that exceeds (more than 10 units of alcohol per week for women and 15 
units for men [1 unit = 140 mL of wine 12%, 340 mL of beer, or 45 mL of 40% 
distilled alcohol]).
7. History of drug abuse within 6 months prior to the Screening visit or recreational 
use of soft drugs (such as marijuana) within 1 month prior to the Screening visit or 
hard drugs (such as cocaine, phencyclidine [PCP], crack, opioid derivatives 
including heroin, and amphetamine derivatives) within 1 year prior to Screening.
8. Subject has a history of anaphylaxis, a documented hypersensitivity reaction, or a 
clinically significant reaction to any drug.
9. History of anaphylactic reaction, a documented hypersensitivity reaction, or a 
clinically important reaction to any drug, or to any of the excipient supporting the 
zavegepant formulations.
10.Donation of plasma within 7 days prior to dosing, or donation or loss of blood 
(excluding volume drawn at Screening) of 50 mL to 499 mL of blood within 30 
days, or more than 499mL within 56 days prior to dosing.
11.Participation in a clinical research study involving the administration of an 
investigational or marketed drug or device within 30 days prior to the dosing, 
administration of a biological product in the context of a clinical research study 
within 90 days prior to the dosing, or concomitant participation in an investigational 
study involving no drug or device administration.
12.Inability or difficulty to swallow tablets or capsules.
13.Poor venous access and/or inability to tolerate catheter venous access.
14.Any reason which, in the opinion of the Investigator, would prevent the subject 
from participating in the study.
Physical and Laboratory Test Findings
15.Subjects with any clinically significant abnormality or significant abnormal 
laboratory test results found during medical screening or Day-1.
16.Subject has a positive test for human immunodeficiency virus (HIV), hepatitis B 
surface antigen (HBsAg), or hepatitis C virus (HCV) antibody during medical 
screening.
17.Evidence of organ dysfunction or any clinically significant deviation from normal in 
physical examination, vital signs, 12-lead electrocardiogram (ECG), or clinical 
laboratory determinations beyondwhat is consistent with the target population.
18.Estimated glomerular filtration rate (eGFR) according to the Modification of Diet in 
Renal Disease (MDRD) study equation ≤60 mL/min/1.73 m
2at Screening.
19.Any of the following laboratory parameters greater than the upper limit of normal 
(ULN) values at Screening or Baseline (Day -1): alkaline phosphatase (ALP) 
aspartate aminotransferase (AST), alanine aminotransferase (ALT), total bilirubin, 
direct bilirubin, and indirect bilirubin, and alkaline phosphatase.Only abnormal 
values between 1-1.5 x ULN may be repeated once for confirmation to less than the 
ULN.
20.Any of the following abnormalities on 12-lead ECG or blood pressure (BP)at 
Screening or Baseline (Day -1):


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a. PR (PR interval) ≥ 210 msec;
b. QRS (QRS complex)≥ 120 msec;
c. QT (QT interval) ≥ 500 msec;
d. QTcF (Fridericia’s corrected QT interval) ≥ 450 msec;
e. Sitting (for at least 5 minutes) systolic BP > 140 mmHg, confirmed by repeat;
f. Sitting (for at least 5 minutes) diastolic BP > 90 mmHg, confirmed by repeat.
21.Any of the following abnormal laboratory test values at Screening or Baseline 
(Day-1):
a. Hemoglobin < 12.8 g/dL for males and < 11.5 g/dL for females;
b. Hematocrit < 37% for males and < 32 % for females;
c. Total white blood cells (WBC) < 3.0 x 109/L;
d. Platelet count<100 x 109/L;
e. Neutrophils < 1.4 x 109/L and < 1.0 x 10
9/L for Afro-American volunteers;
f. Creatine phosphokinase (CPK) > 2 x ULN.
22.Positive test for COVID-19 performed on Day -1 of each period.
23.Positive urine drug screen, alcohol breath test, or urine cotinine test at Screening or 
any Day -1visit.
Study Treatments:
In each period, each subject will receive one of the following single oral dose of 
zavegepant (BHV3500)according to the randomization scheme: 
Treatment A: 1 x zavegepant 100 mg non-enteric coated SGC
Treatment B: 1 x zavegepant 100 mg IR tablet + DDM dosage form
Treatment C:1x zavegepant 200 mg IR tablet(total dose of 200 mg)+ DDM dosage 
form. The dose for TreatmentC may instead be administered as 2 x100mg IR tablets + 
DDM dosage form for a total zavegepant dose of 200 mg.
Treatment D: 4 x zavegepant 25 mg entericcoated SGC (total dose of 100 mg)
In each period, no food will be allowed from at least 10 hours before dosing until at least 
4 hours after dosing. Except for 240 mL of water given with study drug administration, 
no fluids will be allowed for 1 hour before dosing until 1hour post-dose.
Study Procedures:
Bloodsamples for PKanalysis will be collected and safety procedures will be performed 
at pre-defined times throughout the study asspecified in Table 1.
Subjects will bemonitored throughout the study by the clinical staff foradverse events
(AEs)and concomitant medications.
Statistical Analyses:
Safety and tolerability:
Safety and tolerability data will be reported using descriptive statistics. 
Treatment-emergent adverse events(TEAEs) will be summarized descriptively by 
treatment. 
Safety and tolerability to treatments will be evaluated through the assessment of AEs 
(e.g., seriousness, severity, relationship to the study medication, outcome, duration, and 
management), vital signs, 12-lead ECG, and clinical laboratory parameters. AEs will be 
coded using the latest version of the Medical Dictionary for Regulatory Activities 
(MedDRA).


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Any finding or absence of finding relative to each subject’s baseline physical 
examination will be documented. Any abnormal finding noted after dosing will be 
documented as an AE if judged as a clinically significant change from baseline. 
Changes from baseline values in vital signs, 12-lead ECG, and clinical laboratory 
parameters will be evaluated. Clinically significant laboratory abnormalities will be 
identified as Grade 3 to 4 laboratory test results graded according to numeric laboratory 
test criteria in the latest version of Common Technical Criteria for Adverse Events 
(CTCAE) if available, otherwise according to the latest version of Division of Aquired 
Imunodeficiency Syndrome(DAIDS) Table for Grading the Severity of Adult and 
Pediatric Adverse Events.
A complete description of the statistical analyses to be performed on the safety and 
tolerability data will be presented in the Statistical Analysis Plan (SAP).
Pharmacokinetics (PK):
For zavegepant, using the MIXED procedure in Statistical Analysis System (SAS), with 
Sequence, Treatment, and Period as fixed effects, and Subject within Sequence as 
random effect, analysis of variance (ANOVA) will be performed on ln-transformed 
AUC0-t, AUC
0-inf, and C
max. If the study is dosed in more than 1 Group, the statistical 
model may be modified to reflect the multi-Group nature. In case of a non-statistically 
significant TreatmentbyGroup interaction term, the analysis will be rerun excluding this 
term from the ANOVA model in order to obtain ratios and confidence intervals where 
appropriate. The ratio of geometric means and90% confidence intervals (A/D), (B/D), 
and (C/D), based on least-squares means from the ANOVA of the ln-transformed data 
will be calculated for AUC0-inf, AUC
0-t, and C
max.Other ratio of geometric means among 
treatments may be explored.Untransformed T
maxwill be analyzed using the MIXED 
model with the difference of least-squares means from the ANOVA calculated for (A-
D), (B-D), and (C-D).Other differences between treatment least-squares means may be 
explored. The Kel, and T
½el will be summarized descriptively.  
PK data of treatment C will be dose normalized to 100 mg. 


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SCHEDULE OF ASSESSMENTS
Table 1
Schedule of Assessments
PROCEDURE
Screening 
(Day -28 to -2)
Periods 1 to 4
Study Exitor 
Early 
Termination9
D-1
D1  
D2
Informed Consent
X
Demographic Data
X
Medical and Medication Histories
X
Confinement
X  
X
Discharge
X
Study Drug Administration
Zavegepant 1
X
Pharmacokinetics
Blood samples for PK analysis2
X  
X
Safety
Physical Examination
X
X3
X3
Body Measurements (weight, height, and 
BMI)
X
S-STS
X
X
Vital Signs (BP, HR, RR, OT)4
X
X  
X
X
12-lead ECG
X
X
X
Serology (HIV and Hepatitis B and C)
X
COVID-19 Test5
X
Clinical laboratory tests
6
X
X
X
Drug,cotinine, and alcohol screens
X
X
FSH (for post-menopausal females)
X7
Pregnancy Tests
8
X
X
X
Review and Monitoring of AEs and 
Concomitant Medications
Abbreviations: AE = adverse event; BMI = body mass index; BP = blood pressure; ECG = electrocardiogram; FSH 
= follicle-stimulating hormone;HIV = human immunodeficiency virus; HR = heart rate; PK = pharmacokinetic; RR 
= respiratory rate; S-STS = Sheehan suicidality tracking scale; OT = oral temperature.
1. In each period, following a fasting period of at least 10 hours, subjects will receive a single oral dose ofeither 
Treatment A, B, C or D, according to the randomization scheme. Subjects will continue fasting for at least 
4hours post-dose.There will be a washoutperiod of at least 7 days between doses.
A 
►


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2. A total of 16 bloodsamples will be collected for zavegepant concentration analysis: pre-dose (within 1 hour 
prior to dosing) and 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 10, 12, 16, and 24 hours post-dose. The time tolerance 
window for post-dose PK blood samples will be ±1 minute for all samples collected before 8hours post-dose 
and ±3 minutes for all samples collected at 8 hours post-dose through 24 hours post-dose.
3. A complete physical examination will be performed at Screening, and a brief physical examination will be 
performed on Day -1of each periodand at Study Exitor early termination (ET). 
4. Vital signs will be measured after thesubjectshave been resting for at least 5 minutes in aseatedposition. BP, 
HR, RR, and OT will be measured at Screening, Day -1of each periodand Study Exitor ET. In each period, BP 
and HR will be measured within 1 hourbefore study treatment administrationon Day 1and at 2 ± 0.25 hours 
post-dose.
5. A COVID-19 PCR test will be performed on Day -1of each period. If results are not available prior to 
admission, a COVID-19 rapid test will be performed upon admission. COVID-19 testingmay be repeated 
during the subject’s participation at the Investigator’s discretion (e.g., if a subject has signs or symptoms 
suggestive of a COVID-19 infection).
6. Biochemistry, hematology,*and urinalysis will be performed followinga fasting period of at least 8 hours  at 
Screening, on Day -1 of each period, and at Study Exitor ET. *Haptoglobin and reticulocyte count will be 
performed only in the case of a decrease in hemoglobin levels below the lower limit of normal (LLN) on Day -1
of each period and at Study Exitor ET. If the haptoglobin and reticulocyte count results come back normal but 
the hemoglobin levels results are still abnormal after the repeat, the haptoglobin and reticulocyte count tests 
may be repeated upon Investigator’s judgement. Coagulation tests will be performed only in case of abnormal 
liver function tests (LFTs)(i.e., ALP, AST, or ALT is >3xULN)on Day -1of each period and at Study Exitor 
ET.If the coagulation test results come back normal but the LFT results are still abnormal after the repeat, the 
coagulation tests may be repeated upon Investigator’s judgement.
7. FSH levels will be measured at Screening to confirm post-menopausal status.
8. For all females, aurine pregnancy test will be performed at Screening. For women of childbearing potential 
females a urine pregnancy test will be performed at Study Exitor ETand a serum pregnancy test will be 
performed on Day -1 of each period. Subjects with a positive pregnancy test will not be enrolled or will be 
discontinued.
9. Study Exitprocedures will be performed after the last assessment on the morning of Day 2 of Period 4.In case 
of ET,Study Exitprocedures will be performed as soon as possible.


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1 INTRODUCTION
1.1
Background Information
Zavegepantis a selective, high-affinity, small molecule CGRP receptor antagonist in 
development for the treatment of migraine. CGRPis an endogenous 37 amino acid peptide 
contained within pain signaling nociceptive afferents andis thought to play a causal role in 
migraine.Multiple lines of clinical evidence point to a role for CGRP in migraine 
pathophysiology: 1) serum levels of CGRP are elevated during migraine; 2) treatment with anti-
migraine drugs returns CGRP levels to normal coincident with pain relief; and 3) intravenous 
(IV) CGRP infusion produces lasting pain in non-migraineurs and migraineurs.Treatment with a 
CGRP receptor antagonist is thought to relieve migraine by: 1) blocking CGRP-induced 
neurogenic vasodilation (returning dilated intracranial arteries to normal); 2) halting the cascade 
of CGRP-induced neurogenic inflammation; and/or 3) inhibiting the central relay of pain signals 
from the trigeminal nerve to the caudal trigeminal nucleus.
1Efficacy and safety were determined 
in 2 positive pivotal trials assessing intranasal administration of zavegepantfor the acute 
treatment of migraine. A favorable safety profile was seen during a 1 year open-label safety 
study with up to 8 doses per month of intranasal zavegepant for the acute treatment of migraine. 
A summary of the nonclinical investigational programs can be found in the current Investigator’s 
Brochure (IB).1
1.2
Summary of Clinical Experiencewith Zavegepant
Details regarding the clinical experience with zavegepant can be found in the IB.
1
1.2.1
BHV3500-103: Comparative Bioavailability Study (Oral Formulations)
BHV3500-103 is a completed Phase 1, open-label, fixed-sequence, 3-period, comparative, 
bioavailability study of zavegepant administered as a single 50 mg oral soft gelatin capsule or a 
single 50 mg orally disintegrating tablet (ODT)with or without DDM in healthy subjects. A total 
of 12 subjects were treated in this study. Overall, all the 3 treatments of a single oral dose of 50-
mg zavegepant administered to healthy adult subjects under fasting conditions were well 
tolerated and exhibited a favorable safety profile.
1.2.2
BHV3500-106:Safety and Tolerability Study (Soft Gelatin Capsule)
Study BHV3500-106 is a concludedPhase 1, multi-center, open-label safety studyin which 
healthy subjects were dosed with zavegepant oral soft gelatin capsules (4 x 25 mg) every day for 
8 weeks. A total of 364 subjects received zavegepant in this study. Based on preliminary data: 
there were no deaths in this study anda total of 13 (3.6%) subjects discontinued the study due to 
AEs during the on-treatment period. 


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1.2.3
BHV3500-302: Clinical Safety from Safety and Efficacy Dose-ranging 
Study for Preventive Treatment of Migraine (Oral Formulation)
BHV3500-302 is an ongoing Phase 3, double-blind, randomized, placebo-controlled, safety and 
efficacy dose-ranging study of zavegepant administered as an oral soft gelatin capsule for the 
preventive treatment of migraine. 
As of the data cut-off, 17 subjects have been treated with blinded study drug (zavegepant 100 mg 
soft gelatin capsules: 6; zavegepant 200 mg soft gelatin capsules: 5; placebo for100 mg: 3; 
placebo for 200 mg: 3 [estimated based on 2:2:1:1 randomization]). Based on preliminary data: 
There have been no deaths in this study. One subject experienced 2 serious adverse events 
(SAEs)(abdominal pain, migraine) during the observation period before receiving any blinded 
study drug. No subjects discontinued the study due to AEs. 
1.3
Rationale for Study Design
 
 
This study will evaluate the rate and extent of 
absorptionof zavegepant from thesenewcommercially viable 100 mgoral formulations with 
pharmaceutical acceptability when administered to healthy volunteers.The safety and tolerability 
of single oral doses of zavegepant will also be assessed in this population.
In accordance with the FDA Guidance on Bioavailability Studies Submitted in NDAs or INDs,
2
the current study aims to compare the rate and extent of absorption of zavegepant 100 mg oral 
non-enteric coated SGC (Test 1), zavegepant 100 mg IR oral tablet + DDM dosage form (Test 
2), zavegepant 1x 200 mg IR oral tablet + DDMdosage form(Test 3)(the dose for Test 3 may 
instead be administered as 2 x100 mg IR tablets + DDM dosage form), and zavegepant 4 x 25 
mg enteric coated oral SGC (Reference), under fasting conditions.
1.3.1
Dose Selection
Zavegepant will be administered once in each period ata dose of 1 x 100 mg non-enteric coated 
SGC (Treatment A), 1 x 100 mg IR tablet + DDMdosage form (Treatment B), 1x200mg IR 
tablet +DDMdosage form(Treatment C)(the dose for Treatment C may instead be 
administered as 2 x100 mg IR tablets + DDM dosage form), and 4 x 25 mg entericcoated SGC 
(Treatment D)for each subject in accordance with the randomization scheme.
1.3.2
Rationale for theStudy Population
CCI
A healthy volunteer population has been selected for the study because healthy subjects with no 
concomitant diseases and using no concomitant medications represent a homogenous population 
allowing for proper evaluation of the PK, safety, and tolerability of a drug without confounding 
factors.


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No evidence of embryolethality and teratogenicity were found in animal embryofetal 
development studies in rats and rabbits with zavegepant.
1Women of childbearing potential must
use effective methods of contraception before and during exposure to zavegepant in order to 
prevent pregnancy. No data are available on the potential in vivo transfer of zavegepant or its 
metabolites into human breast milk; therefore, lactating women must not receive zavegepant.
Therefore, only male and non-pregnant/non-lactating femalesubjects will be included in the 
study.
1.4
Benefit/Risk Assessment
The inclusion and exclusion criteria have been chosen to select subjects who are known to be 
free from any significant illness, history of autoimmune diseases, and from any condition that 
could impact their safety or interfere with meeting the study objectives. The proposed safety 
screening and monitoring assessments are deemed to be sufficient to monitor potential risks of 
zavegepant administration. There is no anticipated therapeutic benefit for the healthy subjects in 
this study.


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2 OBJECTIVES
The objective of this study is to compare the rate and extent of absorption of zavegepant 100 mg 
oral non-enteric coated SGC (Test 1), zavegepant 100 mg IR oral tablet + DDM dosage form 
(Test 2), zavegepant 1 x 200 mg IR oral tablet + DDM dosage form or zavegepant2 x 100 mg IR 
tablets + DDM dosage form(Test 3), and zavegepant (BHV-3500) 4 x 25 mg enteric coated oral 
SGC (Reference), under fasting conditions.
3 STUDY DESIGN
This isaPhase 1, single center,open-label,singledose, 4-period, crossover study designed to 
compare the PK of zavegepantfrom the Test and Reference products.The study may be dosed in 
more than 1 Group.
The 4 sequences will be: ACBD, CDAB, BADC, and DBCA.
In each period, subjects will receive one of the following: Treatment A, B, C, or Don Day 1, 
followed by 24 hoursof PK and safety assessments.On Day 2 subjects will be discharged from 
the unit and instructed to return after at least a 7 day washout time has passed for subsequent 
periods of treatment.
The study will include a screening visit from Day -28 to Day -2. Eligible subjects will be 
admitted to the clinical site on Day -1 and will be confined until completion of the assessments
on Day 2. There will be a washout period of at least 7days between doses.Study Exitprocedures 
will be performed after the last assessment on the morning of Day 2 of Period 4. Study Exit
procedures willbe performed as soon as possible in case of ET.
The total duration of study participation for each subject from Screening through Study Exitis 
anticipated to be approximately 6.5 weeks.
This study is intended for filing under FDA regulations.
4 STUDY POPULATION
4.1
Number of Subjects
It is planned to enroll approximately52subjectsfor participation in thisstudy.The proposed 
number of subjects isconsidered sufficient to achieve the study objectives.
4.2
Inclusion Criteria
All of the following criteria must be met in order to be considered for inclusion into the study:
1. Subjects must sign and date IEC/Institutional Review Board (IRB)-approved ICFobtained 
prior to the conduct of any study activities.


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2. Male or female ≥ 18 and ≤ 55 years of age, non-smoker (no use of tobacco or nicotine 
products within 3 months prior to Screening), with BMI >18.5 and <30.0 kg/m2 and body 
weight ≥50.0 kg for males and≥45.0 kg for females. 
3. Healthy as defined by:
a. The absence of clinically significant illness and surgery within 4 weeks prior to dosing. 
Subjects vomiting within 24 hours pre-dose will be carefully evaluated for upcoming 
illness/disease. Inclusion pre-dosing is at the discretion of the Investigator;
b. The absenceof clinically significant history of neurological, endocrine, cardiovascular, 
respiratory, hematological, immunological, psychiatric, gastrointestinal, renal, hepatic, 
and metabolic diseasein the estimation of the Investigator.
4. Subject’s score on the S-STSat Screening must be 0 (lifetime lookback).
5. Females must not be breastfeeding or lactating.
6. All females must have a negative urine pregnancy test (minimum sensitivity 25 IU/L or 
equivalent units ofHCG) at Screening. Women of childbearing potentialmust have negative 
serum pregnancy testat admission (Day -1).
7. Females of childbearing potential (defined as premenopausal females capable of becoming 
pregnant [all fertile women]) who are sexually activewith a non-sterile male partner (sterile 
male partners are defined as men vasectomized at least 6 months prior to Screening) must be 
willing to use one of the following acceptable contraceptive methods throughout the study 
and for 30 days after the last study drug administration:
a. Simultaneous use ofnon-hormonalintra-uterine contraceptive device placed at least 4 
weeks prior to first study drug administration, and condom for the male partner;
b. Simultaneous use of hormonal contraceptives, started at least 4weeks prior to study drug 
administration and must agree to use the same hormonal contraceptive throughout the 
study, and condom for the male partner;
c. Simultaneous use of diaphragm or cervical cap with intravaginally applied spermicide 
and male condom for the male partner, starting at least 21 days prior to the first study 
drug administration.
8. For females of non-childbearing potential: must have undergone one of the following 
sterilization procedures at least 6 months prior to dosing:
a. Hysteroscopic sterilization;
b. Bilateral tubal ligation or bilateral salpingectomy;
c. Hysterectomy;
d. Bilateral oophorectomy;
e. Or be post-menopausal with spontaneous amenorrhea for at least 12 consecutive months 
prior to dosing and FSHserum levels 40mIU/mL consistent with post-menopausal 
status.


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9. Male subjects who are not vasectomized for at least 6 months prior to Screening, and who are 
sexually active with a female partner of childbearing potential (childbearing potential 
females are defined as women that are neither post-menopausal nor surgically sterile) must 
be willing to use one of the following acceptable contraceptive methods from the first study 
drug administration until at least 90 days after the last study drug administration:
a. Simultaneous use of a male condom and, for the female partner, hormonal contraceptives 
used since at least 4 weeks prior to the first study drug administration or intra-uterine 
contraceptive device placed since at least 4 weeks prior to the first study drug 
administration;
b. Simultaneous use of amale condom with spermicide and, for the female partner, a 
diaphragm or cervical cap with intravaginally applied spermicide.
10.Male subjects (including men who have had a vasectomy) with a pregnant partner must agree 
to use a condom from the first dosing and for 90 days after the last study drug administration.
11.Male subjects must be willing not to donate sperm for at least 90 days after the last study
drugadministration.
12.Subjects must be able to understand the nature of the study, agree to comply with the 
prescribed dosage regimens, and communicate to study personnel about AEs and 
concomitant medication use, as applicable.
4.3
Exclusion Criteria
Subjects to whom any of the following applies will be excluded from the study:
Medical History and Concurrent Diseases
1. Current diagnosis of viral hepatitis or a history of liver disease.
2. Any history of seizure disorder (e.g., epilepsy) other than a single childhood febrile seizure.
3. Current or recent (within 3 months of the first study drug administration) gastrointestinal
diseasethat may interfere with drug absorption.
4. Subjects with prior gastrointestinal surgery that interferes with absorption and motility (e.g., 
gastric bypass, duodenectomy or gastric banding). 
5. Use of medication for the timeframes specified below and throughoutthe study, with the 
exception of medications exempted by the Investigator on a case-by-case basis if they are 
judged unlikely to affect the PK profile of the study drug or subject safety, and occasional 
use of ibuprofen:
a. Prescription medication within 30 days or 5 half-lives (whichever is longer) prior to the 
first dosing;


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b. Use of any OTCmedications including acetaminophen-containing products within at 
least 14daysor 5 half-lives (whichever is longer) prior to the first dosingexcept for the 
occasional use of ibuprofen;
c. Use of any natural health products (including herbal remediessuch as Butterbur root 
extracts, homeopathic and traditional medicines, probiotics, food supplements such as 
vitamins [ascorbic acid is not allowed],minerals, amino acids, essential fatty acids, and 
protein supplements used in sports) within 14 days or 5 half-lives (whichever is longer) 
prior to the first dosing;
d. Use of any drug known to induce or inhibit hepatic drug metabolism, including St. John’s 
wort, from 30 days prior to the first dosinguntil after the last PK blood sample for the 
study is obtained;
e. A depot injection or an implant of any drug within 3 months prior to the first dosing;
f. Small molecule CGRPreceptor antagonists within 1 month prior to the first dosing;
g. Biologic CGRP receptor antagonist within 6 months prior to the first dosing;
h. Receipt of any vaccination, including COVID-19 vaccine, within 30days prior to first 
dosing.
i. MAOI within 30 days prior to the first dosing.
6. History of significant alcohol abuse or regular use within 6 months prior to Screening that 
exceeds (more than 10 units of alcohol per week for women and 15 units for men[1 unit = 
140 mL of wine12%, 340mL of beer, or 45 mL of 40% distilled alcohol]).
7. History of drug abuse within 6 months prior to the Screening visit or recreational use of soft 
drugs (such as marijuana) within 1 monthprior to the Screening visit or hard drugs (such as 
cocaine, PCP, crack, opioid derivatives including heroin, and amphetamine derivatives) 
within 1 year prior to Screening.
8. Subject has a history of anaphylaxis, a documented hypersensitivity reaction, or a clinically 
significant reaction to any drug.
9. History of anaphylactic reaction, a documented hypersensitivity reaction, or a clinically 
important reaction to any drug, or to any of the excipient supporting the zavegepant 
formulations.
10.Donation of plasma within 7 days prior to dosing, or donation or loss of blood (excluding 
volume drawn at Screening) of 50 mL to 499 mL of blood within 30 days, or more than 
499mL within 56 days prior to dosing.


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11.Participation in a clinical research study involving the administration of an investigational or 
marketed drug or device within 30 days prior to the dosing, administration of a biological 
product in the context of a clinical research study within 90 days prior to the dosing, or 
concomitant participation in an investigational study involving no drug or device 
administration.
12.Inability or difficulty to swallow tablets or capsules.
13.Poor venous access and/or inability to tolerate catheter venous access.
14.Any reason which, in the opinion of the Investigator, would prevent the subject from 
participating in the study.
Physical and Laboratory Test Findings
15.Subjects with any clinically significant abnormality or significant abnormal laboratory test 
results found during medical screeningor Day-1.
16.Subject has a positive test for HIV, HBsAg, or HCVantibody during medical screening.
17.Evidence of organ dysfunction or any clinically significant deviationfrom normal in physical 
examination, vital signs, 12-lead ECG, or clinical laboratory determinations beyond what is 
consistent with the target population.
18.eGFR according to the MDRDstudy equation ≤ 60 mL/min/1.73m2at Screening.
19.Any of the following laboratory parameters greater than the ULNvalues at Screening or 
Baseline (Day -1): ALP, AST,ALT, total bilirubin, direct bilirubin, and indirect bilirubin, 
and alkaline phosphatase. Only abnormal values between 1-1.5 x ULN may be repeated once 
for confirmation to less than the ULN.
20.Any of the following abnormalities on 12-lead ECG or BP at Screeningor Baseline (Day -1):
a. PR (PR interval) ≥ 210 msec;
b. QRS (QRS complex) ≥ 120 msec;
c. QT (QT interval) ≥ 500 msec;
d. QTcF (Fridericia’scorrected QT interval) ≥ 450 msec;
e. Sitting (for at least 5 minutes) systolic BP > 140 mmHg, confirmed by repeat;
f. Sitting (for at least 5 minutes) diastolic BP > 90 mmHg, confirmed by repeat.
21.Any of the following abnormal laboratory test values at Screening or Baseline (Day -1):
a. Hemoglobin < 12.8 g/dL for males and < 11.5 g/dL for females;
b. Hematocrit < 37% for males and < 32 % for females;
c. Total white blood cells (WBC) < 3.0 x 109/L;
d. Platelet count <100 x 10
9/L;


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e. Neutrophils <1.4 x 109/L and <1.0 x 109/L for Afro-American volunteers;
f. CPK >2 x ULN;
22.Positive test for COVID-19 performed on Day -1 of each period.
23.Positive urine drug screen, alcohol breath test, or urine cotinine test at Screening or any 
Day-1 visit.
4.4
Subject Withdrawal and Replacement
Subjectswill be advised that they are free to withdraw from the study at any time. Over the 
course of the study, the Sponsor and the Investigator or designee may withdraw any subject from 
the study for one of the reasons described below; subject withdrawal will be done in accordance 
with the clinical site’s Standard Operating Procedure (SOP):
Safety reason;
Non-compliance with protocol requirements;
Significant protocol deviation;
Positive pregnancy test, drug screen, cotinine test, or alcohol breath test;
Vomitingwithin 4 hours post-dose;
Positive test result for COVID-19 (during anystudy period).
Clinical laboratory results will be reviewed by the Investigatoror designee prior to each dosing 
and subjects will be withdrawn from the study if it is deemed that the subject’s safety may be at 
risk on the basis of these test results.
Subjects excluded from dosing in one period as per criteria listed above, may be invited to 
participate in subsequent periods of the study if deemed appropriate by the Investigator and 
appropriate from a statistical standpoint (i.e., would permit adequate statistical comparison). 
However, subjects with positive pregnancy test, COVID-19test, drug screen, cotinine test, or 
alcohol breath test, will be definitively withdrawn from thestudy.
Subjects who withdraw prior to dosing may be replaced.
Subjects who withdraw or are withdrawnafter study drug administrationwill be asked to remain 
at the clinic until the Investigator or designee agrees that the subject is fine and can be 
discharged. As soon as subject withdrawal is confirmed, blood sampling will be stopped. A PK 
blood sample may be collected at the time of withdrawal if deemed required by the Investigator.
Study Exitor ETprocedures will be performed at the time of withdrawal from the study or as 
soon as possible thereafter.


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5 STUDY TREATMENTS
5.1
Drug Supplies and Accountability
It is the responsibility of the Sponsor to ensure that study drugs provided for this study are
manufactured under Good Manufacturing Practice (GMP) and aresuitable for human use. The 
Sponsor is responsible to ship a sufficient amount of dosage units to allow the clinical site to 
maintain an appropriate sampling for the studyand for drug retention.
The study drugs will be stored at the clinical site as per applicable requirements.Labels will be 
provided in appropriate languages as required by the country in which the study is conducted. 
The content of the labeling will be in accordance with local regulatory specifications and 
requirements. The study drugs will be stored in a locked, environmentally-controlled medication 
room with restricted access. Container(s) will bear a label containing at least the name of the 
study drug, lot and/or batch number, and manufacturing and/or expiry/retest date.
Individual doses for each subject and period will be dispensed at the clinical sitepharmacy, as 
perclinicalsite SOPand according to the randomization scheme,in appropriate 
envelopes/containers labeled with at least the project number, the period number and the subject 
number/spare number.
All study drug received at the site will be inventoried and accounted for throughout the study and 
the result recorded in the drug accountabilityrecord according to the relevant clinical site 
SOP(s).Upon completion of the study, the remaining drug products will be maintained at the 
clinical site, discarded, or returned to the Sponsor, as per Sponsor’s request.
5.2
Identification of Treatments
Treatment A(Test 1):
1 x 100 mgzavegepant non-enteric coated SGC(Biohaven 
PharmaceuticalsHolding Company Limited) administered under 
fasting conditions.
Treatment B(Test 2):
1 x 100 mg zavegepant IR tablet + DDM dosage form(Biohaven 
PharmaceuticalsHolding Company Limited) administered under 
fastingconditions.
Treatment C(Test 3):
1x 200 mg zavegepant IR tablet(total dose of 200 mg)+ DDM 
dosage form. The dose for Treatment C may instead be 
administered as 2 x100 mg IR tablets + DDM dosage form for a 
total zavegepant dose of 200 mg(Biohaven Pharmaceuticals
Holding Company Limited) administered under fasting conditions.
Treatment D(Reference): 4 x 25 mg zavegepant enteric coated SGC(total dose of 100 mg)
(Biohaven PharmaceuticalsHolding Company Limited) 
administered under fasting conditions.


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5.3
Randomization and Blinding
This study will be an open-label study due to the objective nature of the data. Subjects will be 
administered each treatment according to the4-period, block randomization schemeproduced by 
Syneos Health.The 4 sequences will be: ACBD, CDAB, BADC, and DBCA. The randomization 
code will not be available to the bioanalytical facility until the clinical and analytical phases of 
the study have been completed.Since Treatments B and C includes a DDM dosage form as 
compared to TreatmentsA and D, and Treatment D includes4 capsules, thebioanalyticalstaff 
cannot be completely blinded to treatment assignment.
5.4
Study Drug Administration
For all treatments, the zavegepantwill be administered to each subject with 240 mL of water and 
a hand and mouth check will be performed to ensureconsumption of the medication.The volume 
of water may be increased if needed, however, must be documented within the source 
documentation.
Time of dosing(“0”) will be set equal to the time when the first tablet or capsule is administered 
to the subject. The complete dosing procedure must be completed within 2minutes.
Foreach treatmentA, B,C, and Dno food will be allowed from at least 10 hours before dosing 
until at least 4hours post-dose.
Except for water given with study drug administration, no fluids will be allowed from 1 hour 
before dosing until 1 hour post-dose. Water will be provided ad libitumat all other times.
Meals will be standardized and similar in composition between periods.
6 STUDY RESTRICTIONS
6.1
Concomitant Medications
Subjects will be required to avoidreceiving any vaccination (including COVID-19 vaccine) and 
using prescription medications, OTCmedications(including acetaminophen-containing 
products),and natural health products (including herbal remediessuch as Butterbur root or 
extracts, homeopathic and traditional medicines, probiotics, food supplements such as vitamins
[including ascorbic acid], minerals, amino acids, essential fatty acids,and protein supplements 
used in sports)for the period of time specified in exclusion criterion no.5and throughout the 
study.
No concomitant medications will be allowed during the study, with the exception of hormonal 
contraceptives, medications required for the medical management of an AE, medications 
exempted by the Investigator on a case-by-case basis that are judged unlikely to affect the PK 
profile of the study drugsor subject safety, and occasional use of ibuprofen.


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If vaccination is required for any reason, it must first be discussed with and exempted by the 
Investigator on a case-by-case basis to ensure that it does not compromise the PK profile of the 
study drug or the subject safety.
All medications taken by subjects after Screening through the last study day will be documented 
as concomitant medications. Any concomitant medication use, other than the allowed 
medications stated above, will be reviewed and evaluated on a case-by-case basis by the 
Investigator to determine if they affect a subject’s eligibility or continued participation in the 
study, or for potential impact on the study results.
6.2
Drugs, Nicotine,and Alcohol
Subjects will be required to abstain fromusing soft or hard drugs, or any tobacco, or nicotine 
products from Screening and throughout the study.Consumption of alcohol-based products will 
be prohibited from 24 hours prior to each admission until after the last PK blood sample 
collection of each period. A urine drug screen, an alcohol breath test,and a urine cotinine test 
will be performed at Screening and on Day-1of each period.
6.3
Diet
In each period, no food will be allowed from at least 10 hours before dosing until at least 4 hours 
after dosing. Except for water given with study drug administration, no fluids will be allowed for 
1 hour before dosing until 1 hour post-dose. Water will be provided ad libitumat all other times.
In addition, subjects will be required to abstain from:
Food or beverages containing grapefruit, starfruit, pomegranate, pineapple or pomelo 
from 14 days prior to the first study drug administration until the lastPK blood sample 
collection of the study;
Food or beverages containing xanthine derivatives or xanthine-related compounds or 
energy drinks from 48 hours prior to each dosinguntil after the last PK blood sample 
collection of each period;
Food containing poppy seeds from24 hours prior to each admission.
6.4
Posture and Physical Activity
Subjects will berequired to remain seated and avoid lying down or sleeping,unless medically 
necessary or procedurally required, for 2hours after study drug administration. Subjects will be 
allowed to engage in normal activity outside of these requirements.
Because excessive physical activity may increase the level of CPK above the upper normal limit 
value, subjects will be advised to avoid performing such activity at all timesduring the study. 
Vigorous activity will be prohibited at all times during the confinement.


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7 STUDY PROCEDURES
Subjects must provide written informed consent prior to initiation of any study procedures.
Unless otherwise specified, study procedures will be conducted in accordance with clinical site 
SOPs. From Screening through Study Exit, subjects will undergo study procedures at pre-defined 
times as specified in Table 1and as described in sections 7.1and 7.2.
Every effort will be made to schedule and perform the procedures as close to the nominal time as 
possible, giving considerations to appropriate posture conditions, practical restrictions, and other 
procedures to be performed at the same time point.
PK blood sample collectionwill be performed closest to the nominal time. When vital signs 
measurementor ECG recording coincide with a blood collection, they should preferably be 
performed before the blood collection, whenever possible.
Study exit procedures will be performed on Day 2 of Period 4 or within 14 days after the last 
participation of the subject in the study in case of ET.
7.1
Pharmacokinetic Assessments
7.1.1
Pharmacokinetic Blood Sample Collection and Processing
In each period, bloodsamples for PKanalysis will be collectedvia an intravenous catheter or by 
direct venipunctureat the time points indicatedinTable 1.Applicable time tolerance windows 
for PK blood samples are defined in Table 2.


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Table 2
Time Tolerance Windows for PK Blood Samples
Day
Time point
Time window
1
Pre-dose
Within 1hourprior dosing
0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, and 6 
hours post-dose
±1minute
1
8, 10, 12, and 16hourspost-dose
±3minutes 
2
24 hourspost-dose
±3 minutes 
Sample collections done outside the pre-defined time windows will not be considered as protocol 
deviations since actual post-dose sampling times will be used for PK and statistical analyses. 
The planned volume of blood to be collected for this study, including that collected for eligibility 
and safety purposes, should not exceed 300mL. Additional tests or blood draws could be 
performed, if deemed required by the Investigator or study staff.
Procedures for collection, and processing, of PK blood samples will be detailed in a separate 
document.
Plasmaconcentrationsof the study drug will be determined using a validated analy
tical method. 
Details of the analytical method will be provided in a separate document.
7.2
Safety and Tolerability Assessments
Subjects will be monitored throughout the study by the clinical staff for AEs.The Investigator or 
designee will be on site for drug administration and until 4 hours post-dose, and available on call 
for the remainder of the study. If necessary, the Investigator or designeeat the clinical site or a 
healthcare professional ina nearby hospital will administer treatmentfor any AE(s). Acrash cart 
or emergency bag containing the necessary rescue material and appropriate medications will be 
available in the clinic to allow rapid intervention in case of emergency.
Safety parameters, including laboratory results and ECG, will be assessed by the Investigator or 
designee, using the clinical site acceptance ranges as suggested guidelines in making the medical 
assessment.
For eligibility purposes, abnormal vital signs measurements or clinical laboratory test results 
may be repeated once if an abnormal result is observed at the initial reading. Moreover, 
abnormalities found in the ECG may need to be confirmed by repeated measurements. In the 
event that the participation of a subject in the studyis delayed and some screening procedures 
had been performed outside of the prescribed screening window, outdated Screening procedures 
can be repeated.
Safety assessments scheduled during the study will be repeated according to the clinical site 
SOPs or upon request from the Investigator or designee. Any abnormal repeated measurement 


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will be evaluated and repeated, if judged necessary. Further action may be taken upon the 
Investigator or designee’s request.
7.2.1
Physical Examination
Physical examinations will beperformed at the times specified in Table 1.
A complete physical examination will includeassessments of the following: head, eyes, ears, 
nose, throat (HEENT), neck, chest, lungs, abdomen, musculoskeletal, dermatological, 
cardiovascular/peripheral vascular, and general neurological examination.
A brief physical examination will includeassessments of the following: HEENT, chest, lungs, 
abdomen, dermatological, cardiovascular/peripheral vascular, and areas of note elicited from the 
subject.
7.2.2
Body Measurements
Body measurements will be performed at Screening and will includebody weight andheight
measurements, as well asBMI calculation.
7.2.3
Sheehan Suicidality Tracking Scale 
The S-STS is a prospective rating scale to track both treatment-emergent suicidal ideation and 
behaviors.3,4
Thescale will be administered at the times specified in Table 1by a member of the medical 
team, completed on site, and will be in paper. The source document will be provided by the 
Sponsor. If the Investigator determines that a subject is at risk of suicide or self-harm, 
appropriate measures to ensure the subject’s safety and obtain mental health evaluation must be 
implemented. In such case, the subject will not be eligible to participate in the study. If 
determined at the Study Exitor ETprocedures, theevent should be recorded as either an AE or a 
SAE as determined by the Investigator and reported within 24hours to the Sponsor.
7.2.4
Vital Signs
BP, HR, RR, and OTwill be measured after thesubjectshave been resting for at least 5 minutes 
in asittingposition at Screening, Day -1and Study Exitor ET. BPand HRwill be measured 
within 1 hourbefore study treatment administration and at 2 ± 0.25 hours post-dose,having 
rested in a seated position for at least 5 minutes.
7.2.5
12-lead ECG
Standard 12-lead ECG will be recorded after the subjects have been resting for at least 5 minutes 
in a semi-recumbent or supine positionat Screening, Day -1of each periodand Study Exitor 
ET.


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7.2.6
Laboratory Assessments
Blood and urine samples for clinical laboratory assessments will be collected according to the
clinical site SOPs at the times specified inTable 1.The clinical laboratory assessments to be 
performed are listed in Table 3.
Table 3
Laboratory Assessments
Biochemistry
Hematology
Urinalysis
Albumin
ALP
ALT
AST
Calcium
Chloride
CPK
Creatinine
eGFR (calculated using the MDRD
equation)
GGT
Glucose
Phosphorus
Potassium
Sodium
Total, direct and indirect bilirubin1
Total protein
Urea (BUN)
Haptoglobin2
Hematocrit
Hemoglobin2
Platelet count
RBC count
Reticulocyte2
WBC count and differential:
Basophils
Eosinophils
Lymphocytes
Monocytes
Neutrophils
Bilirubin
Blood (occult)
Color and appearance
Glucose
Ketones
Leukocyte esterase
Nitrite
pH
Protein
Specific gravity
Urobilinogen
Microscopic examination (inthe 
eventofabnormalfindings
including urobilinogen)
Coagulation3
COVID-19
4
aPTT
PT
INR
COVID-19 test
Serology
Drug, cotinine, and alcohol
screens
Hormone panel -females only
HBsAg
HCVantibody
HIV antigen/antibody
Amphetamines/methamphetamines
Barbiturates
Benzodiazepines
Cocaine
MDMA
Methadone
Opiates
PCP
THC
Urine cotinine test
Alcohol breath test
FSH(post-menopausal females 
only)
Serum pregnancy test
Urinepregnancy test
Abbreviations: ALP = alkaline phosphatase; ALT = alanine aminotransferase; aPTT = activated partial 
thromboplastin time; AST = aspartate aminotransferase; BUN = blood urea nitrogen;CPK = creatine 
phosphokinase; eGFR = estimated glomerular filtration rate; FSH = follicle-stimulating hormone; GGT = 
gamma-glutamyl transferase; HBsAg = hepatitis B surface antigen; HCV=hepatitis C virus; HIV = human 
immunodeficiency virus; INR = international normalized ratio; MDMA = 3,4-methylenedioxymethamphetamine; 
MDRD = Modification of Diet in Renal Disease; PCP = phencyclidine; PT = prothrombin time; PTT = partial 
thromboplastin time; RBC = red blood cell; THC = tetrahydrocannabinol; WBC = white blood cell.


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1. Considering that indirect bilirubin is calculated from total and direct bilirubin values, indirect bilirubin 
result would not be available in case of direct bilirubin below the limit of quantification.
2. Haptoglobin and reticulocyte count will be performed only in case of decrease in hemoglobin levels below 
the LLN on Day -1 of each period and at Study Exit. If the haptoglobin and reticulocyte count results come 
back normal but the hemoglobin levels results are still abnormal after the repeat, the haptoglobin and 
reticulocyte count tests may be repeated upon Investigator’s judgement.
3. Coagulation tests will be performed only in case of abnormal LFTs (i.e., ALP, AST, or ALT is >3xULN) 
on Day -1 of each period and at Study Exit. If the coagulation test results come back normal but the LFT 
results are still abnormal after the repeat, the coagulation tests may be repeated upon Investigator’s 
judgement.
4. A COVID-19 PCR test will be performed on Day -1in each period. If results are not available prior to 
admission, a COVID-19 rapid test will be performed upon admission. COVID-19 testing may be repeated 
during the subject’s participation at the Investigator’s discretion (e.g., if a subject has signs or symptoms 
suggestive of a COVID-19 infection).
7.3
Adverse Events
7.3.1
Definition of Adverse Event
An AE is defined as any untoward medical occurrence in a patient or clinical trial subject 
administered a pharmaceutical product and which does not necessarily have a causal relationship 
with the 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 a medicinal (investigational) product, whether or not considered related to the medicinal 
(investigational) product.
7.3.2
Recording of Adverse Events
AEs will be recorded and evaluated for their seriousness, severity, and relationship to the study 
drug. AEs will be collected and documented from the time of signing the ICF and throughout the 
study.AEs will be followed-upuntil complete resolution, or until the Investigator or designee 
judges safe to discontinue follow-up. The severity of AEs and relationship to the study drug will 
be classified according to the sections below.
7.3.3
Assessment of Severity
The severity of non-serious AEs and serious AEs will be described and documented using the 
following definitionsinTable 4:


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Table 4
Description of Severity of Adverse Events
Severity
Description
Mild
Awareness of signs and symptoms, but are easily tolerated; are of minor irritant 
type; causing no limitations of usual activities. Signs or symptoms may require 
minor action.
Moderate
Discomfort severe enough to cause some limitations of usual activities and may 
require action.
Severe
Incapacitating with inability to carry out usual activities or significantly affects 
clinical status, and requires specific action and/or medical attention.
An event is defined as ‘Serious’ when it meets at least one of the pre-definedoutcomes as 
described in the definition of an SAE, NOT when it is rated assevere.
7.3.4
Assessment of Relationship to Study Drug
Each AE must be classified based on medical judgementand according to the following 
relationship categories: probable, possible, remote, and unrelated.The definitions for the 
relationship categoriesare as follows:
PROBABLY RELATED(must have first three points):This category applies to AEs that 
are considered, with a high degree of certainty, to be related to the investigational product. 
An AE may be considered probable, if:
1) It follows a reasonabletemporal sequence from the administration of the drug.
2) It cannot be reasonably explained by the known characteristics of the participant’s 
clinical state, environmental or toxic factors or other modes of therapy administered to 
the participant.
3) It disappears or decreases on cessation or reduction in dose (there are important 
exceptions when an AE does not disappear upon discontinuation of the drug, yet drug 
relatedness clearly exists; e.g., (1) bone marrow depression, (2) tardive dyskinesias).
4) It follows aknown pattern of response to the suspected drug.
5) It reappears upon re-challenge.
POSSIBLY RELATED(must have first two points):This category applies to AEs in which 
the connection with the investigational product administration appears unlikely but cannot be 
ruled out with certainty. An AE may be considered possible if, or when:
1) It follows a reasonable temporal sequence from the administration of the drug.
2) It may have been produced by the participant’s clinical state, environmental or toxic 
factors, or other modes of therapy administered to the participant.


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3) It follows a known pattern of response to the suspected drug.
REMOTELY RELATED(must have first two points): In general, this category is 
applicable to an AE that meets the following criteria:
1) It does not follow a reasonable temporal sequence from the administration of the 
investigational product.
2) It may readily have been produced by the participant’s clinical state, environmental or 
toxic factors, or other modes of therapy administered to the participant.
3) It does not follow a known pattern of response to the suspected drug.
4) It does not reappear or worsen when the investigational product is re-administered.
UNRELATED (NOT RELATED):This category is applicable to AEs that are judged to be 
clearly and incontrovertibly due only to extraneous causes (disease, environment, etc.), and 
do not meet the criteria for medication relationship listed under remote, possible, or probable.
Determination of the relationship of non-serious AEs to the study drug:
Probably
related
Possibly 
related
Remotely 
related
Unrelated 
(not 
related)
Clearly due to extraneous causes
–  
–  
–  
+
Reasonable temporal association with 
drug administration
+  
+  
–  
–
May be produced by participant clinical 
state, etc.
–  
+  
+  
+
Known response pattern to suspected 
drug
+  
+  
–  
–
Disappears or decreases on cessation or 
reduction of the dose
+  
–  
–  
–
Reappears on re-challenge
+  
–  
–  
–
Serious AEs will be determined to be “Related” or “Unrelated” to study drug by theQualified Investigator(QI)and 
reported on the SAE reporting forms.
7.3.5
Definition of Serious Adverse Event
A SAE is defined as any untoward medical occurrence that, at any dose:
Results in death;


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Is life-threatening;
Requires inpatient hospitalization or prolongation of existing hospitalization;
Results in persistent or significant disability/incapacity;
Is a congenital anomaly/birth defect, or;
Is otherwise considered to be an important medical eventthat may not be immediately life-
threatening or result in death or hospitalization but may jeopardize the patient or may require 
intervention to prevent one of the other outcomes listed in the definition above. Medical and 
scientific judgement should be exercised in deciding whether an event should be considered 
as an Important Medical Event. Examples of such medical events include:
o Allergic bronchospasm requiring intensive treatment in an emergency room or at home;
o Blood dyscrasias or convulsions that do not result in hospitalization;
o Development of drug dependency or drug abuse.
7.3.5.1
Definition of Terms
Life-threatening: An AE is life-threatening if the participant 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.
In general, hospitalization signifies that the participant 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.
Disability/incapacitating: An AE is incapacitating or disabling if the experience results in a 
substantial and/or permanent disruption of the participant’s ability to carry out normal life 
functions.


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7.3.6
Reporting of Adverse Events
7.3.6.1
Serious Adverse Event Reporting tothe Sponsor
Any SAEwill be reported to the Sponsor (or representative) within 24 hours of learning of the 
event, and then a written report will be completed and provided as soon as possible, but no later 
than 7calendar days of first knowledge of the event. 
The notification to the sponsor should be directed to:
Biohaven PharmaceuticalsHolding Company Limited
7.3.6.2
Serious Adverse Event Reporting to Sponsor’s Pharmacovigilance (PVG) 
Vendor
Any SAE must be reported (using the SAE reporting forms) immediately or no later than 24 
hours after awareness of the event to both the Sponsor and 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:
24 HourSafety Hotline Fax: +1 888 488 9697 
If a form is unable to be submitted within 24 hours, the SAE may be reported by telephone via 
the Safety Hotline Number:
24 HourSafety Hotline Phone:+1 800 201 8725
If only limited information is initially available, follow-up reports are required. If an ongoing 
SAE changes in its intensity or relationship to investigational product or if new information 
becomes available, a follow-up SAE report should be sent within 24 hours of the QI becoming 
aware of the updated information using the same procedure used for the transmission of the 
initial SAEand the same event term should be used.
The minimum information required for an initial SAE report is:
Sender of report: (Investigator name)
Participant identification: (participant number)
Protocol Identifier:  BHV3500-113

PPD
SAE term: (if an SAE is being reported)
PPD


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For all SAEs, the QI must provide the following:
Appropriate and requested follow-up information in the time frame detailed above
Causality of the serious event(s)
Action taken with the investigational product (e.g., increased, reduced, unchanged,
permanently discontinued, interrupted)
Treatment of/intervention for the SAE(s)
Outcome of the serious event(s)
Medical records and laboratory/diagnostic information
The QI will attempt to establish a diagnosis of the event based on signs, symptoms, and/or other 
clinical information. Whenever possible, the diagnosis (not the individual signs/symptoms) will 
be documented as the AE/SAE.  
7.3.6.3
Serious Adverse Event Reporting to the IEC and Regulatory Agency(ies)
It is the responsibility of the clinical site to report suspected, unexpected, serious adverse 
reactions (SUSARs)to the IEC responsible for the study per their policies. Report of fatal or 
life-threatening SUSARs must be made as soon as possible, but no later than 7calendar days 
after first knowledge of the event. Report of SUSARs that are neither fatal nor life-threatening 
must be made as soon as possible, but no later than 15calendar days after first knowledge of the 
event.
The Sponsor (or PVG representative) is responsible for notifying the regulatoryagency(ies) of 
SUSARs observed during the study conduct per their regulations, as soon as possible but no later 
than 7calendar days after becoming aware of the informationwhen fatal or life-threatening, or 
15calendar days when neither fatal nor life-threatening. The Sponsor (or representative) is 
responsible to comply with any other applicable regulatory requirement(s) related to the 
reporting of SAE to other regulatory authority(ies).
7.4
Pregnancy
If a female participant or a female partner of a male participant in the study becomes pregnant 
during the study, the Investigator must report the pregnancy to the Sponsor and the Sponsor’s 
PVG vendor. The pregnancy should be reported using the paper Pregnancy Form, which should 
be faxed to PPD PVG by facsimile (fax), within 24 hours after Investigator/site awareness of the 
event (see Section 7.3.6.2for fax number). If the form cannot be faxed it should be reported via 
phone to the PPD SafetyHotline as described above in Section 7.3.6.3. Oncethe paper form is 
available, the data must be reported per standard procedures.


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A participant becoming pregnant while on study drug will immediately be withdrawn from the 
study and ETstudy procedures will be performed.
The participant or female pregnant partner of a male participant should be followed by the 
Investigator (after obtaining the consent of the female partner, when applicable) until completion 
of the pregnancy. Follow-up information regarding the course of the pregnancy, including 
perinatal and neonatal outcome and, where applicable offspring information must also be 
reported to PPD on a Pregnancy Follow-up Report Form. If the pregnancy ends for any reason 
before the anticipated delivery date, the Investigator should notify the Sponsor and PPD.
If the outcome of the pregnancy meets the criteria for immediate classification as an SAE 
(i.e.,postpartum complication, spontaneous abortion, stillbirth, neonatal death, or congenital 
anomaly), the Investigator should follow the procedures for reporting an SAE as described in 
Section 7.3.6.3.
7.5
Premature Termination of the Study
The study may be prematurely terminated by the Investigator following consultation with the 
Sponsor, by the Sponsor or by the regulatory authorities. Following a decision to discontinue the 
trial, the Investigator will promptly inform the active study subjects and the IEC/IRBresponsible 
for this trial, stating the reasons for discontinuation of the study. It is the responsibility of the 
Sponsor (or representative) to report the premature termination of the study to the regulatory 
authority(ies), when required by the applicable regulatory requirement(s).
8 STATISTICAL ANALYSES
A complete description of the statistical analyses to be performed on PK as well as safety and 
tolerability data will be presented in a SAP.
8.1
Determination of Sample Size
 
 Thus, assuming a CV of 40%, and under the 
scenario of test vs. reference ratio of geometric means of 1.0, the width of the 90% CI for the 
ratio of geometric means is expected to approximately be 0.25 with 52 subjects.The expected 
width of the 90% CI for the ratio of geometric means will slightly decrease/increase from 0.25 as 
the ratio of geometrics means decrease/increase from 1.0.
8.2
Analysis Populations
8.2.1
Safety Population
CCI
The safety population is defined as all subjects who receiveat least one dose of anystudy drug.


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8.2.2
Pharmacokinetic Population
The PK population will include all subjects from the safety population who receive at least one 
dose of zavegepant, and for whom the PKprofile can be adequately characterized.
8.2.3
Pharmacokinetic Statistical Population
The PK statisticalpopulationwill include all subjects fromthe PK population who completeat 
least oneperiod of treatmentfor at least one PK parameter and who have not experienced any 
protocol deviations or other circumstances to exclude the subject from the PK statistical analysis.
A subject with pre-dose concentrations may be excluded from descriptive statistics and ANOVA 
if the pre-dose concentration is greater than 5% of the Cmaxvalue for that subject.
A subject may be excluded from the descriptive statistics and ANOVA if the subject has 
experienced emesis within 2 times median T
max for a given treatment.
8.3
PharmacokineticParameters
The following PKparameters will be calculated based on the PK population by standard 
non-compartmental methods for zavegepant.
AUC0-t: Area under the concentration-time curve from time zero until the last observed 
concentration
AUC0-inf: Area under the concentration-time curve from time zero to infinity
(extrapolated)
Residual area: Percentage of AUC0-infdue to extrapolation from the time of the last 
observed concentration to infinity, calculated as [1 –(AUC
0-t/AUC0-inf)] x 100
Cmax: Maximal observed concentration
Tmax: Time when the maximal concentration is observed
T½ el: Terminal elimination half-life
Kel: Terminal elimination rate constant
Cl/F: Apparentclearance
Vz/F: Apparent volume of distribution
PK of Treatment C will be normalized to a dose of 100 mg.
Additional PK parameters may be calculated.
8.4
Pharmacokinetic Statistical Analysis
Statistical analysis described in this section will be based on the PK statistical population.
Individual and mean plasma concentration versus time curves will be presented for both linear 
and semi-log scales. Descriptive statistics (arithmetic and geometric means, standard deviation 


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[SD], CV%, minimum [Min], maximum [Max], and median) of the plasma concentrations versus 
time will be presented as well for the PKparameters.
For zavegepant, using the MIXED procedure in SAS, with Sequence, Treatment, and Period as 
fixed effects, and Subject within Sequence as random effect, ANOVAwill be performed on ln-
transformed AUC
0-t, AUC
0-inf, and C
max. No adjustments will be made to alpha for multiple 
pairwise comparisons. If the study is dosed in more than 1 Group, the statisticalmodel may be 
modified to reflect the multi-Group nature. In case of a non-statistically significant Treatmentby
Group interaction term, the analysis will be rerun excluding this term from the ANOVA model in 
order to obtain ratios and confidence intervalswhere appropriate. The ratio of geometric means 
and 90% confidence intervals (A/D), (B/D), and (C/D) based on least-squares means from the 
ANOVA of the ln-transformed data will be calculated for AUC
0-inf, AUC
0-t, and C
max. Other ratio 
of gemometric means among treatments may be explored. Untransformed Tmaxwill be analyzed 
using the MIXED model with the difference of least-squares means from the ANOVA calculated 
for (A-D), (B-D), and (C-D). Other differences of least-square means betweentreatments may be 
explored.The Kel, and T
½ elwill be summarized descriptively.  
If the study is dosed in more than one Group thefollowing terms will be included in the model: 
Group, Sequence, Sequence by Group, Period within Group, Treatment, and Treatment by 
Group. A random effect of Subject within Sequence by Group will also be included. If the term 
of Treatment by Group is found to be not statistically significant (i.e., p >0.05), then the 
Treatment by Group term specified in the previous model would be removed from the model to 
calculate the ratio and 90% CI for each AUC parameter specified above and Cmax, as applicable.
Additional PKstatistical analysis may be performed.
8.5
Safety and Tolerability Analysis
Demographic parameters will be summarized descriptively.TEAEs will be summarized 
descriptively by treatment. Safety and tolerability analysis will be performed for all subjects in 
the safety population. No inferential statistical analysis of safety data is planned.
Safety and tolerability to treatments will be evaluated through the assessment of AEs (e.g., 
seriousness, severity, relationship to the study medication, outcome, duration, and management), 
vital signs, 12-lead ECG, and clinical laboratory parameters. AEs will be coded using the latest 
version of the MedDRA.
Any finding or absence of finding relative to each subject’s baseline physical examination will 
be documented. Any abnormal finding noted after dosing will be documented as an AE if judged 
as a clinically significant change from baseline. 
Changes from baseline values in vital signs, ECG, and clinical laboratory parameters will be 
evaluated. Clinically significant laboratory abnormalities will be identified as Grade 3 to 4 
laboratory test results graded according to numeric laboratory test criteria in the latest version of 
CTCAE if available, otherwise according to the latest version of DAIDS Table for Grading the 
Severity of Adult and Pediatric Adverse Events,CorrectedVersion.


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Additional safety and tolerability data analysis may be performed.
9 DATA COLLECTION
The electronic source data capture system is the primary data collection instrument for the study. 
Collection screen in the electronic source data capture system will be utilized for the collection 
of all data. Data will be entered using the English language and should be kept current to enable 
the monitor to review the subjects’ status throughout the course of the study. The case report 
forms (CRFs) will automatically be populated using the electronic source data capture system.
Source data should be attributable, legible, contemporaneous, original, accurate, and complete. 
Source documents will be maintained in order to maintain data integrity. The Investigator and/or 
the clinical staff have the responsibilityof ensuring the accuracy, completeness, legibility, and 
timeliness of the source data.
Details on the data management process will be described in a Data Management Plan (DMP).
10REGULATORY CONSIDERATIONS AND QUALITY ASSURANCE
10.1 IEC/IRBApproval of Protocol and Other Study Documents
The Investigator(s) agree to provide the IEC/IRBwith all appropriate documents, including a 
copy of the protocol/amendments, ICFs, advertising text (if any), Investigator’s Brochure (if 
any),and any other written information provided to study subjects. The trial will not begin until 
the Investigators have obtained the IEC/IRBfavorablewritten approvals for the above-
mentioned study documents. A properly executed written ICF shall be read, signed, and dated by 
each subject prior to entering the trial or prior to performing any study procedure. The original 
signed and dated ICF will be kept at the clinical siteand a copy will be given to the subject.
In the event that the protocol is amended, the revised protocol must be approved by the IEC/IRB
prior to its implementation, unless the changes involve only logistical or administrative aspects 
of the trial. If a revised ICF is introduced during the study
, each subject’s further consent must be 
obtained. The new version of the ICF must be approved by the IEC/IRB, prior to subsequently 
obtaining each subject’s consent.
The Investigator and the Sponsor’s representative must sign the protocol and its amendments (if 
any) before initiating the study.
It is the Sponsor’sresponsibility to submit the protocol and its amendments (if any), and the 
ICFs to regulatory authorities when necessary.
10.2 Compliance
This study will be conducted in compliance with the protocol, GCP, all applicable regulations, 
and any IEC/IRBrequirements 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 


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Helsinki, with the exception that registration of such Phase 1 trials in a publicly accessible 
database is not mandatory.As required by the Canadian regulatory agency, a Clinical Trial 
Application will be submitted before the beginning of the study and a No Objection Letter must 
be received prior to dosing.
10.3 Quality Assurance and Monitoring
The Sponsor or its designee will perform the quality assurance (QA)and quality control (QC)
activities of this study; however, responsibility for the accuracy, completeness, security, and 
reliability of the study data presented to the Sponsor lies with the Investigator generating the 
data. When applicable, QAprocedures will be performed according to the site SOPs.
The study will be monitored according to the site monitoring plan and SOP to ensure that it is 
conducted and documented properly according to the protocol, GCP, and all applicable 
regulatory requirements. The Sponsor is entitledto access information aboutthe status ofthe 
study and to reviewthe original documents of the study.
The Sponsor may arrange audits as part of the implementation of QAto ensure that the study is 
being conducted in compliance with the protocol, SOPs, GCP, and all applicable regulatory 
requirements. In such case, audits will be independent of and separate from the routine 
monitoring and QCfunctions.
10.4 Confidentiality and Retention of Study Records
This document contains trade secrets and commercial information that is confidential and may 
not be disclosed to third parties. Persons to whom this study protocol is disclosed must be 
informed that all the information herein is confidential and may not be further divulged. These 
restrictions will apply as well to all future communications if deemed privileged or confidential. 
Publication of the study results may only be allowed with written permission from the Sponsor.
All information on a subject obtained duringthe conduct of the studywill be kept confidential.
Subjects will be identified byan anonymized identifier on all samples and study records
provided to the Sponsor or designee. In compliance withICH GCP, the Sponsor’s authorized 
representatives, monitor(s), auditor(s), IEC/IRB, and regulatory authority(ies) will be granted 
direct access to the subject’s original trial-related records for verification of clinical trial 
procedures and/or data, without violating the confidentiality of the subject, to the extent 
permitted by the applicable laws and regulations. Consent from the subject for disclosureof such 
information will be obtained in writing in the ICF. In addition, should a subject require medical 
care or hospitalization during the course of the study, the clinical site may contact the treating 
physician with the subject’s consent, except that consent may not be requested if there is an 
emergency situation. If the results of the study are published, the subject’s identitywill remain 
confidential.
The clinical site will maintain adequate study records according to applicable regulatory 
requirements. The Sponsor will be notified prior to the destruction of study records.


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11REFERENCES
1.
Zavegepant(BHV-3500). Investigator Brochure. Biohaven Pharmaceuticals Inc. Version 
5.0,Dated 23-Nov-2021.
2.
Center for Drug Evaluation and Research (CDER), FDA. Draft Guidance for Industry: 
Bioequivalence Studies with Pharmacokinetic Endpoints for Drugs Submitted Under an 
ANDA. April2022.
3.
Sheehan, D.V., et al. Comparative Validation of the S-STS, the ISST-Plus, and the C 
SSRS for Assessing the Suicidal Thinking and Behavior FDA 2012 Suicidality 
Categories. Innov Clin Neurosci, 2014. 11(9-10):32-46. 
4.
Sheehan, D.V., J.M. Giddens, and I.S. Sheehan. Status Update on the SheehanSuicidality 
Tracking Scale (S-STS), 2014. Innov Clin Neurosci, 2014. 11(9-10):93-140.

SAP_001.pdf: 
 
 
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SAP Version: Final 1.0 31-JAN-2023 
Filing requirements: TMF 
Page 1 of 28 
 
 
 
Statistical Analysis Plan for Interventional Studies (Early Phase) 
 
 
 
A Phase 1, Open-Label, Randomized, 4-Period, 4-Way Crossover, 
Comparative Bioavailability Study of Zavegepant (BHV-3500) 
Oral Formulations Under Fasting Conditions 
 
Sponsor Study Number: BHV3500-113 
Syneos Health Project Code: 222025 
 
Final Version: 1.0 
Date: 31-JAN-2023 
 
 
Contract Research Organization:  
Syneos Health Clinical Research 
Services, LLC (« Syneos Health ») 
1951 NW 7th Avenue, Suite 400 
Miami, FL 33136 
USA 
 
Sponsor:  
Biohaven Pharmaceuticals  
Holding Company Limited 
215 Church Street,  
New Haven, CT 06510 
USA  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CONFIDENTIAL 


Statistical Analysis Plan for Interventional Studies (Early Phase) 
 
Sponsor: Biohaven Pharmaceuticals Holding Company Limited; Protocol No.: BHV3500-113 (222025) 
 
 
This document is confidential. 
SAP Version: Final 1.0 31-JAN-2023 
Filing requirements: TMF 
Page 2 of 28 
SIGNATURES 
 
Sponsor Study No.: BHV3500-113 
Syneos Health Project No.: 222025 
 
Study Title: A Phase 1, Open-Label, Randomized, 4-Period, 4-Way Crossover, Comparative 
Bioavailability Study of Zavegepant (BHV-3500) Oral Formulations Under Fasting 
Conditions 
 
 
Author: 
 
 
 
Signature:___________________________ 
 Date:_______________________________ 
 
Syneos Health 
 
 
Sponsor’s 
Representative: 
  
Signature: ___________________________ 
 
 
 
Date:_______________________________ 
Clinical Pharmacology  
and Pharmacometrics  
Biohaven Pharmaceuticals  
Holding Company Limited 
 
Sponsor’s 
Representative: 
  
          Signature: ___________________________ 
                             
   Date:_______________________________ 
                             Biohaven Pharmaceuticals  
                             Holding Company Limited  
 
Sponsor’s 
Representative: 
  
          Signature: ___________________________ 
                             
    Date:_______________________________ 
                             
 
                             Biohaven Pharmaceuticals  
                             Holding Company Limited  
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD


Statistical Analysis Plan for Interventional Studies (Early Phase) 
 
Sponsor: Biohaven Pharmaceuticals Holding Company Limited; Protocol No.: BHV3500-113 (222025) 
 
 
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Filing requirements: TMF 
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TABLE OF CONTENTS 
 
SIGNATURES................................................................................................................................2 
TABLE OF CONTENTS ..............................................................................................................3 
LIST OF ABBREVIATIONS .......................................................................................................5 
1 
INTRODUCTION ..................................................................................................................7 
2 
STUDY OBJECTIVES ..........................................................................................................8 
3 
STUDY DESIGN ....................................................................................................................9 
3.1 
General Design ...................................................................................................................9 
3.2 
Study Procedures ...............................................................................................................9 
3.3 
Treatment Administration ................................................................................................9 
3.4 
Sample Size .........................................................................................................................9 
3.5 
Participant Withdrawal and Replacement ....................................................................10 
4 
CHANGES FROM THE PROTOCOL ..............................................................................11 
5 
PHARMACOKINETIC AND SAFETY PARAMETERS................................................11 
6 
ANALYSIS POPULATIONS ..............................................................................................12 
6.1 
Screened Population ........................................................................................................12 
6.2 
Randomized Population ..................................................................................................12 
6.3 
Safety Population .............................................................................................................12 
6.4 
Pharmacokinetic Population ...........................................................................................12 
6.5 
Pharmacokinetic Statistical Population .........................................................................12 
7 
INTERIM ANALYSIS .........................................................................................................13 
8 
SCHEDULE OF ANALYSIS ...............................................................................................14 
9 
STUDY POPULATION AND EXPOSURE .......................................................................15 
9.1 
Participant Disposition ....................................................................................................15 
9.2 
Protocol Deviations ..........................................................................................................15 
9.3 
Demographic and Baseline Characteristics ...................................................................15 
9.4 
Medical History ................................................................................................................15 
9.5 
Prior and Concomitant Medications ..............................................................................15 
10 SAFETY ANALYSIS ...........................................................................................................16 
10.1 
Physical Examination Findings ......................................................................................16 
10.2 
Adverse Events .................................................................................................................16 
10.3 
Laboratory Parameters ...................................................................................................17 
10.4 
Vital Signs .........................................................................................................................18 
10.5 
12-lead Electrocardiograms ............................................................................................18 
10.6 
Sheehan Suicidality Tracking Scale (S-STS) .................................................................18 
11 PHARMACOKINETIC ANALYSES .................................................................................19 
11.1 
Below the Lower Limit of Quantification and the No Reportable 
Concentration ...................................................................................................................19 
11.2 
Difference between the Scheduled and the Actual Sampling Times ...........................19 
11.3 
PK Parameters .................................................................................................................20 
11.4 
Statistical Analyses...........................................................................................................21 
11.4.1 
PK Parameters in Plasma .........................................................................................21 
11.4.2 
Treatment Comparisons ............................................................................................21 
12 PERCENTAGES AND DECIMAL PLACES....................................................................23 


Statistical Analysis Plan for Interventional Studies (Early Phase) 
 
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13 DATA HANDLING ..............................................................................................................25 
14 MISSING DATA ...................................................................................................................26 
15 SOFTWARE .........................................................................................................................27 
16 REFERENCE LIST..............................................................................................................28 
  


Statistical Analysis Plan for Interventional Studies (Early Phase) 
 
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LIST OF ABBREVIATIONS 
Abbreviation 
Description 
AE 
adverse event 
ANOVA 
analysis of variance 
ALP 
alkaline phosphatase 
ALT 
alanine transaminase 
APTT 
activated partial thromboplastin time 
AST 
aspartate aminotransferase 
ATC 
Anatomical Therapeutic Chemical 
AUC 
area under the concentration-time curve 
AUCinf 
area under the concentration-time curve from time zero to infinity (extrapolated) 
AUCextrap% 
percentage of AUCinf due to extrapolation from the time of the last observed 
concentration to infinity 
AUClast 
area under the concentration-time curve from time zero until the last observed 
concentration 
BLQ 
below the lower limit of quantification  
BMI 
body mass index 
CI 
confidence interval 
CL/F 
apparent clearance 
Cmax 
maximal observed concentration 
CPK 
creatine phosphokinase 
CTCAE 
Common Technical Criteria for Adverse Events 
CV 
coefficient of variation 
DAIDS 
Division of Acquired Immunodeficiency Syndrome 
DDM 
dodecylmaltoside 
ECG 
electrocardiogram 
eDISH 
evaluation of drug induced serious hepatotoxicity 
eGFR 
estimated glomerular filtration rate 
FDA 
Food and Drug Administration 
FSH 
follicle stimulating hormone 
GGT 
gamma-glutamyl transferase 
IR 
immediate release 
INR 
international normalized ratio 
Kel 
terminal elimination rate constant 
Kel Lower  
the timepoint where ln-linear Kel calculation begins   
Kel Upper  
the actual sampling time of the last measurable concentration used to estimate the Kel  
LFT 
liver function test 
LLN 
lower limit of normal 
Ln 
natural logarithm 
max 
maximum 
MedDRA® 
Medical Dictionary for Regulatory Activities 
min 
minimum 


Statistical Analysis Plan for Interventional Studies (Early Phase) 
 
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N/A 
not applicable 
PK 
pharmacokinetic(s) 
PT 
preferred term or prothrombin time 
RBC 
red blood cells 
Rsq 
R-squared 
SAP 
statistical analysis plan 
SD 
standard deviation 
SGC 
soft gel capsule 
SOC 
system organ class 
S-STS 
Sheehan suicidality tracking scale 
T1/2 
terminal elimination half-life 
TEAE 
treatment-emergent adverse event 
TLFs 
tables, listings, and figures 
Tmax 
time when the maximal concentration is observed 
ULN 
upper limit of normal 
Vz/F 
apparent volume of distribution 
WBC 
white blood cells 
WHO DD 
World Health Organization Drug Dictionary 
 


Statistical Analysis Plan for Interventional Studies (Early Phase) 
 
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1 INTRODUCTION 
This document outlines the pre-specified plan for the summarization and analysis of clinical data 
collected in Sponsor Study BHV3500-113 and is intended to give a detailed description of the 
summaries and the analyses that will be generated for the present study by Syneos Health or a 
designee. Analyses specified in this plan are based on the Biohaven Pharmaceuticals Holding 
Company Limited Study Protocol No. BHV3500-113, version 2.0 (Amendment 01) dated 
August 16, 2022 (Syneos Health Project No. 222025). Safety, tolerability, and pharmacokinetic 
(PK) analyses will be described.  
The plan may change due to unforeseen circumstances; any changes made after the plan has been 
finalized will be documented. No revision to this document is required for changes which do not 
affect the statistical analysis methods, definitions, or rules defined in this document. If additional 
analyses are required to supplement the planned analyses described in this document, the 
changes and justification for the changes will be outlined in the associated clinical study report. 
No change will be made without prior approval of the Sponsor. 
When applicable, all methodologies and related processes will be conducted according to Syneos 
Health’s standard operating procedures, as appropriate. Shells for all statistical tables, listings, 
and figures (TLFs) referred to in this document will be displayed in a separate document. 
 
 


Statistical Analysis Plan for Interventional Studies (Early Phase) 
 
Sponsor: Biohaven Pharmaceuticals Holding Company Limited; Protocol No.: BHV3500-113 (222025) 
 
 
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2 STUDY OBJECTIVES 
The objective of this study is to compare the rate and extent of absorption of zavegepant 100 mg 
oral non-enteric coated soft gel capsule (SGC) (Test 1), zavegepant 100 mg immediate release 
(IR) oral tablet + dodecylmaltoside (DDM) dosage form (Test 2), zavegepant 1 x 200 mg IR oral 
tablet + DDM dosage form or zavegepant 2 x 100 mg IR tablets + DDM dosage form (Test 3), 
and zavegepant (BHV-3500) 4 x 25 mg enteric coated oral SGC (Reference), under fasting 
conditions. 
 
 


Statistical Analysis Plan for Interventional Studies (Early Phase) 
 
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3 STUDY DESIGN 
3.1 
General Design 
This is a Phase 1, single center, open-label, single dose, 4-period, crossover study designed to 
compare the PK of zavegepant from the Test and Reference products. The study may be dosed in 
more than 1 Group. 
The 4 sequences will be: ACBD, CDAB, BADC, and DBCA. In each period, participants will 
receive one of the following: Treatment A, B, C, or D on Day 1, followed by 24 hours of PK and 
safety assessments. On Day 2 participants will be discharged from the unit and instructed to 
return after at least a 7 day washout time has passed for subsequent periods of treatment. 
3.2 
Study Procedures 
The overall schedule of procedures and assessments is provided in the protocol. 
3.3 
Treatment Administration 
Randomization schedules will be generated through SAS® for Windows software, prior to study 
execution. Participants enrolled in this study will be assigned to ACBD, CDAB, BADC, or 
DBCA sequences using a blocked randomization.  
On Day 1 of each period, participants will receive a single oral dose of one of the following oral 
treatments, under fasting conditions, according to the assigned sequence on the randomization 
schedule. 
 
Treatment 
Description 
A (Test 1)  
1 x 100 mg zavegepant non-enteric coated SGC (Biohaven Pharmaceuticals Holding 
Company Limited) administered under fasting conditions. 
B (Test 2)  
1 x 100 mg zavegepant IR tablet + DDM dosage form (Biohaven Pharmaceuticals 
Holding Company Limited) administered under fasting conditions. 
C (Test 3)  
1 x 200 mg zavegepant IR tablet (total dose of 200 mg) + DDM dosage form. The dose 
for Treatment C may instead be administered as 2 x 100 mg IR tablets + DDM dosage 
form for a total zavegepant dose of 200 mg (Biohaven Pharmaceuticals Holding 
Company Limited) administered under fasting conditions. 
D (Reference) 
4 x 25 mg zavegepant enteric coated SGC (total dose of 100 mg) (Biohaven 
Pharmaceuticals Holding Company Limited) administered under fasting conditions. 
 
3.4 
Sample Size 
Approximately fifty- two (52) healthy, non-smoking, male and female participants, aged 18 to 55 
years, will be enrolled in this study.  


Statistical Analysis Plan for Interventional Studies (Early Phase) 
 
Sponsor: Biohaven Pharmaceuticals Holding Company Limited; Protocol No.: BHV3500-113 (222025) 
 
 
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Page 10 of 28 
 
 
 Thus, assuming a CV of 40%, and under the scenario of test 
versus reference ratio of geometric means of 1.0, the width of the 90% confidence interval (CI) 
for the ratio of geometric means is expected to approximately be 0.25 with fifty- two (52) 
participants. The expected width of the 90% CI for the ratio of geometric means will slightly 
decrease/increase from 0.25 as the ratio of geometrics means decrease/increase from 1.0. 
3.5 
Participant Withdrawal and Replacement 
Over the course of the study, the Sponsor and the Investigator or designee may withdraw any 
participant from the study for one of the reasons described below; participant withdrawal will be 
done in accordance with the clinical site’s SOP: 
• Safety reason; 
• Non-compliance with protocol requirements; 
• Significant protocol deviation; 
• Positive pregnancy test, drug screen, cotinine test, or alcohol breath test; 
• Vomiting within 4 hours post-dose; 
• Positive COVID-19 test. 
Participants excluded from dosing in one period as per criteria listed above, may be invited to 
participate in subsequent periods of the study if deemed appropriate by the Investigator and 
appropriate from a statistical standpoint (i.e., would permit adequate statistical comparison). 
However, participants with positive pregnancy test, COVID-19 test, drug screen, cotinine test, or 
alcohol breath test will be definitively withdrawn from the study.  
Participants experiencing emesis following study drug administration may be withdrawn. An 
evaluation will be done on a case-by-case basis in order to decide if withdrawal is appropriate. 
Participants who withdraw, or are withdrawn, prior to dosing may be replaced. Participants who 
withdraw, or are withdrawn, from the study after dosing will not be replaced.  
 
 
CCI


Statistical Analysis Plan for Interventional Studies (Early Phase) 
 
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4 CHANGES FROM THE PROTOCOL 
There are no changes in planned analyses compared to the protocol. 
 
5 PHARMACOKINETIC AND SAFETY PARAMETERS  
For PK analyses, AUClast, AUCinf, and Cmax calculated using zavegepant concentration data will 
be the primary endpoints. AUCextrap%, Tmax, T½, Kel, Vz/F and CL/F for zavegepant will be 
secondary endpoints; reference section 11.3. 
Safety and tolerability parameters are secondary endpoints; reference section 10. 
 
 


Statistical Analysis Plan for Interventional Studies (Early Phase) 
 
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6 ANALYSIS POPULATIONS 
All participants’ inclusion status into each analysis population will be determined after database 
lock for the final analysis. 
6.1 
Screened Population 
The screened population will include all participant who sign the informed consent form. 
6.2 
Randomized Population 
The randomized population will include all participants who are randomized. 
6.3 
Safety Population 
The safety population is defined as all participants who receive at least one dose of any study 
drug. In each period, participants will be analyzed according to treatment received.  
6.4 
Pharmacokinetic Population 
The PK population will include all participants from the safety population who receive at least 
one dose of zavegepant, and for whom the PK profile can be adequately characterized. The PK 
population will be used for calculation of PK parameters. 
6.5 
Pharmacokinetic Statistical Population 
The PK statistical population will include all participants from the PK population who complete 
at least one period of treatment for at least one PK parameter and who have not experienced any 
protocol deviations or other circumstances to exclude the participant from the PK statistical 
analysis. 
A participant with pre-dose concentrations may be excluded from descriptive statistics and 
ANOVA if the pre-dose concentration is greater than 5% of the Cmax value for that participant. A 
participant may be excluded from the descriptive statistics and ANOVA if the participant has 
experienced emesis within 2 times median Tmax for a given treatment. For the period where this 
would apply as appropriate, data (concentrations and PK parameters) from these participants will 
be presented in data listings but excluded from the statistical analyses. 
 
 


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7 INTERIM ANALYSIS 
No formal interim analysis is planned. However, a preliminary descriptive PK analysis may be 
performed when the final PK concentration data will be available. For this analysis, the 
scheduled times could be used in the calculation of the PK parameters. 
 
 


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8 SCHEDULE OF ANALYSIS 
The final statistical analysis will be performed once all participants completed the study, the 
bioanalysis of all samples are complete and the database is locked. 
 
 


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9 STUDY POPULATION AND EXPOSURE 
Each participant’s inclusion or exclusion from each analysis population will be presented in a 
data listing. The study drug administration details, including date and time of administrations, 
will also be listed by participant. 
9.1 
Participant Disposition 
The number of participants who were screened, screened failures, who were enrolled, who were 
randomized, who were dosed, who completed the study, and who were discontinued from the 
study and reasons for discontinuation, will be summarized. This summary table will also include 
the number of participants in each analysis population. The data (frequency and the percentage 
of participants) will be presented by treatment group and/or overall as appropriate, and listed by 
participant. 
9.2 
Protocol Deviations 
Participant data will be examined for evidence of protocol deviations. All protocol deviations 
will be categorized and listed by participant. 
9.3 
Demographic and Baseline Characteristics 
All demographic and baseline characteristics (including weight, height, and body mass 
index [BMI]) will be summarized overall, and they will be listed by participant.  
Descriptive statistics (mean, standard deviation [SD], minimum [min], median, and maximum 
[max]) will be calculated for continuous variables, using the last results obtained prior to first 
study drug administration. Frequency counts and percentages will be tabulated for categorical 
variables. 
9.4 
Medical History 
Medical history will be presented by participant in a data listing. The Medical Dictionary for 
Regulatory Activities (MedDRA) Version 25.0 will be used to classify all medical history 
findings by system organ class (SOC) and preferred term (PT).  
9.5 
Prior and Concomitant Medications 
Prior medications are medications started before and ongoing at the time of ICF, or started at the 
time of ICF and in either case stopped prior to first study drug administration. Concomitant 
medications are medications started before and ongoing at the time of study drug administration, 
or started after first study drug administration. Both prior and concomitant medications will be 
listed by participant. The World Health Organization Drug Dictionary (WHO DD) Version B3, 
Mar 2022 will be used to define the anatomical therapeutic chemical (ATC) classification code 
(2nd level), and preferred name for each prior and concomitant medication. When 2nd level 
classification code is not available, 1st level classification will be used instead.  


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10 SAFETY ANALYSIS 
Safety and tolerability analysis will be performed for all participants in the safety population. No 
inferential statistical analysis of safety data is planned. 
Safety and tolerability to treatments will be evaluated through the assessment of adverse events 
(AEs), vital signs, 12-lead electrocardiograms (ECGs), and clinical laboratory parameters. Safety 
and tolerability data will be reported using descriptive statistics (mean, median, SD, Min, Max, 
and sample size).  
10.1 Physical Examination Findings 
Participants will undergo a complete physical examination at screening, and a brief physical 
examination on Day -1 of each period and at study exit. Individual results will be presented in a 
data listing. 
Any abnormal findings judged to be clinically significant will be documented as medical history 
or as an AE, depending upon time of observation, as appropriate. Any physical examination 
findings documented as AEs will be included in AE summaries.  
10.2 Adverse Events 
AEs, which are collected from the time of enrollment, will be coded using the latest version of 
MedDRA (Version 25.0).  
All AE summaries will be restricted to treatment-emergent adverse events (TEAEs) only. TEAEs 
will be defined as AEs that occur on or after the date and time of first study drug administration. 
Any AE that first occurs prior to first study drug administration but worsens in severity after the 
first study drug administration will also be considered a TEAE. Non-TEAEs are those that occur 
prior to the first administration of the study medication and resolved prior to dosing or that first 
occur prior to the first study drug administration, but do not worsen in severity after dosing. 
TEAEs will be attributed to the most recent study drug taken. A TEAE with a start date and time 
during the washout period (ending at the time of next study drug administration) will be 
attributed to the study drug taken during the previous treatment period (unless there was 
worsening following the next drug administration). 
TEAEs will be summarized by treatment for the safety population. The number and percentage 
of participants experiencing TEAEs and the number of TEAEs will be tabulated. Participants 
who experience the same AE (in terms of MedDRA PT) more than once will only be counted 
once for that event, however, the total number of events will also be counted per category. This 
also applies to sub-categories and SOCs displayed in the summaries. 
In each table, TEAEs will be sorted by SOC and PT in descending order of overall frequency. 
The following summaries will be presented: 
• Overall summary of TEAEs 


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• TEAEs by SOC and PT 
• TEAEs by SOC, PT, and maximum severity 
• TEAEs by SOC, PT, and maximum relationship to study drug  
• Serious TEAEs by SOC and PT 
All AEs will be presented in data listings. This will include a separate listing of TEAEs, Non-
TEAEs and serious AEs. AEs leading to discontinuation will also be listed separately. 
10.3 Laboratory Parameters 
Clinical laboratory tests, including biochemistry, hematology, and urinalysis will be performed at 
screening and at Day -1 of each period, and at study exit. 
Biochemistry will include albumin, alkaline phosphatase (ALP), alanine transaminase (ALT), 
aspartate aminotransferase (AST), calcium, chloride, creatinine, creatine phosphokinase (CPK), 
estimated glomerular filtration rate (eGFR), calculated using the Modification of Diet in Renal 
Disease (MDRD) equation, gamma-glutamyl transferase (GGT), glucose, phosphorus, 
potassium, sodium, total, direct and indirect bilirubin, total protein, and urea (BUN). Considering 
that indirect bilirubin is calculated from total and direct bilirubin values, indirect bilirubin result 
would not be available in case of direct bilirubin below the limit of quantification. Hematology 
will include: haptoglobin, hematocrit, hemoglobin, platelet count, red blood cell (RBC) count, 
reticulocyte, and white blood cell (WBC) count and differential (basophils, eosinophils, 
lymphocytes, monocytes, neutrophils). Haptoglobin and reticulocyte count will be performed 
only in case of decrease in hemoglobin levels below the lower limit of normal (LLN) on Day -1 
of each period and at study exit. Urinalysis will include bilirubin, blood (occult), color and 
appearance, glucose, ketones, leukocyte esterase, nitrite, pH, protein, specific gravity, 
urobilinogen, and microscopic examination (in the event of abnormal findings). 
Coagulation tests (activated partial thromboplastin time [aPTT), international normalized ratio 
[INR] and prothrombin time [PT]) will be performed only in case of abnormal LFTs (i.e., ALP, 
AST, or ALT is >3x upper limit of normal [ULN]) on Day -1 of each period and at study exit. 
The results will be listed if applicable. 
Other laboratory assessments include serology tests, drug, cotinine, and alcohol screens, 
COVID-19 tests, and hormone screens (for female participants). Serology tests and follicle-
stimulating hormone (FSH) levels will be measured at screening only. Drug, cotinine, and 
alcohol screens will be performed at screening and at Day -1 of each period. A COVID-19 test 
will be performed on Day -1 of each period. Pregnancy tests will be administered to females of 
childbearing potential at screening, Day -1 of each period, and at study exit. Results of urine 
drug screens, serology tests, pregnancy tests, alcohol breath tests, and urine cotinine tests will be 
listed. 
Individual clinical laboratory results, change from baseline and reference ranges will be 
presented in data listings. Baseline will be defined as the last results (scheduled or unscheduled) 


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obtained prior to the first drug administration. Abnormal results will be flagged, as appropriate, 
in these listings. Clinically significant laboratory abnormalities will be identified as Grade 3 to 4 
laboratory test results graded according to numeric laboratory test criteria in the latest version of 
Common Technical Criteria for Adverse Events (CTCAE), if available, otherwise, according to 
the latest version of Division of Acquired Immunodeficiency Syndrome (DAIDS) Table for 
Grading the Severity of Adult and Pediatric Adverse Events. 
Additionally, a listing presenting abnormal LFTs (values greater than 3 times the upper limit of 
the normal [ULN] range for ALT, ALP or AST and values greater than 2 times ULN for total 
bilirubin) will be provided. An evaluation of drug-induced serious hepatotoxicity (eDISH) will 
be provided graphically. For this eDISH plot, the data will consist of the maximum values of 
ALT and total bilirubin that are observed at any time during or after dosing with zavegepant. 
10.4 Vital Signs 
Blood pressure, heart rate, respiratory rate, and oral temperature will be measured at screening, 
Day -1 of each period and at study exit. Blood pressure and pulse rate will be measured at pre-
dose, and at 2 hours post-dose in each period. 
Individual results and reference ranges will be presented in a data listing. For each vital sign 
measurement, observed values and changes from baseline for quantitative test results will be 
summarized by treatment or overall, as appropriate, for each timepoint using descriptive 
statistics. Baseline will be defined for each vital sign measurement as the last results (scheduled 
or unscheduled) obtained prior to study drug administration in each period. Unscheduled results 
will not be used in the summary tables except for baseline if applicable. 
10.5 12-lead Electrocardiograms 
Standard 12-lead ECGs will be recorded at screening, on Day -1 of each period, and at study 
exit. 
Individual results and change from baseline will be presented in a data listing. Baseline will be 
defined for each ECG parameter as the last results (scheduled or unscheduled) obtained prior to 
first study drug administration. Abnormal results will be flagged, as applicable. 
10.6 Sheehan Suicidality Tracking Scale (S-STS) 
The S-STS will be administered at screening and at study exit. Individual total scores with 
change from baseline will be presented in a data listing. 
 
 


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11 PHARMACOKINETIC ANALYSES 
11.1 Below the Lower Limit of Quantification and the No Reportable 
Concentration 
Plasma concentrations will be listed and summarized, by nominal sampling time, and treatment. 
Concentrations below the quantification limit (BLQ) will be set to zero for calculation of PK 
parameters and in summary tables. Samples with invalid concentration (due to bioanalytical 
issue) will be replaced by “0.00” when it occurs prior to dosing. Otherwise they will be set to 
missing for tabulation, graphical representation, and calculation purposes if it occurs after 
dosing. BLQ will be displayed in listings. For geometric mean calculations for PK parameters 
involving zero values, zero values will be substituted with 0.0001.  
For individual plots, the BLQ values will be set to zero. For mean plots, BLQ will be set to zero. 
11.2 Difference between the Scheduled and the Actual Sampling Times 
The actual clock time for dosing and the actual clock time for each collection time for the PK 
samples will be recorded using electronic data capture. For all sampling times, the actual 
sampling times will be calculated as the difference between the actual clock time of sample 
collection and the actual clock time of dosing. The actual post-dose sampling times expressed in 
hours and rounded off to three decimal digits will be used to calculate the PK parameters, except 
for pre-dose samples occurring prior to dosing, which will always be reported as zero (0.000), 
regardless of the time difference. Scheduled nominal sampling times will be presented in 
concentration tables and mean graphs, while actual sampling times will be presented in the 
individual graphs in the PK section of the report. Actual sampling times also will be used for 
final PK parameter derivation. If actual sampling time is missing, then nominal time will be 
used. A listing of the actual times for PK sampling will be provided for PK samples. 


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11.3 PK Parameters 
Blood samples will be collected for zavegepant PK analysis at pre-dose (within 1 hour prior to 
dosing), and 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 10, 12, 16, and 24 hours post-dose in each 
period. Bioanalysis of all associated plasma samples should be completed prior to the initiation 
of the PK and statistical analyses. Analysis will be performed using a fully-validated analytical 
method by a qualified bioanalytical laboratory. 
The following PK parameters will be calculated, based on the PK population, by standard 
non-compartmental methods using the plasma concentrations of zavegepant.  
Parameter  
Definition  
AUClast 
area under the concentration-time curve from time zero until the last observed 
concentration 
AUCinf 
area under the concentration-time curve from time zero to infinity (extrapolated) 
AUCextrap% 
percentage of AUC0-inf due to extrapolation from the time of the last observed concentration 
to infinity, calculated as [1 – (AUClast/AUCinf)] x 100 
Cmax 
maximal observed concentration 
Tmax 
time when the maximal concentration is observed 
T1/2 
terminal elimination half-life 
Kel 
terminal elimination rate constant 
CL/F 
apparent clearance 
Vz/F 
apparent volume of distribution 
PK of Treatment C (AUCs and Cmax) will be normalized to a dose of 100 mg. 
Additional PK parameters may be calculated. 
Note: AUC parameters will be calculated using linear up log down trapezoidal method, where 
the linear trapezoidal rule is used any time the concentration data is increasing, and the 
logarithmic trapezoidal rule is used any time that the concentration data is decreasing. 
Note: Kel will be the negative of the estimated slope of the linear regression of the ln-transformed 
concentration versus time profile in the terminal elimination phase. The best fit method, in 
Phoenix WinNonlin, will be used to calculate the Kel from at least three concentration data 
points, excluding Cmax. Rsq (R-squared) adjusted, the goodness of fit statistic for the terminal 
elimination phase, adjusted for the number of points used in the estimation of Kel must be ≥ 0.9. 
If the Kel cannot be measured (e.g.: there are fewer than three non-zero concentrations in the 
terminal elimination phase or Rsq adjusted <0.9), the PK parameters derived from Kel (AUCinf, 
AUCextrap%, T½, CL/F, Vz/F) will be presented in listing with a flag and excluded from 
descriptive statistics and statistical analyses. The timepoint where ln-linear Kel calculation begins 
(Kel Lower) and the actual sampling time of the last measurable concentration used to estimate the 
Kel (Kel Upper), as well as the Rsq adjusted for the ln-linear regression for the calculation of the 
elimination rate constant will be reported.  


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If the AUCextrap% is more than 20%, the individual result should be flagged as well as all 
parameters depending on AUCinf. All the derived parameters (i.e., AUCinf, AUCextrap%, T½, CL/F, 
Vz/F) will be flagged accordingly, and they will be removed from the analyses and the 
descriptive statistics. 
Some PK parameters may not be calculated for all participants, at the discretion of the Syneos 
pharmacokineticist with Sponsor agreement if the concentration data is not deemed to be 
amenable to evaluation. Explanations for PK parameters that could not be estimated will be 
provided in the report. 
11.4 Statistical Analyses 
Statistical analysis described in this section will be based on the PK statistical population.  
11.4.1 
PK Parameters in Plasma 
Individual, mean and median plasma concentration versus time curves will be presented for both 
linear and semi-log scales. Descriptive statistics (arithmetic and geometric means, SD, CV%, 
geometric mean CV%, Min, Max, and median) of the plasma concentrations versus time will be 
presented as well for the PK parameters. 
11.4.2 
Treatment Comparisons 
For zavegepant, using the MIXED procedure in SAS, an ANOVA will be performed on ln-
transformed (dose-normalized to 100 mg) AUClast, AUCinf, and Cmax. No adjustments will be 
made to alpha for multiple pairwise comparisons. As the study was dosed in more than one 
Group, the following terms will be included in the statistical model: Group, Sequence, Sequence 
by Group, Period within Group, Treatment, and Treatment by Group. A random effect of 
Participant within Sequence by Group will also be included. In case of a non-statistically 
significant Treatment by Group interaction term, the analysis will be rerun excluding this term 
from the ANOVA model in order to obtain ratios and confidence intervals where appropriate. 
The ratio of geometric means and 90% confidence intervals (A/D), (B/D), and (C/D) based on 
least-squares means from the ANOVA of the ln-transformed data will be calculated for AUClast, 
AUCinf, and Cmax. The point estimates and confidence intervals will be exponentiated using base 
e in order to obtain a point and interval estimate for the ratio of geometric means. Other ratio of 
geometric means among treatments may be explored. Untransformed Tmax will also be analyzed 
using the MIXED model with the difference of least-squares means from the ANOVA calculated 
for (A-D), (B-D), and (C-D). Other differences of least-square means between treatments may be 
explored. The Kel, and T½ will be summarized descriptively. 
The SAS code to fit the model will follow the format below (using the Mixed Procedure). The 
input variables, datasets, and labels are depicted in italicized red text and have been given 
generic names. 
 
 


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proc mixed data = basepk; 
  class Group Sequence Period Treatment Participant; 
  model VAR = Group Sequence Sequence*Group Period(Group) Treatment 
              Treatment*Group / ddfm = kenwardroger; 
  random Participant(Sequence*Group); 
  lsmeans Treatment; 
  estimate 'A versus D' Treatment 1 0 0 -1 / cl alpha = 0.1; 
  estimate 'B versus D' Treatment 0 1 0 -1 / cl alpha = 0.1; 
  estimate 'C versus D' Treatment 0 0 1 -1 / cl alpha = 0.1; 
  ods output estimates = estimates tests3 = tests covparms = covparms; 
run; 
Additional PK statistical analysis may be performed. 


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12 PERCENTAGES AND DECIMAL PLACES 
Percentages: 
Percentages based on count data should be displayed as follows in TLFs: 
• 0 < percentage < 0.1 as “<0.1”  
• 99.9 < percentage < 100 as “>99.9” 
• 100 percentage as “100” 
• 0 count without a percentage in frequency tables 
• Rounded to 1 decimal place otherwise.  
For response rates (proportions), measures of variability such as standard error (SE) and 
confidence interval (CI) should be displayed rounded to 1 decimal place.  
Continuous Variables Non-PK Data: 
Descriptive statistics for continuous variables in tables should be displayed as follows:  
• Values and changes from baseline 
o Minimum and maximum: same precision as the data collected or rounded to a specified 
precision if derived 
o Mean and percentiles: rounded to 1 decimal place more than the data collected or derived 
o Measure of variability (e.g., standard deviation [SD], SE, CI): rounded to 2 decimal 
places more than the data collected or derived 
• Percent change from baseline 
o Minimum and maximum: rounded to 0 decimal places (i.e., integers) 
o Mean and percentiles: rounded to 1 decimal place 
o Measure of variability: rounded to 2 decimal places.  
Individual data in listings should be displayed to the same precision as the data collected or 
rounded to a specified precision if derived. 
Derived variables should be calculated using all precision from collected components. For 
example, BMI should be derived as needed using all precision from collected height and weight. 
However, the specified precision for reporting BMI should be 1 decimal place. 
Continuous Variables PK Data: 
Concentration data for parameter calculations: The concentration data as reported by the 
respective bioanalytical groups should be used, without rounding, for all analyses. 


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Concentration data listings: By default, concentration values should be presented in listings 
exactly as reported by the respective bioanalytical groups. However, in cases when concentration 
data may be supplied electronically with unrealistic precision, rounded values may be presented. 
A default of 3 significant figures is suggested, and the rounding used should be described in the 
clinical study report. 
Parameter data listings: The non-compartmental parameters should not be reported to any greater 
precision than that of the concentration data. A default of 3 significant figures is preferred. 
Concentration and parameter summary data: The following guidance for reporting precision is 
intended to provide specifications for programming and defaults for documents based on those 
presentations. It is recognized that data from external sources may follow different standards. 
Refer to below for additional guidance on parameter summary statistics for study report and 
summary documents. 
Parameter values (and if applicable, concentration values) should be rounded to the same 
precision used in data listings prior to any statistical analysis or descriptive summaries. 
Descriptive summaries: 
• Means, mediana, CIs - 1 more significant figure than the data 
• SD - 1 more significant figure than means 
• CV% - whole numbers 
• Min, Max - same significant figures as the data 
a Exception: for Tmax, Tlag, and any other parameters which are direct time observations, median 
will have the same significant figures as the data (mean is generally not presented for these 
parameters). 
Statistical summaries: 
• Means, differences, CIs (non-transformed data) - 1 more significant figure than the data. 
 
 
 


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13 DATA HANDLING 
For the final analyses, the PK, safety, and tolerability data will be received as SAS datasets. 
Screening failures and ineligible volunteer’s data (participant disposition) will be received from 
the clinical site as source data. 
 
 


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14 MISSING DATA 
There will be no imputation for missing data, unless otherwise specified. Missing data will be 
presented in participant listings as either “-” (unknown or not evaluated) or “N/A” (not 
applicable), with the corresponding definition in the footnotes. Missing descriptive statistics, or 
probability values (p-values), which cannot be estimated will be presented as “-”. 
Incomplete AE start and stop dates will be imputed as follows: 
• If an AE is recorded with an onset date corresponding to a dosing day, but the time is 
missing, then the AE will be assigned to that day treatment (e.g., an AE with an onset date on 
Day 1 without time will be allocated to the treatment received on Day 1, and considered 
treatment-emergent). 
• If an AE is recorded with an onset date that does not correspond to a dosing day, but the time 
is missing, then the AE will be assigned to the planned treatment that covers the AE onset 
day and considered treatment-emergent if onset date is after the date of first dosing. 
• If an AE is recorded with an onset date where day and time are both missing, then the AE 
allocation to the planned treatment will be done on a case-by-case basis considering available 
information (i.e., AE recording date, AE end date, AE comments, participant disposition). 
For PK analysis, only observed concentration data will be used in the data analysis, except for 
concentration values BLQ as described in section 11.1. No attempt will be made to extrapolate or 
interpolate estimates for missing data. 
 
 


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15 SOFTWARE  
All tables, figures, and listings and statistical analyses will be generated using SAS for Windows, 
release 9.4 (SAS Institute Inc., Cary, NC, USA) software in accordance with Food and Drug 
Administration (FDA) guidelines.  
Phoenix WinNonlin, version 8.3.4 (Certara USA, Inc., Princeton, NJ) will be used for all PK 
analyses. This software was validated by Syneos in compliance with US 21 CFR Part 11 
regulation. 
 
 


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16 REFERENCE LIST