A Pharmacokinetic Study of Zavegepant Intranasal in Healthy Adults Comparing Conventional Venous Blood Sampling With Patient-Centric Sampling
Phase: PHASE1
Conditions: Healthy
Sponsor: Pfizer

Zavegepant (PF-07930207)
Protocol C5301022
Final Protocol Amendment 1, 12 June 2023
PFIZER CONFIDENTIAL
CT02-GSOP Clinical Pharmacology Protocol Template (14 April 2023)
Page 1
Title Page
A PHARMACOKINETIC STUDY OF ZAVEGEPANT INTRANASAL IN HEALTHY 
ADULTS COMPARING CONVENTIONAL VENOUS BLOOD SAMPLING WITH 
PATIENT-CENTRIC SAMPLING
Study Intervention Number:
PF-07930207
Study Intervention Name:
Zavegepant
US IND Number:
134120
EudraCT/EU CT Number:
Not applicable
ClinicalTrials.gov ID:  
Not available
Pediatric Investigational Plan Number:
Not applicable
Protocol Number:
C5301022
Phase:
1
Sponsor Legal Address:
Pfizer Inc.
66 Hudson Boulevard East
New York, NY 10001
Brief Title: A Study to Compare Zavegepant Concentration Using Samples Collected 
From the Vein Versus Patient-Centric Microsampling
This document and accompanying materials contain confidential information belonging to Pfizer. Except as 
otherwise agreed to in writing, by accepting or reviewing these documents, you agree to hold this 
information in confidence and not copy or disclose it to others (except where required by applicable law) or 
use it for unauthorized purposes. In the event of any actual or suspected breach of this obligation, Pfizer 
must be promptly notified.
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Zavegepant (PF-07930207)
Protocol C5301022
Final Protocol Amendment 1, 12 June 2023
PFIZER CONFIDENTIAL
CT02-GSOP Clinical Pharmacology Protocol Template (14 April 2023)
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Document History
Document
Version Date
Amendment 1
12 June 2023
Original protocol
10 May 2023
This amendment incorporates all revisions to date, including amendments made at the 
request of country health authorities and IRBs/ECs and any protocol administrative change 
letter(s).
Protocol Amendment Summary of Changes Table
Amendment 1 (09 June 2023)
Overall Rationale for the Amendment: 
Dysgeusia (bad/metallic/bitter taste) has been reported as the most common 
treatment-emergent adverse event with zavegepant. Because of this adverse event, patients 
may not adhere to their medications which may limit the effectiveness of treatment with 
zavegepant. Therefore, understanding this adverse event (eg, time-course, description of the 
taste sensation) and potential strategies to mask this unpleasant taste could help improve 
patient experience and adherence. This amendment was mainly considered to add an 
exploratory objective to this study to evaluate zavegepant-induced dysgeusia and whether 
eating a butterscotch candy before zavegepant IN administration will help manage dysgeusia.
Changes were made to the protocol to support this exploratory objective, along with other 
editorial changes, as described below.
Description of Change
Brief Rationale
Section # and Name
Substantial Modification(s)
Added a tertiary 
(exploratory) objective to 
the protocol to evaluate the 
effect of the administration 
of 10 mg of zavegepant IN 
with a butterscotch candy on 
dysgeusia compared to 
zavegepant IN alone.
Based on data from 
zavegepant IN clinical trials, 
dysgeusia 
(bad/metallic/bitter taste) 
has been reported as the 
most common 
treatment-emergent adverse 
event with zavegepant. 
Because of this adverse 
event, patients may not 
adhere to their medications 
which may limit the 
effectiveness of treatment 
1.1 Synopsis
3. Objectives and Endpoints
4.1 Overall Design
6.1.1. Administration
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Protocol C5301022
Final Protocol Amendment 1, 12 June 2023
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Description of Change
Brief Rationale
Section # and Name
with zavegepant. Therefore, 
understanding this adverse 
event (eg, time-course, 
description of the taste 
sensation) and potential 
strategies to mask the 
unpleasant taste could help 
improve patient experience 
and adherence. As an 
exploratory objective of this 
study, we will prospectively 
evaluate the unpleasant taste 
sensation and whether eating 
a butterscotch candy before 
zavegepant IN 
administration will help 
manage dysgeusia.
Provided rationale for the 
tertiary objective added
To clarify the reason for 
adding this objective to the 
trial.
1.1 Synopsis
2.1 Study Rationale
4.2 Scientific Rationale for 
Study Design
Added inclusion criterion #5 
that requires participants to 
be willing to consume a 
butterscotch candy
To support the tertiary 
objective of evaluating the 
effect of the administration 
of 10 mg of zavegepant IN 
with a butterscotch candy on 
dysgeusia compared to 
zavegepant IN alone.
1.1 Synopsis
5.1 Inclusion Criteria
Edited an exclusion criterion 
to exclude participants who 
are active smokers or use 
tobacco or 
nicotine-containing products 
within 1 months of 
screening
Smokers were excluded 
since smoking causes loss of 
taste and induces dysgeusia.
1.1 Synopsis
5.1 Exclusion Criteria
Added an exclusion criterion 
to exclude participants with 
a condition that affect ability 
to taste eg, dysgeusia, 
respiratory infection, cold
To ensure that study 
participants can provide 
meaningful and adequate 
feedback for the taste 
assessment
1.1 Synopsis
5.1 Exclusion Criteria
Updated the study design by 
adding one additional 
This will support the tertiary 
objective added, which will 
1.1 Synopsis
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Zavegepant (PF-07930207)
Protocol C5301022
Final Protocol Amendment 1, 12 June 2023
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Description of Change
Brief Rationale
Section # and Name
day/period for running the 
taste assessment of 
zavegepant + butterscotch 
and compare it to 
zavegepant administration in 
period 1. Also, updated 
Section 5.3.2 Meals and 
Dietary Restrictions to 
clarify the food restriction 
prior to the taste assessment 
questionnaire.
be helpful in better 
understanding zavegepant-
induced dysgeusia and 
evaluating whether this 
simple strategy of using 
butterscotch will be useful 
in mitigating dysgeusia with 
minor changes in the study 
design.
1.3 Schedule of Activities, 
Table 1
5.3.2. Meals and Dietary 
Restrictions
Provided text to support the 
analysis of the taste 
assessment questionnaire 
data under the tertiary 
objective.
To provide clarity on how 
this data will be analyzed 
and collected.
1.1 Synopsis
9.2. Analysis Sets
9.3.1 General 
Considerations
10.11 Appendix 11: Taste 
Assessment Questionnaire
Added one additional day 
and period to support the 
taste assessment evaluation 
as described for the study's 
tertiary objective.
To support the tertiary 
objective added.
1.3 Schedule of Activities, 
Table 1
Added urine cotinine test to 
be performed at screening 
and on Day -1.
To ensure that participants 
are non-smokers as required 
by the nonsmoker exclusion 
criterion
1.3 Schedule of Activities, 
Table 2
10.2 Appendix 2: Clinical
Laboratory Tests
Deleted the original footnote 
‘b’ to clarify that blood-to-
plasma ratio samples will be 
collected for all participants 
regardless of the type of 
Tasso device used.
This will ensure that we 
have sufficient blood-to-
plasma ratio data in healthy 
participants, which will 
support the conversion of 
zavegepant dried blood 
concentrations data to their 
equivalent plasma 
concentrations for adequate 
comparison between the 
Tasso and venous sampling 
methods.
1.3 Schedule of Activities, 
Table 2
8.5 Pharmacokinetics
Non-substantial Modification(s)
Appendix 11 includes the
taste assessment 
Added for the collection of
the data need to fulfil the 
10.11 Appendix 11: Taste 
Assessment Questionnaire
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Zavegepant (PF-07930207)
Protocol C5301022
Final Protocol Amendment 1, 12 June 2023
PFIZER CONFIDENTIAL
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Description of Change
Brief Rationale
Section # and Name
questionnaire that will be 
used for the tertiary 
objective of this study
tertiary objective of this 
study
Added the taste assessment 
questionnaire, and 
consumption of butterscotch 
candy as placeholders.
To support the tertiary 
objective added and clarify 
the SoA related to this 
objective
1.3 Schedule of Activities, 
Table 1
Added Days for each period.
To support the tertiary 
objective added and provide 
clarity.
1.3 Schedule of Activities, 
Table 2
Program level changes have 
been made based on 
availability of evidence 
supporting these changes. 
The majority of the changes 
include adding information 
about the unidose nasal 
device used for 
administering zavegepant. 
Information related to the 
risk assessment of using this 
device, reporting AE related 
to the use of this device or 
what to do in case of a 
device deficiency.
To ensure consistency 
within protocols across the 
zavegepant clinical program 
and provide more 
information about the 
unidose nasal device as 
required by the protocol 
template.
2.3.1 Risk assessment
6.1.1 Administration
6.1.2 Medical Devices
8.4.9 Medical Device 
Deficiencies
10.9 Appendix 9: AEs, 
ADEs, SAEs, SADEs, 
USADEs, and Device 
Deficiencies
Editorial updates to use 
consistent wording and 
terminology. Formatting 
updates.
For clarification and to 
ensure consistency.
Throughout the protocol
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Zavegepant (PF-07930207)
Protocol C5301022
Final Protocol Amendment 1, 12 June 2023
PFIZER CONFIDENTIAL
CT02-GSOP Clinical Pharmacology Protocol Template (14 April 2023)
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TABLE OF CONTENTS
LIST OF TABLES...................................................................................................................11
1. PROTOCOL SUMMARY...................................................................................................12
1.1. Synopsis ..................................................................................................................12
1.2. Schema ....................................................................................................................20
1.3. Schedule of Activities .............................................................................................21
2. INTRODUCTION ...............................................................................................................25
2.1. Study Rationale .......................................................................................................25
2.2. Background .............................................................................................................26
2.2.1. Nonclinical Overview.................................................................................27
2.2.2. Clinical Overview.......................................................................................27
2.2.2.1. Safety Overview........................................................................27
2.2.2.2. Efficacy Overview.....................................................................27
2.2.2.3. Clinical Pharmacology..............................................................28
2.3. Benefit/Risk Assessment.........................................................................................29
2.3.1. Risk Assessment.........................................................................................30
2.3.2. Benefit Assessment.....................................................................................31
2.3.3. Overall Benefit/Risk Conclusion................................................................31
3. OBJECTIVES AND ENDPOINTS.....................................................................................31
4. STUDY DESIGN.................................................................................................................31
4.1. Overall Design.........................................................................................................31
4.2. Scientific Rationale for Study Design.....................................................................32
4.2.1. Choice of Contraception/Barrier Requirements .........................................34
4.3. Justification for Dose ..............................................................................................34
4.4. End of Study Definition ..........................................................................................34
5. STUDY POPULATION......................................................................................................34
5.1. Inclusion Criteria.....................................................................................................35
5.2. Exclusion Criteria....................................................................................................36
5.3. Lifestyle Considerations..........................................................................................38
5.3.1. Contraception..............................................................................................38
5.3.2. Meals and Dietary Restrictions...................................................................39
5.3.3. Caffeine, Alcohol, and Tobacco .................................................................39
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Protocol C5301022
Final Protocol Amendment 1, 12 June 2023
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5.3.4. Activity .......................................................................................................40
5.4. Screen Failures ........................................................................................................40
6. STUDY INTERVENTION(S) AND CONCOMITANT THERAPY.................................40
6.1. Study Intervention(s) Administered........................................................................40
6.1.1. Administration............................................................................................41
6.1.2. Medical Devices .........................................................................................42
6.2. Preparation, Handling, Storage, and Accountability...............................................42
6.2.1. Preparation and Dispensing........................................................................43
6.3. Assignment to Study Intervention...........................................................................43
6.4. Blinding...................................................................................................................43
6.4.1. Blinding of the Sponsor..............................................................................44
6.5. Study Intervention Compliance...............................................................................44
6.6. Dose Modification...................................................................................................44
6.7. Continued Access to Study Intervention After the End of the Study......................44
6.8. Treatment of Overdose............................................................................................44
6.9. Prior and Concomitant Therapy..............................................................................45
7. DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL...........................................................................45
7.1. Discontinuation of Study Intervention ....................................................................45
7.1.1. Potential Cases of Acute Kidney Injury .....................................................46
7.2. Participant Discontinuation/Withdrawal From the Study.......................................47
7.2.1. Withdrawal of Consent...............................................................................48
7.3. Lost to Follow-Up ...................................................................................................48
8. STUDY ASSESSMENTS AND PROCEDURES...............................................................49
8.1. Administrative Procedures ......................................................................................49
8.2. Efficacy Assessments..............................................................................................50
8.3. Safety Assessments .................................................................................................50
8.3.1. Physical Examinations................................................................................50
8.3.2. Nasal Inspection..........................................................................................51
8.3.3. Vital Signs ..................................................................................................51
8.3.3.1. Blood Pressure and Pulse Rate..................................................51
8.3.4. Electrocardiograms.....................................................................................51
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8.3.5. Clinical Safety Laboratory Assessments ....................................................52
8.3.6. Pregnancy Testing ......................................................................................52
8.4. Adverse Events, Serious Adverse Events, and Other Safety Reporting .................52
8.4.1. Time Period and Frequency for Collecting AE and SAE Information.......53
8.4.1.1. Reporting SAEs to Pfizer Safety...............................................54
8.4.1.2. Recording Nonserious AEs and SAEs on the CRF...................54
8.4.2. Method of Detecting AEs and SAEs ..........................................................54
8.4.3. Follow-Up of AEs and SAEs......................................................................54
8.4.4. Regulatory Reporting Requirements for SAEs...........................................55
8.4.5. Environmental Exposure, Exposure During Pregnancy or 
Breastfeeding, and Occupational Exposure.....................................................55
8.4.5.1. Exposure During Pregnancy......................................................55
8.4.5.2. Exposure During Breastfeeding ................................................57
8.4.5.3. Occupational Exposure .............................................................57
8.4.6. Cardiovascular and Death Events...............................................................57
8.4.7. Disease-Related Events and/or Disease-Related Outcomes Not 
Qualifying as AEs or SAEs..............................................................................57
8.4.8. Adverse Events of Special Interest.............................................................58
8.4.8.1. Lack of Efficacy........................................................................58
8.4.9. Medical Device Deficiencies......................................................................58
8.4.9.1. Time Period for Detecting Medical Device Deficiencies .........58
8.4.9.2. Regulatory Reporting Requirements for Device 
Deficiencies .......................................................................................58
8.4.10. Medication Errors.....................................................................................59
8.5. Pharmacokinetics ....................................................................................................59
8.6. Genetics...................................................................................................................61
8.6.1. Specified Genetics ......................................................................................61
8.6.2. Retained Research Samples for Genetics ...................................................61
8.7. Biomarkers ..............................................................................................................61
8.8. Immunogenicity Assessments.................................................................................61
8.9. Health Economics ...................................................................................................61
9. STATISTICAL CONSIDERATIONS ................................................................................61
9.1. Statistical Hypotheses .............................................................................................61
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9.2. Analysis Sets ...........................................................................................................62
9.3. Statistical Analyses .................................................................................................62
9.3.1. General Considerations...............................................................................62
9.3.2. Pharmacokinetic Analysis ..........................................................................63
9.3.2.1. Derivation of PK Parameters.....................................................63
9.3.2.2. Statistical Methods for Pharmacokinetic Data..........................64
9.3.3. Safety Analyses ..........................................................................................65
9.4. Interim Analyses .....................................................................................................65
9.5. Sample Size Determination.....................................................................................65
10. SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS..........................................................................................................66
10.1. Appendix 1: Regulatory, Ethical, and Study Oversight Considerations...............66
10.1.1. Regulatory and Ethical Considerations ....................................................66
10.1.1.1. Reporting of Safety Issues and Serious Breaches of the 
Protocol or ICH GCP.........................................................................66
10.1.2. Financial Disclosure .................................................................................67
10.1.3. Informed Consent Process ........................................................................67
10.1.3.1. Electronic Consent ..................................................................68
10.1.4. Data Protection .........................................................................................68
10.1.5. Committees Structure ...............................................................................68
10.1.5.1. Data Monitoring Committee ...................................................68
10.1.6. Dissemination of Clinical Study Data ......................................................69
10.1.7. Data Quality Assurance ............................................................................70
10.1.8. Source Documents....................................................................................71
10.1.9. Use of Medical Records............................................................................71
10.1.10. Study and Site Start and Closure ............................................................72
10.1.11. Publication Policy...................................................................................73
10.1.12. Sponsor’s Medically Qualified Individual..............................................73
10.2. Appendix 2: Clinical Laboratory Tests .................................................................75
10.3. Appendix 3: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-Up, and Reporting .....................................................................76
10.3.1. Definition of AE .......................................................................................76
10.3.2. Definition of an SAE ................................................................................77
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10.3.3. Recording/Reporting and Follow-Up of AEs and/or SAEs During 
the Active Collection Period............................................................................78
10.3.4. Reporting of SAEs....................................................................................82
10.4. Appendix 4: Contraceptive and Barrier Guidance ................................................84
10.4.1. Male Participant Reproductive Inclusion Criteria....................................84
10.4.2. Female Participant Reproductive Inclusion Criteria.................................84
10.4.3. Woman of Childbearing Potential ............................................................85
10.4.4. Contraception Methods.............................................................................86
10.5. Appendix 5: Genetics............................................................................................88
10.6. Appendix 6: Liver Safety: Suggested Actions and Follow-Up Assessments .......89
10.7. Appendix 7: Kidney Safety: Monitoring Guidelines ............................................91
10.7.1. Laboratory Assessment of Change in Kidney Function and 
Detection of Kidney Injury..............................................................................91
10.7.2. Age-Specific Kidney Function Calculation Recommendations...............91
10.7.2.1. Adults (18 Years and Above)—2021 CKD-EPI 
Equations ...........................................................................................91
10.7.3. Kidney Function Calculation Tools..........................................................91
10.7.4. Adverse Event Grading for Kidney Safety Laboratory 
Abnormalities...................................................................................................92
10.8. Appendix 8: ECG Findings of Potential Clinical Concern ...................................93
10.9. Appendix 9: AEs, ADEs, SAEs, SADEs, USADEs, and Device 
Deficiencies: Definitions and Procedures for Recording, Evaluating, 
FollowUp, and Reporting in Medical Device Studies...............................................95
10.9.1. Definition of AE and ADE .......................................................................95
10.9.2. Definition of SAE, SADE, and USADE ..................................................95
10.9.3. Definition of Device Deficiency...............................................................96
10.9.4. Recording/Reporting and Follow-Up of Medical Device 
Deficiencies......................................................................................................96
10.10. Appendix 10: Prohibited Concomitant Medications That May Result in 
DDI............................................................................................................................99
10.11. Appendix 11: Taste Assessment Questionnaire................................................100
10.12. Appendix 12: Abbreviations .............................................................................107
11. REFERENCES ................................................................................................................111
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LIST OF TABLES
Table 1.
Study Schedule of Assessment.................................................................21
Table 2.
Pharmacokinetic Sampling Timepoints....................................................24
Table 3.
Plasma PK Parameters for Protocol C5301022........................................64
Table 4.
Protocol-Required Laboratory Assessments.............................................75
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1. PROTOCOL SUMMARY 
1.1. Synopsis 
PROTOCOL TITLE: A Pharmacokinetic Study of Zavegepant Intranasal in Healthy Adults 
Comparing Conventional Venous Blood Sampling with Patient-Centric Sampling
Brief Title: A Study to Compare Zavegepant Concentration Using Samples Collected From 
the Vein Versus Patient-Centric Microsampling
Regulatory Agency Identification Number(s):
US IND Number:
134120
EudraCT/EU CT Number:
Not applicable
ClinicalTrials.gov ID:  
Not available
Pediatric Investigational Plan Number:
Not applicable
Protocol Number:
C5301022
Phase:
1
Abbreviation: CT = clinical trial; EU = European Union; EudraCT = European Union Drug Regulating 
Authorities Clinical Trials (European Clinical Trials Database); ID = identification; IND = Investigational 
New Drug; US = United States
Rationale:
Zavegepant (PF-07930207) is a high affinity, selective, and structurally unique, small 
molecule calcitonin gene-related peptide (CGRP) receptor antagonist, which was recently 
approved by the Food and Drug Administration (FDA) for the acute treatment of migraine 
with or without aura in adults via intranasal (IN) administration. As a component of 
zavegepant clinical development, future pediatric studies will be conducted to evaluate the 
safety, tolerability, and pharmacokinetics (PK) of zavegepant in participants 6 to less than 
12 years of age with migraine. 
Recruiting and retaining pediatric patients in clinical trials has always been challenging due 
to a variety of factors, including inconvenience with patient preferences. To overcome some 
of those challenges, it is essential to prioritize patient-centric approaches that cater to the 
unique needs of pediatric patients. One such approach is patient-centric sampling (PCS), 
which aims to reduce the burden on pediatric patients by minimizing the volume of the 
biological samples required and being less invasive with minimal to no pain compared to the 
venous phlebotomy collection method, which is particularly beneficial for pediatrics who are 
fearful of needles. Additionally, PCS offers greater flexibility to pediatric patients and their 
families by allowing at-home sample collection for those who may have difficulty traveling 
to clinics.
To allow the use of PCS in zavegepant pediatric studies, a bridging or comparative study 
comparing the PCS approach with an equivalent conventional sampling technique is needed 
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as a regulatory expectation to demonstrate the concordance of data from PCS in a controlled 
environment prior to implementation in large‐scale clinical trials. Therefore, the primary 
objective of this study is to establish the correlation between zavegepant concentration from 
samples collected using PCS devices compared to conventional venous blood sampling. In 
addition, if feasible, this study will also determine the PK and safety of zavegepant IN in 
Japanese participants.
Lastly, based on data from zavegepant IN clinical trials, dysgeusia (bad/metallic/bitter taste) 
has been reported as the most common treatment-emergent adverse event with zavegepant. 
Because of this adverse event, patients may not adhere to their medications which may limit 
the effectiveness of treatment with zavegepant. Therefore, understanding this adverse event 
(eg, time-course, description of the taste sensation) and potential strategies to mask the 
unpleasant taste could help improve patient experience and adherence. As an exploratory 
objective, this study will also evaluate the palatability attributes of zavegepant IN 
administration and whether eating a butterscotch candy before zavegepant IN administration 
will help manage dysgeusia.
Objectives and Endpoints:
Objectives
Endpoints
Primary: 
Primary:

Characterize the PK profile of zavegepant from 
samples collected using Tasso Devices 
(Tasso-Plus and Tasso-M20) vs standard 
venous phlebotomy following IN 
administration of 10 mg of zavegepant IN 
formulation in healthy participants
Zavegepant concentrations from 
samples collected using Tasso 
devices vs standard venous 
phlebotomy
PK parameters: AUCinf (if data 
permit), AUClast, Cmax, Tmax, t½, 
CL/F and Vz/F, as data permits
Secondary: 
Secondary:

Evaluate the safety and tolerability following 
IN administration of 10 mg of zavegepant IN 
formulation in healthy participants 
Assessment of TEAEs, and clinical 
laboratory tests
Abbreviation: AUCinf = area under plasma concentration-time profile from time 0 extrapolated to infinite 
time; AUClast = area under the plasma concentration-time profile from time 0 to the time of the last 
quantifiable concentration (Clast); CL/F = apparent clearance; Cmax, = maximum plasma concentration;
t½ = terminal half-life; TEAE = treatment-emergent adverse event; Tmax = time to Cmax; Vz/F = apparent 
volume of distribution
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Overall Design:
Brief Summary
This is a Phase 1, non-randomized, open-label study in healthy participants to primarily
characterize the PK profile of IN zavegepant from samples collected using Tasso Devices 
(Tasso-Plus, for liquid blood sample collection and Tasso-M20, for dried blood sample 
collection) compared to standard venous phlebotomy. Leveraging these data will establish a 
correlation between the 2 methods and meet regulatory expectations before implementing 
these patient-centric blood collection devices in future studies. This study consists of 2 
periods. 
In period 1, 50% (n=7) of the enrolled participants will use Tasso-Plus, and the other 50% 
(n=7) will use Tasso-M20 to ensure having adequate PK data collected from each device. For 
each participant, PK samples will be collected after zavegepant administration in period 1 
using the assigned Tasso device simultaneously with collecting venous blood samples. In 
addition, taste assessments will be performed at time intervals of 1 (immediately after 
dosing), 5, 10 and 20 minutes after zavegepant IN administration. Also, if feasible, 4 
Japanese participants will be enrolled among those 14 participants to evaluate the PK and 
safety of zavegepant IN in Japanese vs. non-Japanese participants. 
In period 2, a butterscotch candy will be given 5 minutes before administering the 
zavegepant IN study intervention. Taste assessment will also be performed after zavegepant 
IN administration with a butterscotch candy in period 2. For taste assessment, each 
participant will record the sensory attributes at timed intervals of 1 (immediately after 
dosing), 5, 10 and 20 minutes after zavegepant administration in each period.
Screening evaluation will occur within 28 days prior to the study drug administration
(Day 1). Participants will be admitted to the CRU on Day -1 and will remain in the clinical 
research unit (CRU) through completion of procedures on Day 3. Participants will receive a 
10 mg dose of IN zavegepant on Day 1, and a second dose of 10 mg zavegepant IN 24 hours 
after administering the first dose. The PK of zavegepant will be characterized following the 
first dose. A telephone follow-up will be made 28-35 days after the second (last) dose. 
In this study, if more than 2 participants prematurely discontinue for reasons unrelated to the 
safety of the investigational product, participants may be replaced at the discretion of the 
principal investigator (PI) and sponsor study team.
Number of Participants:
Approximately 14 participants will be enrolled in the study. If feasible, 4 Japanese 
participants will be enrolled among those 14 participants.
Note: "Enrolled" means a participant’s, or their legally authorized representative’s, 
agreement to participate in a clinical study following completion of the informed consent 
process and assignment to study intervention. A participant will be considered enrolled if the 
informed consent is not withdrawn prior to participating in any study activity. Potential 
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participants who are screened for the purpose of determining eligibility for the study, but do 
not participate in the study, are not considered enrolled, unless otherwise specified by the 
protocol.
Study Population:
Key inclusion and exclusion criteria are listed below:
Inclusion Criteria 
Participants must meet the following key inclusion criteria to be eligible for enrollment into 
the study:
1. Male or female ≥18 years of age and older at the time of signing the informed consent 
document (ICD).

For Japanese participants to be enrolled, they need to meet the following 
inclusion criteria: Japanese participants must have 4 Japanese grandparents 
who were born in Japan.
2. Male and female participants who are overtly healthy as determined by medical 
evaluation.
3. Body max index (BMI) 16.0-32.0 kg/m2 and body weight ≥45.0 kg (99 lb).
4. Females must not be breastfeeding or lactating and must have a negative urine or 
serum pregnancy test (minimum sensitivity 25 international units per liter [IU/L] or 
equivalent units of human chorionic gonadotropin [HCG]) at screening. 
Woman/women of childbearing potential (WOCBP) must have negative urine or 
serum pregnancy test at admission.
5. Participants are willing to consume a butterscotch candy.
Exclusion Criteria 
Participants with any of the following characteristics/conditions will be excluded:
1. Evidence or history of clinically significant hematological, renal, endocrine, 
pulmonary, gastrointestinal, cardiovascular, hepatic, psychiatric, neurological, or 
allergic disease (including drug allergies, but excluding untreated, asymptomatic, 
seasonal allergies at the time of dosing).
2. Clinically significant history of nasal conditions that may affect the administration or 
absorption of the nasal product (eg, severe septum deviation or nasal deformity, 
inflammation, perforation, mucosal erosion, localized infection or ulceration, 
congestion, polyposis, rhinorrhea, nasal surgery within the previous 6 months, or 
nasal trauma).
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3. Significant history of seizure disorder other than a single childhood febrile seizure 
(eg, epilepsy) or history of gallstone or cholecystectomy. 
4. Any other medical or psychiatric condition, including recent (within the past year) or 
active suicidal ideation/behavior or laboratory abnormality or other conditions or 
situations related to coronavirus disease 2019 (COVID-19) pandemic that may 
increase the risk of study participation or, in the investigator’s judgment, make the 
participant inappropriate for the study.
5. Use of organic anion transporting polypeptide 1B3 (OATP1B3) inhibitors within 
14 days or 5 half-lives, whichever is longer, before first dosing. 
6. Participation in a clinical research study involving the administration of an 
investigational or marketed drug or device within 30 days prior to investigational 
product (IP) dosing, administration of a biological product in the context of a clinical 
research study within 90 days prior to IP dosing, or concomitant participation in an 
investigational study involving no drug or device administration.
7. Any clinically significant abnormal laboratory test results or positive test found 
during medical screening. A single repeat for positive drug screen may be allowed at 
the discretion of the PI.
8. Evidence of organ dysfunction or any clinically significant deviation from normal in 
physical examination or nasal inspection beyond what is consistent with the target 
population.
9. Participants with ANY of the following abnormalities in clinical laboratory tests at 
screening: 

Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) level 
> 1.5 × upper limit of normal (ULN);

Total bilirubin level >1.5 × ULN;

Estimated glomerular filtration rate (eGFR) of <60 mL/min/1.73m².
10. Use of tobacco or nicotine-containing products within 1 month of screening or a
positive urine cotinine test (ie, active smokers and those who currently use 
nicotine-containing products are excluded from participation in this study).
11. Conditions that affect ability to taste eg, dysgeusia, respiratory infection, cold, or 
other conditions as evaluated by the PI.
12. Presence of piercings or any physical findings in the nose that, in the opinion of the 
PI, would likely interfere with the successful completion of the dosing procedure.
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13. Investigator site staff directly involved in the conduct of the study and their family 
members, site staff otherwise supervised by the investigator, and sponsor and sponsor 
delegate employees directly involved in the conduct of the study and their family 
members. 
14. History of alcohol abuse or binge drinking and/or any other illicit drug use or 
dependence within 6 months of Screening. Binge drinking is defined as a pattern of 
5 (male) and 4 (female) or more alcoholic drinks in about 2 hours. As a general rule, 
alcohol intake should not exceed 14 units per week (1 unit = 8 ounces (240 mL) beer, 
1 ounce (30 mL) of 40% spirit, or 3 ounces (90 mL) of wine).
15. Any reason that, in the opinion of the PI, would prevent the participant from 
participating in the study.
Study Arms and Duration:
This study consists of 2 periods. In period 1, eligible participants will receive the first IN 
dose of zavegepant 10 mg via nasal spray. Study staff will administer the IN spray in 
1 nostril to each participant. A total of approximately 14 participants will be enrolled, out of 
which 50% of participants (n=7) will use Tasso-Plus blood collection device, while the other 
50% of participants (n=7), will use Tasso-M20 blood collection device. All 14 participants 
will have 6 PK samples collected using the assigned Tasso device simultaneously with
collecting venous blood samples at the following time points, 30 minutes, 1, 2-, 4-, 8-, and 
12-hour postdose. In addition, taste assessments will be performed at time intervals of 1 
(immediately after dosing), 5, 10 and 20 minutes after zavegepant IN administration. If 
feasible, 4 Japanese participants will be enrolled among those 14 participants to evaluate the 
PK and safety of zavegepant IN in Japanese vs non-Japanese participants. For Japanese 
participants, a total of 12 venous blood samples will be collected at the following time points, 
0, 15 minutes, 30 minutes, 1, 1.5-, 2-, 3-, 4-, 6-, 8-, 12-, and 24-hour.
In period 2, a butterscotch candy will be given 5 minutes before administering the 
zavegepant IN study intervention. As noted earlier, taste assessment will also be performed 
after zavegepant IN administration with a butterscotch candy in period 2. For taste 
assessment, each participant will record the sensory attributes at timed intervals of 
1 (immediately after dosing), 5, 10 and 20 minutes after zavegepant administration in each 
period.
Study Intervention
Intervention Name
Zavegepant
Use
Experimental
IMP or NIMP/AxMP
IMP
Dose Formulation
Nasal spray
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Study Intervention
Unit Dose Strength(s)
10 mg
Route of Administration
IN
Abbreviation: AxMP = auxiliary medicinal product; IMP = investigational medicinal product; 
IN = intranasal; NIMP = noninvestigational medicinal product
Study Arm(s)
Arm Title
Zavegepant
Arm Description
All participants will receive zavegepant 10 mg IN 
spray in period 1 and a butterscotch candy + 
zavegepant 10 mg IN spray in period 2
Abbreviation: IN = intranasal
Statistical Methods:
There is no statistical hypothesis for this study. Approximately 14 evaluable participants will 
be enrolled in this study. The sample size determined for this study was based on the 
established scientific recommendation for having 30 to 40 PK data points at minimum from 
each method to ensure the adequate comparison between PCS (test) and venous sampling
(reference). A sample size of 7 evaluable participants per cohort, with 6 Tasso-venous paired 
PK samples to be collected from each participant (7 × 6 = 42 data points) will be sufficient to 
meet the scientific community recommendation for having an adequate Tasso-venous plasma 
PK bridging study.
For summary statistics by sampling time, the nominal PK sampling time will be used. For
individual participant plots by time, the actual PK sampling time will be used. Actual PK 
sampling times will also be used in the derivation of PK parameters. PK parameters will be 
estimated using non-compartmental analysis. Box and whisker plots for individual 
participant parameters (area under plasma concentration-time profile from time 0 
extrapolated to infinite time [AUCinf], area under the plasma concentration-time profile from 
time 0 to the time of the last quantifiable concentration [AUClast], and maximum plasma 
concentration [Cmax]) will be constructed for each of the Tasso devices used (Tasso-Plus and 
Tasso-M20), by blood collection method, and overlaid with geometric means. For the taste 
assessment, the data used in the analysis will be transcribed and rescaled to a score from 0 to 
100 from the raw measurements on the questionnaire. The sensory attributes (overall liking, 
bitterness, tongue/mouth burn, throat burn, sour taste, salty taste, and sweet taste) from the 
taste questionnaires will be listed and descriptively summarized by study intervention in each 
period, with the main difference being the use of butterscotch in period 2.
Ethical Considerations:
All study intervention risks are communicated through the Investigator’s Brochure (IB). 
Based on the totality of available clinical and nonclinical data and taking into account the 
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measures to monitor and minimize risk to study participants, the overall benefit/risk profile 
supports the clinical investigation of zavegepant 10 mg IN administration in healthy adults. 
There is no anticipated therapeutic benefit for the healthy participants in this study. 
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1.2. Schema
Not applicable.
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1.3. Schedule of Activities
The SoA table provides an overview of the protocol visits and procedures. Refer to the STUDY ASSESSMENTS AND 
PROCEDURES section of the protocol for detailed information on each procedure and assessment required for compliance with the 
protocol. 
The investigator may schedule visits (unplanned visits) in addition to those listed in the SoA table, in order to conduct evaluations or 
assessments required to protect the well-being of the participant.
Table 1.
Study Schedule of Assessment
Visit Identifier
Abbreviations used in this table 
may be found in Appendix 12.
Screen
Period 1
Period 2
Telephone
F/U
Early 
Discontinuation
Notes
Days Relative to Day 1
Day -
28 to 
Day -2
Day -
1
Day 1
Day 2
Day 3
Day 30-37

All screening should be done ≤28 days before the first dose. 

Day relative to start of study intervention (Day 1).

Follow-up may occur via telephone contact and must occur 28-35
days after administration of the final dose of study intervention. 
Days within each period
Day -
1
Day 1
Day 1
Day 2
Informed consent
X

Informed consent should be obtained prior to undergoing any 
study-specific procedures. 

See Section 10.1.3 for additional information.
CRU confinement 
X


X
Inclusion/exclusion criteria
X
X

See Section 5.1 and Section 5.2.
Demography (including height 
and body weight)
X

See Section 8.3.1.
Medical/medication history 
X
X

Medication history will be updated at each visit.
Review 
alcohol/caffeine/tobacco
X
X
Physical exam
X
X

A full physical examination may be done at screening or Day -1; 
otherwise, brief physical exam is envisioned for findings during 
previous PE or new/open AEs, at the investigator's discretion.
Nasal inspection
X
X
X
X

The nasal passages and turbinates will be visually inspected with a 
nasal speculum and light on Day -1 (to exclude participants with 
mucosal erythema, congestion, septal defects etc.), and 24 h 
(± 30 min) postdose to detect evidence of nasal inflammation or 
edema. 
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Table 1.
Study Schedule of Assessment
Visit Identifier
Abbreviations used in this table 
may be found in Appendix 12.
Screen
Period 1
Period 2
Telephone
F/U
Early 
Discontinuation
Notes
Days Relative to Day 1
Day -
28 to 
Day -2
Day -
1
Day 1
Day 2
Day 3
Day 30-37

All screening should be done ≤28 days before the first dose. 

Day relative to start of study intervention (Day 1).

Follow-up may occur via telephone contact and must occur 28-35
days after administration of the final dose of study intervention. 
Days within each period
Day -
1
Day 1
Day 1
Day 2
Taste Assessment 
Questionnaire
X
X

Review taste questionnaire and instructions with participants prior to 
the first taste assessment on Period 1, Day 1. Each participant will 
record the sensory attributes at timed intervals of 1 (immediately 
after dosing), 5, 10 and 20 min after administering the study 
intervention, using a Taste Assessment Questionnaire (see 
Appendix 11).
Butterscotch candy
X

A butterscotch candy is to be given to the participants 5 min prior to 
the administering of 10 mg zavegepant IN on Period 2.

Participants will be instructed not to chew or crush the candy but 
allow it to dissolve over time.
Vital signs (BP and Pulse Rate)
X

Supine BP and pulse rate will be performed at screening. 
Single 12-Lead ECG
X

Supine ECGs will be performed at screening.
Safety laboratory
X
X
X
X

Screening, Day -1, and 24 h (± 30 min) after the first dose. See 
Appendix 2 for safety laboratory tests in the study.

For period 2, day 1, safety lab samples will be collected prior to 
dosing.

Participants should fast for at least 4 hours before blood samples for 
safety labs are drawn.
Pregnancy test (WOCBP only)
X
X
X
X

Serum or urine β-hCG for female participants of childbearing 
potential.
Contraception check 
X
X
X
X
FSH
X

For confirmation of postmenopausal status only. See Section 10.4.3
for the definition of postmenopausal. 
Alcohol breath, urine drug 
screening and urine cotinine
testing
X
X

Alcohol breath test will be performed at the discretion of the 
investigator.

Urine cotinine (mandatory) will be performed at Screening, and on 
Period 1 Day -1. This test may be performed at any other time at the 
discretion of the investigator.
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Table 1.
Study Schedule of Assessment
Visit Identifier
Abbreviations used in this table 
may be found in Appendix 12.
Screen
Period 1
Period 2
Telephone
F/U
Early 
Discontinuation
Notes
Days Relative to Day 1
Day -
28 to 
Day -2
Day -
1
Day 1
Day 2
Day 3
Day 30-37

All screening should be done ≤28 days before the first dose. 

Day relative to start of study intervention (Day 1).

Follow-up may occur via telephone contact and must occur 28-35
days after administration of the final dose of study intervention. 
Days within each period
Day -
1
Day 1
Day 1
Day 2
HIV, HBsAg, HBsAb,
HBcAb, HCVAb
X

HBsAb is to be run if HBsAg and/or HBcAb are positive.
Retained Research Sample for 
Genetics (Prep D1)
X
Study intervention 
administration
X
X
PK blood sampling
X
X
X

See Table 2 for details.

Period 2 Day 1 PK sample will be 24 hr post dosing in Period 1 
Day 1. Sample will be collected for Japanese participants only.
CRU discharge 
X

Discharge from CRU after completing protocol-required activities on 
the day.
Serious and nonserious AE 
monitoring
X



X
X
X

See Section 8.4.3 for follow-up AE and SAE assessments.
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Table 2.
Pharmacokinetic Sampling Timepoints
Visit Identifier 
Notes
Study Day
Day 1
Day 2
Hour 0 = Predose sample collection
The predose blood draw will be taken within 1 h before 
dosing. 
See Section 8.5 for details of PK sample collection.
Days within each period
Period 1, Day 1
Period 2, 
Day 1
Time Before/After Dose
0 h
0.25 h
0.5 h 
1 h
1.5 h
2 h
3 h
4 h
6 h
8 h
12 h
24 h
Study intervention
administration
X
Venous PK sampling 
Xb
Xb
X
X
Xb
X
Xb
X
Xb
X
X
Xb
Tasso PK samplinga
X
X
X
X
X
X
Blood: plasma ratio
X
X
a. Tasso PK sampling will be performed using either Tasso-Plus or Tasso-M20 device.
b. To be collected for Japanese participants only.
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2. INTRODUCTION
Zavegepant (PF-07930207; formerly BHV-3500) is a selective, high-affinity, small molecule 
CGRP receptor antagonist that was approved by the FDA on March 9, 2023, for the acute 
treatment of migraine with or without aura in adults via IN administration.1 Zavegepant
10 mg nasal spray offers a novel IN CGRP receptor antagonist therapy for the acute 
treatment of migraine with the potential to address important unmet medical needs in the 
migraine patient population. IN zavegepant provides rapid onset, durable efficacy without the 
risk of medication overuse headache and without contraindications or warnings regarding use 
by patients with cardiovascular disease.
CGRP is an endogenous 37 amino acid peptide contained within pain-signaling nociceptive
afferents and is thought to play a causal role in migraine.2,3 Multiple lines of clinical evidence
point to a role for CGRP in migraine pathophysiology: 1) serum levels of CGRP are elevated
during migraine;4 2) treatment with anti-migraine drugs returns CGRP levels to normal
coincident with pain relief;5 and 3) IV CGRP infusion produces lasting pain in non-
migraineurs and migraineurs.3,6
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 (which leads to peripheral
and central sensitization); and/or 3) inhibiting the central relay of pain signals from the
trigeminal nerve to the caudal trigeminal nucleus.2,7
2.1. Study Rationale 
As a component of zavegepant clinical development, future pediatric studies will be 
conducted to evaluate the safety, tolerability, and PK of zavegepant in participants 6 to less 
than 12 years of age with migraine. Recruiting and retaining pediatric patients in clinical 
trials has always been challenging due to a variety of factors, including inconvenience with 
patient preferences. To overcome some of those challenges, it is essential to prioritize 
patient-centric approaches that cater to the unique needs of pediatric patients. One such 
approach is PCS, which aims to reduce the burden on pediatric patients by minimizing the 
volume of the biological samples required and being less invasive with minimal pain 
compared to the venous phlebotomy collection method, which is particularly beneficial for 
pediatrics who are fearful of needles. Additionally, PCS offers greater flexibility to pediatric 
patients and their families by allowing at-home sample collection for those who may have 
difficulty traveling to clinics.
To allow the use of PCS in zavegepant pediatric studies, a bridging or comparative study 
comparing the PCS approach with an equivalent conventional sampling technique is needed 
as a regulatory expectation to demonstrate the concordance of data from PCS in a controlled 
environment prior to implementation in large‐scale clinical trials. Therefore, the primary 
objective of this study is to establish the correlation between zavegepant concentration from 
samples collected using PCS devices compared to conventional venous blood sampling. In 
addition, if feasible, this study will also determine the PK and safety of zavegepant IN in 
Japanese participants.
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Lastly, based on data from zavegepant IN clinical trials, dysgeusia (bad/metallic/bitter taste) 
has been reported as the most common treatment-emergent adverse event with zavegepant.
For instance, in a Phase 2/3, double-blind, randomized, placebo-controlled study 
(BHV3500-2018,9), dysgeusia was reported as the most common TEAEs with zavegepant 
10 and 20 mg IN and placebo (13.5% to 16.1% vs 3.5%, respectively). Similarly, results 
from a Phase 3 study of zavegepant IN administration for the treatment of acute migraine 
BHV3500-30110 have reported dysgeusia as the most common TEAEs after zavegepant 
10 mg IN administration with an incidence rate of 20.5% vs 4.7% in placebo. Because of this 
adverse event, patients may not adhere to their medications which may limit the effectiveness 
of treatment with zavegepant. Therefore, understanding this adverse event (eg, time-course, 
description of the taste sensation) and potential strategies to mask the unpleasant taste could
help improve patient experience and adherence. As an exploratory objective, this study will 
evaluate palatability attributes of zavegepant and whether eating a butterscotch candy before 
zavegepant IN administration will help manage dysgeusia.
2.2. Background 
Migraine is a chronic neurological condition characterized by attacks of headache that 
usually feature unilateral, throbbing pain accompanied by nausea or sensitivity to light and 
sound.11 Migraine affects about 1.04 billion people globally,12 approximately three-quarters 
of whom are women. During migraine attacks, most people have functional impairments, 
often leading to absence from or reduced productivity at work or school and limiting 
participation in family, social, and leisure activities.13 Migraine-related disability extends to 
periods between attacks14 and can include physical symptoms (gastroparesis), which can 
slow absorption of oral drugs, and psychological symptoms (anger, anxiety, depression, 
hopelessness15). Persistent stigma about migraine16 leads many people to understate or 
under-report the negative effects of migraine and to avoid discussing their condition.14
The use of medication for the acute treatment of migraine attacks is ubiquitous.17,18 For the 
past 30 years, serotonin receptor agonists (ie, triptans) have been the most widely prescribed 
class of acute antimigraine medication. All 7 drugs in the triptan class are available for oral 
administration; two (sumatriptan and zolmitriptan) are available as nasal sprays and only 
sumatriptan is available for parenteral or rectal administration. Some non-oral therapies have 
shorter Tmax than oral therapies;19 shorter Tmax values might be associated with a more rapid 
onset of treatment effects.20 The recommendation for the use of non-oral triptans is based on 
favorable pharmacokinetic profiles,19,20 a small set of comparative studies indicating that, for 
some agents, nasal formulations outperform tablets,21,22 and clinical practice experience.23
Oral triptans provide a pain-free response in 20%–40% of patients with migraine and 
consistent benefits in 39%–79%.18,24,25,26 Yet recurrence rates range from 20% to 40% of 
patients with migraine, and clinical use is limited by cardiovascular contraindications and 
precautions, which are most common among men older than 40 years and postmenopausal 
women.18,24,25,26 Additionally, medication overuse is a recognized risk that can result in 
medication-overuse headache and the transformation of episodic migraine into chronic 
migraine.25
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Although alternatives to oral triptans have long been available, the findings that CGRP is a 
key element of migraine pathophysiology27,28,29 have resulted in the development of highly 
specific, safe,30 and effective31 medications for acute treatment. Two small-molecule CGRP 
receptor antagonists (gepants) have received regulatory approval for the acute treatment of 
migraine in the USA: rimegepant, an orally disintegrating tablet, and ubrogepant, an oral 
tablet. Rimegepant has also been approved for the acute treatment of migraine in the EU and 
the UK. This new class of agents attempts to address the limitations of acute treatment with 
traditional migraine medications, but neither drug is available in a non-oral formulation. 
Zavegepant nasal spray is the first non-oral gepant approved for the acute treatment of 
migraine.1 The clinical pharmacology of zavegepant has been well characterized in a 
comprehensive program based on 10 Phase 1 studies.32 Efficacy and safety were determined 
in 2 positive pivotal trials assessing IN administration of zavegepant for 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 IN zavegepant for the acute treatment of migraine.33
2.2.1. Nonclinical Overview
A summary of the nonclinical investigational programs can be found in the current
IB.
2.2.2. Clinical Overview
2.2.2.1. Safety Overview
In clinical studies, approximately 2,700 participants have been administered zavegepant IN, 
and approximately 606 participants have been administered oral zavegepant. Administration 
of zavegepant was well tolerated at 5 mg, 10 mg, and 20 mg as a single IN spray in 1,185 
adult participants with migraine (BHV3500-2018,9). A similar safety profile was observed in 
the 629 adult participants administered a single dose of zavegepant 10 mg IN for the acute 
treatment of migraine (BHV3500-30110).
Zavegepant, 10 mg IN, was well tolerated in a completed long-term safety study (up to 
8 doses per month) in 603 adult participants with migraine for up to 52 weeks 
(BHV3500-20234). The most frequently occurring adverse events in clinical studies to date 
have been associated primarily with IN administration (eg, dysgeusia, throat irritation, nasal 
congestion, nasal discomfort), as well as nausea and back pain, and the majority have been of 
mild to moderate intensity.
2.2.2.2. Efficacy Overview
In a Phase 2/3, double-blind, randomized, placebo-controlled, dose-ranging study of 
zavegepant (5 mg, 10 mg, or 20 mg) IN for the acute treatment of migraine, zavegepant 
doses of 10 mg and 20 mg via IN administration demonstrated statistically significant 
efficacy on both coprimary endpoints of freedom from pain at 2 hours postdose and freedom 
from MBS at 2 hours postdose.
A Phase 3 study of zavegepant IN administration for the treatment of acute migraine
BHV3500-30110) demonstrated statistically significant efficacy for both coprimary endpoints 
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as well as for 13 of the 17 secondary endpoints, including significant evidence of ultrarapid 
onset and durability of response.
A Phase 2/3 study of oral zavegepant in the preventive treatment of migraine 
(BHV3500-302) is currently ongoing.
2.2.2.3. Clinical Pharmacology
Based on the completed clinical studies of IN and PO zavegepant, the following observations 
were made regarding the zavegepant PK properties. Zavegepant is rapidly absorbed (Tmax: 
0.54 hours) following a single zavegepant 10 mg IN dose. The terminal elimination half-life 
of zavegepant 10 mg IN dose is approximately 3 hours.35 While the effective half-life of 
zavegepant, which is considered more clinically relevant than the elimination half-life as it 
takes into account the entire plasma concentration-time profile, ranged from approximately 5 
to 8 hours across dose levels ranging from 5 to 40 mg IN. Zavegepant exhibits less than dose-
proportional increases in exposure following single IN dose administration over the dose 
range from 1 mg to 40 mg. No evidence of meaningful accumulation was observed across a 
dose range of 5 to 20 mg zavegepant IN after repeated QD dosing. 
The results of the DDI study showed that co-administration of sumatriptan with zavegepant
IN does not result in a meaningful change in the PK of sumatriptan or of zavegepant. 
Co-administration of sumatriptan with zavegepant IN does not cause elevations in mean 
arterial blood pressure or of systolic or diastolic blood pressure greater than those observed 
with sumatriptan alone. Lack of a clinically significant effect on the exposures of EE and 
LNG following co-administration of zavegepant 20 mg IN and oral contraceptive support 
that zavegepant is not a clinically relevant inhibitor of CYP3A4. Zavegepant may be 
administered with an oral contraceptive without dose frequency adjustment. A 16% increase 
in the Cmax and a 1.9-fold increase in zavegepant AUC were observed in participants with 
moderate hepatic impairment.
Co-administration of itraconazole (strong CYP3A4 inhibitor and P-gp inhibitor) with IN
zavegepant showed no clinically relevant changes in the exposure of zavegepant. However, 
co-administration of itraconazole with a single dose of zavegepant oral soft gelatin capsule 
50 mg increased the AUC and Cmax of oral zavegepant by approximately 59% and 77%, 
respectively, suggesting that the increase is likely due to P-gp inhibition of zavegepant efflux 
transport by itraconazole in the gastrointestinal tract. In addition, coadministration of 
rifampin, a strong CYP3A inducer and an inhibitor of OATP1B3 and NTCP transporters with 
oral zavegepant 100 mg, showed an increase in zavegepant AUC by 2.3-fold and Cmax by
2.2-fold in the presence of rifampin, suggesting that drugs that inhibit the OATP1B3 or 
NTCP transporters could increase the exposure of zavegepant. Therefore, concomitant 
administration of zavegepant with inhibitors of OATP1B3 or NTCP transporters should be 
avoided. Furthermore, it is unlikely that induction of CYP3A would substantially impact 
zavegepant exposure when zavegepant is administered either IN or oral. The 10 mg IN 
zavegepant exposures were approximately 17% lower for Cmax and 10% lower for AUCinf 
during a migraine attack than in the non-migraine period; however, the decrease in exposure 
in the migraine state is not clinically meaningful. There was no clinically relevant 
prolongation of the QTc interval by zavegepant.
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2.3. Benefit/Risk Assessment
The safety and tolerability of zavegepant doses greater than 10 mg IN were explored in early 
clinical development, including single doses of 0.1 mg through 40 mg and daily multiple 
doses up to 2 weeks ranging from 5 to 40 mg (refer to IB). Across these single and multiple 
dose ranges, zavegepant was found to be generally safe and well tolerated.
The inclusion and exclusion criteria of this study have been chosen to select participants who 
are known to be free from any significant illness, history of autoimmune diseases, and 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 
the potential risks of zavegepant administration. There is no anticipated therapeutic benefit 
for the healthy participants in this study. 
More detailed information about the known and expected benefits and risks and reasonably 
expected AEs of zavegepant may be found in the USPI1 which is the SRSD for this study. 
Refer to the Study Intervention(s) table in Section 6.1 for a complete description of SRSDs.
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2.3.1. Risk Assessment
Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
Study Intervention Zavegepant
Hypersensitivity reactions
Hypersensitivity reactions including facial swelling 
and urticaria have occurred with zavegepant.
Site staff and participants are instructed 
throughout protocol and ICD to immediately 
report all AEs post-dosing for further 
management instructions.  
AEs associated with IN administration, such as 
dysgeusia, throat irritation, nasal congestion and 
nasal discomfort.
The potential risks are based on AEs reported in 
studies of zavegepant IN administration, and the 
majority have been of mild to moderate intensity.
Eligibility criteria have been selected to ensure 
that only appropriate participants are included in 
the study (see Section 5.1). Nasal inspection will 
be conducted on Day -1 (to exclude participants 
with mucosal erythema, congestion, septal 
defects etc), and 24 h (± 30 min) postdose per the 
SoA. AEs and clinical laboratory results will be 
monitored on an ongoing basis.
Study Procedures 
The study intervention will be administered 
intranasally via a liquid spray device.
The IN administration could be affected by some 
human and operational factors, such as the way of 
handling the devices and the way of inhalation and 
exhalation. These may lead to higher variabilities in 
PK data.
Enhanced site training and participant education 
in terms of the study intervention administration.
For all the study participants, all attempts would 
be made for study intervention administration 
performed by no more than 3 study staff 
members to minimize variability in device 
handling.
Relatively intensive PK sampling and narrow 
time window within 1 hour post dose.
Risk of PK sample collection outside the required 
time window might be higher.
Enhance site communication and training. Actual 
PK sampling times will be used in the derivation
of PK parameters.
Other 
Atypical PK sampling methodology (Tasso 
devices)
Risk of improper collection procedure that could 
lead to compromised sample(s)
Enhanced site communication and training on 
Tasso device collection and handling procedures
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2.3.2. Benefit Assessment
Zavegepant is not expected to provide any clinical benefit to healthy participants. This study 
is designed primarily to generate pharmacokinetic, safety, and tolerability data in healthy 
adults. As noted earlier, data from this study will be used to support the future clinical 
development of zavegepant in pediatrics.
2.3.3. Overall Benefit/Risk Conclusion
Considering all available nonclinical and clinical data regarding the reassuring safety and 
tolerability of zavegepant to date and measures to monitor and minimize risk to study 
participants in this study, the overall benefit/risk profile supports the further clinical 
development of zavegepant in healthy adults.
3. OBJECTIVES AND ENDPOINTS
Objectives
Endpoints
Primary: 
Primary: 
Characterize the PK profile of 
zavegepant from samples collected using 
Tasso Devices (Tasso-Plus and Tasso-
M20) vs. standard venous phlebotomy 
following IN administration of 10 mg of 
zavegepant IN formulation in healthy 
participants
Zavegepant concentrations from samples 
collected using Tasso devices vs. standard 
venous phlebotomy
PK parameters: AUCinf (if data permit), 
AUClast, Cmax, Tmax, t½, CL/F and Vz/F, as 
data permits
Secondary: 
Secondary:
Evaluate the safety and tolerability 
following IN administration of 10 mg of 
zavegepant IN formulation in healthy 
participants
Assessment of TEAEs, and clinical safety 
laboratory tests
Tertiary/Exploratory:
Tertiary/Exploratory:
Evaluate the effect of the administration 
of 10 mg of zavegepant IN with a 
butterscotch candy on dysgeusia 
compared to zavegepant IN alone
Taste Assessment Survey Scoring Metrics 
after study intervention: overall liking, 
bitterness, tongue/mouth burn, throat burn, 
sour taste, salty taste, and sweet taste
4. STUDY DESIGN
4.1. Overall Design
This is a single-center, Phase 1, non-randomized, open-label, 2-period study in healthy 
participants to primarily evaluate the correlation of zavegepant concentration from samples 
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collected using Tasso Devices (Tasso-Plus and Tasso-M20) compared to standard venous 
phlebotomy. This study consists of two periods which will include approximately 
14 participants. 
In period 1, 50% (n=7) of participants will use Tasso-Plus, while the other 50% (n=7) will 
use Tasso-M20. All 14 participants will have 6 PK samples collected using the assigned 
Tasso device simultaneously with collecting venous blood samples at the following time 
points, 30 minutes, 1, 2-, 4-, 8-, and 12-hour postdose, as described in the SoA, Table 2. In 
addition, taste assessments will be performed at time intervals of 1 (immediately after 
dosing), 5, 10 and 20 minutes after zavegepant IN administration. Also, if feasible, 
4 Japanese participants will be enrolled among those 14 participants to evaluate the PK and 
safety of zavegepant IN in Japanese vs. non-Japanese participants. For Japanese participants, 
a total of 12 venous blood samples will be collected at the following time points, 0, 
15 minutes, 30 minutes, 1, 1.5-, 2-, 3-, 4-, 6-, 8-, 12-, and 24-hour (refer to SoA, Table 2).
In period 2, a butterscotch candy will be given 5 minutes before administering the 
zavegepant IN study intervention. Taste assessment will also be performed after zavegepant 
IN administration with a butterscotch candy in period 2. For taste assessment, each 
participant will record the sensory attributes at timed intervals of 1 (immediately after 
dosing), 5, 10 and 20 minutes after zavegepant administration in each period.
Healthy participants will be screened within 28 days prior to the first administration of the 
study intervention to confirm that they meet the participant selection criteria for the study. 
Eligible participants will be admitted to the CRU on Day -1 and will be confined in the CRU 
until Discharge on Day 3 (SoA), approximately 24 hours after the second dose. Enrolled 
participants will receive a single IN dose of zavegepant 10 mg (0.1 mL) in each period. PK 
venous blood samples as well as Tasso PK sampling, using Tasso-Plus and Tasso-M20, will 
be collected at specified intervals as per SoA (Table 2) for PK assessments. 
The primary analysis will occur when all participants have PK samples collected. The 
expected duration of participation from screening until follow-up telephone contact is 
approximately 9 weeks.
4.2. Scientific Rationale for Study Design
As a component of the clinical development of zavegepant, future pediatric studies will be 
conducted to evaluate the safety, tolerability, and PK of zavegepant in participants 6 to less 
than 12 years of age with migraine. Recruiting and retaining pediatric patients in clinical 
trials has always been challenging due to a variety of factors, including inconvenience with 
patient preferences. To overcome some of those challenges, it is essential to prioritize 
patient-centric approaches that cater to the unique needs of pediatric patients. One such 
approach is PCS, which aims to reduce the burden on pediatric patients by minimizing the 
volume of the biological samples required and being less invasive with minimal pain 
compared to the venous phlebotomy collection method, which is particularly beneficial for 
pediatrics who are fearful of needles. Additionally, PCS offers greater flexibility to pediatric 
patients and their families by allowing at-home sample collection for those who may have 
difficulty traveling to clinics.
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To allow the use of PCS in zavegepant pediatric studies, a bridging or comparative study 
comparing the PCS approach with an equivalent conventional sampling technique is needed 
as a regulatory expectation to demonstrate the concordance of data from PCS in a controlled 
environment prior to implementation in large‐scale clinical trials.36 Therefore, the primary 
objective of this study is to establish the correlation between zavegepant concentration from 
samples collected using PCS devices compared to conventional venous blood sampling. PK 
sampling time points and duration, as described in SoA, Table 2, were selected to adequately 
capture the rapid absorption of zavegepant, since it has a Tmax of 0.54 hours, as well as 
zavegepant elimination phase. Based on zavegepant PK data, zavegepant has an elimination 
half-life of ~ 3 hours and an effective half-life of 6.55 hours following a single zavegepant 
10 mg IN dose. For Tasso bridging analysis, having PK samples that covers zavegepant 
relevant concentration up to 12 hours will be sufficient to have adequate concentration-time 
comparison between the 2 methods. While for the Japanese participants, having PK 
timepoints up to 24 hours will cover >3 half-lives, which will be sufficient to adequately 
estimate zavegepant half-life in Japanese. That’s why 24 hours PK samples will only be 
requested for Japanese enrolled participants, as described in SoA, Table 2.
A healthy participant population is considered for the study because healthy participants 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. Six PK samples will be collected from the Tasso devices at the same 
time of collecting venous blood samples, as described in the SoA, Table 2. Those 
6 Tasso-venous paired samples collected in 7 participants for each device (7 × 6 = 42 data 
points) are sufficient to meet the scientific community recommendation for having an 
adequate Tasso-venous phlebotomy PK bridging study.36 Different PK sampling times were 
selected to cover the concentration-time profile of zavegepant IN. Of note, blood-to-plasma 
ratio samples will be aliquoted from the same venous blood draw as specified in the SoA, 
Table 2. These samples will be crucial for determining the blood-to-plasma ratio value for 
each participant to convert the dried blood concentrations collected using Tasso-M20 to their 
equivalent plasma concentrations for adequate comparison between the 2 methods. 
If feasible, 4 Japanese participants will be enrolled among the 14 participants planned for this 
study to determine the PK and safety of zavegepant IN in this population since there is no PK 
and safety data available for the use of zavegepant IN in this population. Leveraging this data 
will be useful in supporting the development of zavegepant IN in Japan. However, the 
recruitment of these Japanese participants will be optional, and the completion of this trial 
will not require their enrollment.
As noted earlier, data from clinical trials of zavegepant IN formulation have shown dysgeusia 
(bad/metallic/bitter taste) as the most common treatment-emergent adverse event following 
zavegepant administration (refer to IB). We hypothesize that the mechanism of dysgeusia 
associated with zavegepant nasal spray administration relates to the postnasal dripping of 
residual spray into the oral cavity and contact with the posterior tongue and taste buds, 
triggering the taste receptor cells. To test this hypothesis and better understand this adverse 
event (its intensity, onset, and duration), a taste assessment questionnaire will be performed 
at 1 (immediately after dosing), 5, 10 and 20 minutes after zavegepant IN administration.
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Previous case studies have shown that simple interventions like sucking butterscotch or 
drinking a fruit punch–flavored powdered drink have successfully managed dysgeusia 
following the use of sumatriptan or esketamine nasal sprays, respectively.37,38 Therefore,
finding strategies to mask zavegepant-induced bitter taste can help improve patient 
experience and adherence. As an exploratory objective, this study will explore whether 
giving a butterscotch candy before zavegepant IN administration will help manage dysgeusia.
To do that, a second dose of 10 mg zavegepant IN will be administered 24 hours after the 
first dose. Participants will be instructed to eat a butterscotch candy approximately 5 minutes 
prior to zavegepant IN administration in period 2. Taste assessments will be compared for the 
14 subjects after zavegepant administration alone in period 1 vs. zavegepant and butterscotch 
candy in period 2. Administering a second dose of 10 mg zavegepant IN 24 hours after the 
first dose is well-supported by zavegepant IN clinical trials data which shows no
dose-limiting AEs after administering single doses as high as 40 mg IN and multiple doses of 
20 mg for up to 14 days (refer to IB).
4.2.1. Choice of Contraception/Barrier Requirements 
Human reproductive safety data is not available for zavegepant, but no evidence of embryo 
lethality and teratogenicity was found in animal embryofetal development studies in rats and 
rabbits with zavegepant (refer to IB). Therefore, the use of a highly effective method of 
contraception is required (see Appendix 4). 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. Only male and non-pregnant/non-lactating female participants 
will be included in the study.
4.3. Justification for Dose
The 10 mg IN dose of zavegepant was selected as the optimal therapeutic dose for the acute 
treatment of migraine as it provided efficacy with minimized systemic exposure of 
zavegepant. Based on that, this dose was the approved dose by the FDA for the acute 
treatment of migraine. Therefore, the exposure achieved following 10 mg zavegepant IN is 
the most relevant for this study and for future pediatric studies. Overall, the data
demonstrated that IN zavegepant 10 mg is effective for the acute treatment of migraine.
4.4. End of Study Definition
The end of the study is defined as the date of the last visit of the last scheduled procedure 
shown in the SoA for the last participant in the trial.
A participant is considered to have completed the study if they have completed all periods of 
the study, including the last visit.
5. STUDY POPULATION
This study can fulfill its objectives only if appropriate participants are enrolled, including 
participants across diverse and representative racial and ethnic backgrounds. If a 
prescreening tool is utilized for study recruitment purposes, it will include collection of 
information that reflects the enrollment of a diverse participant population, including, where 
permitted under local regulations, age, sex, race, and ethnicity. The following eligibility 
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criteria are designed to select participants for whom participation in the study is considered 
appropriate. All relevant medical and nonmedical conditions should be taken into 
consideration when deciding whether a particular participant is suitable for this protocol.
Prospective approval of protocol deviations to recruitment and enrollment criteria, also 
known as protocol waivers or exemptions, is not permitted.
5.1. Inclusion Criteria
Participants are eligible to be included in the study only if all of the following criteria apply:
Age and Sex:
1. Male or female ≥18 years of age and older at the time of signing the ICD.

Refer to Appendix 4 for reproductive criteria for male (Section 10.4.1) and female 
(Section 10.4.2) participants.

For Japanese participants to be enrolled, they need to meet the following inclusion 
criteria: Japanese participants must have 4 Japanese grandparents who were born 
in Japan.
Other Inclusion Criteria: 
2. Male and female participants who are overtly healthy as defined by:

the absence of clinically significant illness and surgery within 4 weeks prior to 
dosing. Participants vomiting within 24 hours Predose will be carefully evaluated 
for upcoming illness/disease.

the absence of clinically significant history of neurological, endocrinal, 
cardiovascular, pulmonary, hematological (eg, neutropenia), immunologic, 
psychiatric, gastrointestinal, renal, hepatic, and metabolic disease. 
3. BMI 16.0-32.0 kg/m2 and body weight ≥45.0 kg (99 lb).
4. Females must not be breastfeeding or lactating and must have a negative urine or serum 
pregnancy test (minimum sensitivity 25 IU/L or equivalent units of HCG) at screening. 
WOCBP must have negative urine or serum pregnancy test at admission.
5. Participants are willing to consume a butterscotch candy.
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5.2. Exclusion Criteria
Participants are excluded from the study if any of the following criteria apply:
Medical Conditions:
1. Evidence or history of clinically significant hematological, renal, endocrine, 
pulmonary, gastrointestinal, cardiovascular, hepatic, psychiatric, neurological, or 
allergic disease (including drug allergies, but excluding untreated, asymptomatic, 
seasonal allergies at the time of dosing).

Current diagnosis of viral hepatitis or a history of liver disease.

History of HIV infection, hepatitis B, or hepatitis C; positive testing for HIV,
HBsAg, HBsAb, HBcAb, or HCVAb. Hepatitis B vaccination is allowed.
2. Clinically significant history of nasal conditions that may affect the administration or 
absorption of the nasal product (eg, severe septum deviation or nasal deformity, 
inflammation, perforation, mucosal erosion, localized infection or ulceration, 
congestion, polyposis, rhinorrhea, nasal surgery within the previous 6 months, or nasal 
trauma). 
3. Significant history of seizure disorder other than a single childhood febrile seizure (eg, 
epilepsy) or history of gallstone or cholecystectomy. 
4. Any other medical or psychiatric condition, including recent (within the past year) or 
active suicidal ideation/behavior or laboratory abnormality or other conditions or 
situations related to COVID-19 pandemic that may increase the risk of study 
participation or, in the investigator’s judgment, make the participant inappropriate for 
the study. 
Prior/Concomitant Therapy:
5. Refer to Section 6.9 Prior and Concomitant Therapy. Any of the products taken during 
the timeframe specified below will be reviewed and evaluated by the principal 
investigator to determine participant’s eligibility:

Use of OATP1B3 inhibitors (refer to Appendix 10), within 14 days or 
5 half-lives (whichever is longer) prior to the first dosing;

Prescription medication within 14 days prior to the first dosing (hormonal
contraception allowed);

OTC products within 7 days prior to the first dosing;

Oxymetazoline (or other nasal spray decongestants) from at least 14 days 
prior to the first dosing until after the last PK blood sample collection of the 
study;
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
A depot injection or an implant of any drug (other than hormonal 
contraceptives) within 3 months prior to the first dosing;

Natural health products (including herbal remedies such 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) within 7 days prior to the 
first dosing until after the last PK blood sample collection of the study; with 
the exception of the occasional use of ibuprofen.
Prior/Concurrent Clinical Study Experience:
6. Participation in a clinical research study involving the administration of an 
investigational or marketed drug or device within 30 days prior to IP dosing, 
administration of a biological product in the context of a clinical research study within 
90 days prior to IP dosing, or concomitant participation in an investigational study 
involving no drug or device administration.
Diagnostic Assessments:
7. Any clinically significant abnormal laboratory test results or positive test found during 
medical screening. A single repeat for positive drug screen may be allowed at the 
discretion of the PI.
8. Evidence of organ dysfunction or any clinically significant deviation from normal in 
physical examination or nasal inspection beyond what is consistent with the target 
population.
9. Screening supine BP ≥140 mm Hg (systolic) or ≥90 mm Hg (diastolic) for participants 
<60 years; and ≥150/90 mm/Hg for participants ≥60 years old, following at least 
5 minutes of supine rest. If systolic BP is ≥140 or 150 mm Hg (based on age) or
diastolic ≥90 mm Hg, the BP should be repeated 2 more times and the average of the 
3 BP values should be used to determine the participant’s eligibility. 
10. Standard 12-lead ECG that demonstrates clinically relevant abnormalities that may 
affect participant safety or interpretation of study results (eg, QTcF >450 ms, complete 
LBBB, signs of an acute or indeterminate- age myocardial infarction, ST-T interval 
changes suggestive of myocardial ischemia, second- or third- degree AV block, or 
serious bradyarrhythmias or tachyarrhythmias). If QTcF exceeds 450 ms, or QRS 
exceeds 120 ms, the ECG should be repeated twice and the average of the 3 QTcF or 
QRS values used to determine the participant’s eligibility. Computer-interpreted ECGs 
should be overread by a physician experienced in reading ECGs before excluding a 
participant.
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11. Participants with ANY of the following abnormalities in clinical laboratory tests at 
screening, as assessed by the study-specific laboratory and confirmed by a single repeat
test, if deemed necessary: 

AST or ALT level >1.5 × ULN.

Total bilirubin level >1.5 × ULN. Participants with a history of Gilbert’s 
syndrome may have direct bilirubin measured and would be eligible for this study 
provided the direct bilirubin level is ≤ULN.

eGFR of <60 mL/min/1.73m². eGFR is calculated using the recommended 
formulas in Section 10.7.2 to determine eligibility and to provide a baseline to 
quantify any subsequent kidney safety events.
Other Exclusion Criteria:
12. Use of tobacco or nicotine-containing products within 1 month of screening or a
positive urine cotinine test (ie, active smokers and those who currently use nicotine-
containing products are excluded from participation in this study).
13. Conditions that affect ability to taste eg, dysgeusia, respiratory infection, cold, or other 
conditions as evaluated by the PI. 
14. Presence of piercings or any physical findings in the nose that, in the opinion of the PI, 
would likely interfere with the successful completion of the dosing procedure.
15. Investigator site staff directly involved in the conduct of the study and their family 
members, site staff otherwise supervised by the investigator, and sponsor and sponsor 
delegate employees directly involved in the conduct of the study and their family 
members. 
16. History of alcohol abuse or binge drinking and/or any other illicit drug use or 
dependence within 6 months of Screening. Binge drinking is defined as a pattern of 
5 (male) and 4 (female) or more alcoholic drinks in about 2 hours. As a general rule, 
alcohol intake should not exceed 14 units per week (1 unit = 8 ounces (240 mL) beer, 
1 ounce (30 mL) of 40% spirit, or 3 ounces (90 mL) of wine).
17. Any reason that, in the opinion of the PI, would prevent the participant from 
participating in the study.
5.3. Lifestyle Considerations
The following guidelines are provided:
5.3.1. Contraception 
The investigator or their designee, in consultation with the participant, will confirm that the 
participant is utilizing an appropriate method of contraception for the individual participant 
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from the permitted list of contraception methods (see Appendix 4, Section 10.4.4) and will 
confirm that the participant has been instructed in its consistent and correct use. The 
investigator or designee will advise the participant to seek advice about the donation and 
cryopreservation of germ cells prior to the start of study intervention, if applicable.
At time points indicated in SoA, the investigator or designee will inform the participant of 
the need to use highly effective contraception consistently and correctly and document the 
conversation and the participant’s affirmation in the participant’s chart. Participants need to 
affirm their consistent and correct use of at least 1 of the selected methods of contraception, 
considering that their risk for pregnancy may have changed since the last visit. 
In addition, the investigator or designee will instruct the participant to call immediately if the 
selected contraception method is discontinued and document the requirement to use an 
alternate protocol-specified method, including if the participant will no longer use abstinence 
as the selected contraception method, or if pregnancy is known or suspected in the participant 
or partner.
5.3.2. Meals and Dietary Restrictions

Participants must abstain from all food and drink (except water) at least 4 hours prior 
to any safety laboratory, and at least 10 hours prior to taking the study intervention in 
period 1, Day 1, and in period 2, Day 1.

Breakfast may be provided in the morning of Day 3.

Lunch and dinner will be provided at appropriate times.

An evening snack may be permitted.

Participants will refrain from consuming red wine, grapefruit, or grapefruit-related 
citrus fruits (eg, Seville oranges, pomelos, fruit juices) from 7 days prior to the first 
dose of study intervention until collection of the final PK blood sample. 

While participants are confined, their total daily nutritional composition should be 
approximately 55% carbohydrate, 30% fat, and 15% protein. The daily caloric intake 
per participant should not exceed approximately 3200 kcal.
5.3.3. Caffeine, Alcohol, and Tobacco

Participants will abstain from caffeine-containing products for 24 hours prior to the 
start of dosing until the collection of the final PK sample. 

Participants will abstain from alcohol for 24 hours prior (or as specified above for red 
wine) to admission to the CRU and continue abstaining from alcohol until the 
collection of the final PK sample. Participants may undergo an alcohol breath test or 
blood alcohol test at the discretion of the investigator.
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
Participants will abstain from the use of tobacco- or nicotine-containing products for 
more than 1 month prior to screening and during confinement in the CRU. 
5.3.4. Activity

Participants will abstain from strenuous exercise (eg, heavy lifting, weight training, 
calisthenics, aerobics) for at least 48 hours prior to each blood collection for clinical 
laboratory tests. Walking at a normal pace will be permitted.
5.4. Screen Failures
Screen failures are defined as participants who consent to participate in the clinical study but 
are not subsequently enrolled in the study. Screen failure data are collected and remain as 
source and are not reported on the CRF.
Individuals who do not meet the criteria for participation in this study (screen failure) may be 
rescreened with the approval of the principal investigator.
6. STUDY INTERVENTION(S) AND CONCOMITANT THERAPY
Study interventions are all prespecified investigational and noninvestigational medicinal 
products, medical devices, and other interventions (eg, surgical and behavioral) intended to 
be administered to the study participants during the study conduct. 
For the purposes of this protocol, study intervention refers to zavegepant.
6.1. Study Intervention(s) Administered
Zavegepant is formulated as 10 mg for IN single-dose administration. The study intervention 
will be provided in single-use unidose nasal spray devices fully prepared and ready for 
administration. 
Study Intervention(s)
Intervention Name
Zavegepant
Type
Drug
Use
Experimental
IMP or NIMP/AxMP
IMP
Dose Formulation
Nasal spray
Unit Dose Strength(s)
10 mg
Dosage Level(s)
10 mg
Route of Administration
IN
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Study Intervention(s)
Sourcing
Provided centrally by the sponsor.
Refer to the IP manual.
Packaging and Labeling
Study intervention will be provided in unidose nasal 
spray. Each nasal spray will be labeled according to local 
regulatory requirements.
Study intervention will be provided to the site as bulk 
labeled nasal spray for dispensing by the pharmacy and 
administration by site personnel.
SRSD
USPI
Current Name or Alias
Zavegepant
Study Arm(s)
Arm Title
Zavegepant
Arm Description
All participants will receive zavegepant 10 mg IN spray
in period 1 and a butterscotch candy + zavegepant 10 mg 
IN spray in period 2
6.1.1. Administration
Following an overnight fast of at least 10 hours, on Day 1 of period 1, participants will 
receive study intervention at approximately 0800 hours (plus or minus 2 hours). Administer 
study intervention according to the IPM. On Day 1 of period 2, following an overnight fast of 
at least 10 hours, participants will receive a butterscotch candy followed 5 minutes later by 
study intervention. Participants will be instructed not to chew or crush the candy but allow it 
to dissolve over time.
Administration of study intervention will be performed by an appropriately qualified and 
trained member of the study staff as allowed by local, state, and institutional guidance. Study 
staff will administer the IN spray in 1 nostril to each participant. Study staff will record 
which nostril was used for drug administration. After the dose is administered, participants 
will be asked to remain seated upright for approximately 10 minutes in order to avoid any 
study intervention leakage. Participants must inform the staff if they sneeze or if the product 
drips out of their nose during or shortly after the administration. Of note, for all the study 
participants, all attempts would be made for study intervention administration performed by 
no more than 3 study staff members to minimize variability in device handling.
Participants must inform the study staff if they believe the device did not function properly, 
ie, if they believe the device did not dispense a spray content. All occurrences of dose 
misadministration or unidose nasal spray malfunction should be communicated to the 
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sponsor as soon as possible. Under no circumstance may a participant be administered a 
supplementary dose of study medication.
Following administration of study intervention(s), participants will be observed for 
10 minutes by an appropriately qualified and trained member of the study staff. Appropriate 
medication and other supportive measures for management of a medical emergency will be 
available in accordance with local guidelines and institutional guidelines.
6.1.2. Medical Devices
1. The study intervention, zavegepant (10 mg dose), uses a unitdose nasal spray device 
constituent for delivery to the intended user population. Instructions for medical 
device use are provided in the IPM. 
2. All medical device deficiencies (including malfunction, use error, and inadequate 
labeling) for the above-listed medical devices shall be documented and reported by 
the investigator throughout the clinical investigation (see Section 8.4.9) and 
appropriately managed by the sponsor.
6.2. Preparation, Handling, Storage, and Accountability
1. The investigator or designee must confirm that appropriate conditions (eg, 
temperature) have been maintained during transit for all study interventions received 
and any discrepancies are reported and resolved before use of the study intervention. 
2. Only participants enrolled in the study may receive study intervention and only 
authorized site staff may supply, prepare, and/or administer study intervention.
3. All study interventions must be stored in a secure, environmentally controlled, and 
monitored (manual or automated recording) area in accordance with the labeled 
storage conditions with access limited to the investigator and authorized site staff. At 
a minimum, daily minimum and maximum temperatures for all site storage locations 
must be documented and available upon request. Data for nonworking days must 
indicate the minimum and maximum temperatures since previously documented upon 
return to business.
4. Any excursions from the study intervention label storage conditions should be 
reported to Pfizer upon discovery along with actions taken. The site should actively 
pursue options for returning the study intervention to the labeled storage conditions, 
as soon as possible. Once an excursion is identified, the study intervention must be 
quarantined and not used until Pfizer provides permission to use the study 
intervention. Specific details regarding the excursion definition and information to
report for each excursion will be provided to the site in the PCRU local/site 
procedures.
5. Any storage conditions stated in the SRSD will be superseded by the storage 
conditions stated on the label.
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6. Study interventions should be stored in their original containers.
7. The investigator, institution, head of the medical institution (where applicable), or 
authorized site staff is responsible for study intervention accountability, 
reconciliation, and record maintenance (ie, receipt, reconciliation, and final 
disposition records), such as the IPAL or sponsor-approved equivalent. All study 
interventions will be accounted for using a study intervention accountability 
form/record.
8. Further guidance and information for the final disposition of unused study 
interventions are provided in the PCRU’s local/site procedures. All destruction must 
be adequately documented. If destruction is authorized to take place at the 
investigator site, the investigator must ensure that the materials are destroyed in 
compliance with applicable environmental regulations, institutional policy, and any 
special instructions provided by Pfizer.
Upon identification of a product complaint, notify the sponsor within 1 business day of 
discovery.
6.2.1. Preparation and Dispensing
Within this protocol, preparation refers to the investigator site activities performed to make 
the study intervention ready for administration or dispensing to the participant by qualified 
staff. Dispensing is defined as the provision of study intervention, concomitant treatments, 
and accompanying information by qualified staff member(s) to a healthcare provider, 
participant, in accordance with this protocol. Local health authority regulations or 
investigator site guidelines may use alternative terms for these activities.
See the IPM for instructions on how to prepare the study intervention for administration. 
Study intervention should be prepared and dispensed by an appropriately qualified and 
experienced member of the study staff (eg, physician, nurse, physician’s assistant, nurse 
practitioner, pharmacy assistant/technician, or pharmacist) as allowed by local, state, and
institutional guidance. A second staff member will verify the dispensing.
6.3. Assignment to Study Intervention
The investigator will assign participant numbers to the participants as they are screened for 
the study. Pfizer will provide a randomization schedule to the investigator and, in accordance 
with the randomization numbers, the participant will receive the study treatment regimen 
assigned to the corresponding randomization number.
6.4. Blinding
This is an open-label study. 
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6.4.1. Blinding of the Sponsor
As this is an open-label study, the sponsor may conduct unblinded reviews of the data during 
the course of the study for the purpose of safety assessment, facilitating PK modeling, and/or 
supporting clinical development.
6.5. Study Intervention Compliance
When participants are dosed at the site, they will receive study intervention directly from the 
investigator or designee, under medical supervision. The date and time of each dose 
administered in the clinic will be recorded in the source documents and recorded in the CRF.
6.6. Dose Modification
By design, this study only includes the administration of IN dose of zavegepant in each 
period at a fixed dosage level (10 mg). As such, dose modifications will not be made during 
the study.
6.7. Continued Access to Study Intervention After the End of the Study
No study intervention will be provided to participants at the end of their study participation.
6.8. Treatment of Overdose
There is no clinical experience with overdose of zavegepant. This is a single and fixed-dose 
study; thus, the probability of having a treatment overdose is low. For this study, any dose of 
zavegepant greater than 40 mg (the maximum dose that has been explored to-date) within a 
24-hour time period will be considered an overdose.
There is no specific treatment for an overdose.
In the event of an overdose, the investigator should:
1. Contact the study medical monitor within 24 hours.
2. Closely monitor the participant for any AEs/SAEs and laboratory abnormalities as 
medically appropriate and follow up until resolution, stabilization, the event is 
otherwise explained, or the participant is lost to follow-up (as defined in Section 7.3).
3. Document the quantity of the excess dose as well as the duration of the overdose in 
the CRF.
4. Overdose is reportable to Pfizer Safety only when associated with an SAE.
5. Obtain a blood sample for PK analysis within 2 hours from the last dose of study 
intervention if requested by the study medical monitor (determined on a case-by-case
basis).
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6.9. Prior and Concomitant Therapy
Concomitant administration of zavegepant with inhibitors of OATP1B3 may result in a 
significant increase in zavegepant exposure. Avoid concomitant administration of zavegepant
with drugs that inhibit OATP1B3 transporter, as listed in Appendix 10. 
Participants will be asked to refrain from using prescription medication, OTC products, or 
natural health products that may potentially affect their safety and/or the PK profile of the 
study drug. Any of these products taken during the timeframe specified below will be 
reviewed and evaluated by the PI in order to determine if they affect a participant’s eligibility 
or continued participation in the study. Product restriction timeframes are as follows:

Prescription medication within 14 days prior to the first dosing until after the last PK 
blood sample collection of the study (hormonal contraception allowed);

OTC products within 7 days prior to the first dosing;

Oxymetazoline (or other nasal spray decongestants) from at least 14 days prior to the 
first dosing until after the last PK blood sample collection of the study;

A depot injection or an implant of any drug (other than hormonal contraceptives) 
within 3 months prior to the first dosing;

Natural health products (including herbal remedies such 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) within 7 days prior to the first dosing until after the last 
PK blood sample collection of the study.
All concomitant treatments taken during the study must be recorded with indication, daily 
dose, and start and stop dates of administration. All participants will be questioned about 
concomitant treatment at each clinic visit.
Treatments taken within 28 days before the first dose of study intervention will be 
documented as a prior treatment. Treatments taken after the first dose of study intervention 
will be documented as concomitant treatments.
7. DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL
7.1. Discontinuation of Study Intervention
It may be necessary for a participant to permanently discontinue study intervention. Reasons 
for permanent discontinuation of study intervention include the following:

AE (including Grade 3 severity or greater and considered by the investigator to be
related to study intervention);

SAE considered by the investigator to be related to study intervention;
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
Requirement for prohibited concomitant medication;

Study terminated by sponsor;

Withdrawal by participant or legally authorized representative.
Discontinuation of study intervention does not represent withdrawal from the study. If study 
intervention is permanently discontinued, the participant should remain in the study to be 
evaluated for subsequent scheduled assessments. See the SoA for data to be collected at the 
time of discontinuation of study intervention and follow-up for any further evaluations that 
need to be completed.
In the event of discontinuation of study intervention, it must be documented on the 
appropriate CRF/in the medical records whether the participant is discontinuing further 
receipt of study intervention or also from study procedures, further study follow-up, and/or 
future collection of additional information.
7.1.1. Potential Cases of Acute Kidney Injury
Participants exposed to IMP demonstrating transient or sustained increase in Screat (with 
decrease in Screat-based eGFR or eCrCL) require expedited evaluation to differentiate AKI 
from DICI. DICI is defined as transporter-mediated effect related to altered renal tubular 
creatinine handling without histological injury.
AKI may be due to one or more types of injury, including DIKI. Differentiation of DIKI 
from other causes of AKI and from DICI may require clinical, radiographic, histopathologic, 
and laboratory assessments, as well as nephrology consultation.
Follow-up Assessments
The participant should return to the site for evaluation as soon as possible, preferably within 
48 hours of awareness of the abnormal results. 
Evaluation should include physical examination, laboratory tests, detailed medical and 
surgical history, review of all medications (including recreational drugs and supplements 
[herbal]), family history, sexual history, travel history, blood transfusion, and potential 
occupational exposure to chemicals. 
Laboratory assessments should include simultaneous serum cystatin C (Scys) and serum 
creatinine (Screat) tests. Estimates of eGFR, eCrCl and Screat-based eGFR and combined 
Screat-Scys-based eGFR should also be derived using the appropriate equation described in 
Appendix 7.
Assessments of urine albumin-to-creatinine ratio or urine volume may also be performed as 
appropriate.
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If appropriate, nephrology consultation may be recommended to facilitate differentiation of 
renal parenchymal disease, pre-renal azotemia, and post-renal obstruction. 
Differentiating Acute Kidney Injury from DICI
A confirmed Screat increase is defined as:
(i) ≥0.3 mg/dL (≥26.5 µmol/L) within 48 hours OR 
(ii) confirmed Screat increase ≥1.5 times baseline (known or suspected to have occurred 
within the prior 7 days). 
Based on the assessments performed, suspected AKI (including DIKI) may be differentiated 
from DICI as follows.
Adult participants
AKI (including DIKI)
Any one of the below
DICI
Scys & Screat
Simultaneous, confirmed serum cystatin 
C (Scys) increase and confirmed Screat 
increase 
Confirmed Screat increase without 
confirmed increase in reflex Scys 
AND 
Confirmed Screat-based eGFR 
decrease without confirmed combined 
Screat-Scys-based eGFR decrease.
eGFR
Decrease in Screat-based eGFR and 
combined Screat-Scys-based eGFR (when 
available)
Albuminuria or 
proteinuria
Confirmed albuminuria increase (see 
Appendix 7 for Grades A1 to A3 
quantitation)
Urine volume
Urine volume <0.5 mL/kg/h for 6 
consecutive hours
Regardless of the presence or absence of increase in Screat, DIKI and other causes of AKI 
may be suspected if either there is new-onset or worsening albuminuria or proteinuria are 
detected.
All confirmed cases of clinically relevant decrease in kidney function should be considered 
potential cases of DIKI if no other reason for the kidney function abnormalities has been 
found.
7.2. Participant Discontinuation/Withdrawal From the Study
A participant may withdraw from the study at any time at their own request. Reasons for 
discontinuation from the study include the following:

Refused further study procedures;
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
Lost to follow-up;

Safety reason 

Death;

Study terminated by sponsor.
At the time of discontinuing from the study, if possible, an early discontinuation visit should 
be conducted. See the SoA for assessments to be collected at the time of study 
discontinuation and follow-up and for any further evaluations that need to be completed. 
The early discontinuation visit applies only to participants who are enrolled/randomized and 
then are prematurely withdrawn from the study. Participants should be questioned regarding 
their reason for withdrawal.
The participant will be permanently discontinued from the study intervention and the study at 
that time.
If a participant withdraws from the study, they may request destruction of any remaining 
samples taken and not tested, and the investigator must document any such requests in the 
site study records and notify the sponsor accordingly.
If the participant withdraws from the study and also withdraws consent (see Section 7.2.1 for 
disclosure of future information, no further evaluations will be performed and no additional 
data will be collected. The sponsor may retain and continue to use any data collected before 
such withdrawal of consent.
7.2.1. Withdrawal of Consent 
Participants who request to discontinue receipt of study intervention will remain in the study 
and must continue to be followed for protocol-specified follow-up procedures. The only 
exception to this is when a participant specifically withdraws consent for any further contact 
with them or persons previously authorized by the participant to provide this information. 
Participants should notify the investigator in writing of the decision to withdraw consent 
from future follow-up, whenever possible. The withdrawal of consent should be explained in 
detail in the medical records by the investigator, as to whether the withdrawal is only from 
further receipt of study intervention or also from study procedures and/or posttreatment study 
follow-up, and entered on the appropriate CRF page. In the event that vital status (whether 
the participant is alive or dead) is being measured, publicly available information should be 
used to determine vital status only as appropriately directed in accordance with local law.
7.3. Lost to Follow-Up 
A participant will be considered lost to follow-up if the participant repeatedly fails to return 
for scheduled visits and is unable to be contacted by the study site.
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The following actions must be taken if a participant fails to attend a required study visit:

The site must attempt to contact the participant and reschedule the missed visit as 
soon as possible. Counsel the participant on the importance of maintaining the 
assigned visit schedule and ascertain whether the participant wishes to and/or should 
continue in the study;

Before a participant is deemed lost to follow-up, the investigator or designee must 
make every effort to regain contact with the participant (where possible, 3 telephone 
calls and, if necessary, a certified letter to the participant’s last known mailing 
address or local equivalent methods). These contact attempts should be documented 
in the participant’s medical record;

Should the participant continue to be unreachable, the participant will be considered 
to have withdrawn from the study. 
8. STUDY ASSESSMENTS AND PROCEDURES
8.1. Administrative Procedures
The investigator (or an appropriate delegate at the investigator site) must obtain a signed and 
dated ICD before performing any study -specific procedures. 
Study procedures and their timing are summarized in the SoA. Protocol waivers or 
exemptions are not allowed.
Adherence to the study design requirements, including those specified in the SoA, is essential 
and required for study conduct.
All screening evaluations must be completed and reviewed to confirm that potential 
participants meet all eligibility criteria. The investigator will maintain a screening log to 
record details of all participants screened and to confirm eligibility or record reasons for 
screening failure, as applicable.
Participants will be screened within 28 days prior to the administration of the study 
intervention to confirm that they meet the study population criteria for the study. If the time 
between screening and dosing exceeds 28 days as a result of unexpected delays (eg, delayed 
drug shipment), then participants do not require rescreening if the laboratory results obtained 
prior to first dose administration meet eligibility criteria.
A participant who qualified for this protocol but did not enroll from an earlier cohort/group
may be used in a subsequent cohort/group without rescreening, provided laboratory results 
obtained prior to the first dose administration meet the eligibility criteria for this study. In 
addition, other clinical assessments or specimen collections, eg, retained research samples, 
may not need to be repeated, as appropriate.
Every effort should be made to ensure that protocol-required tests and procedures are 
completed as described. However, it is anticipated that from time to time there may be 
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circumstances outside the control of the investigator that make it unfeasible to perform the 
test. In these cases, the investigator must take all steps necessary to ensure the safety and 
well-being of the participant. When a protocol-required test cannot be performed, the 
investigator will document the reason for the missed test and any corrective and preventive 
actions that they have taken to ensure that required processes are adhered to as soon as 
possible. The study team must be informed of these incidents in a timely manner.
If an IV catheter is utilized for blood sample collections, ECGs and vital sign assessments 
(pulse rate and BP) should be collected prior to the insertion of the catheter.
For samples being collected and shipped, detailed collection, processing, storage, and 
shipment instructions and contact information will be provided to the investigator site prior 
to initiation of the study.
The total blood sampling volume for each individual participant in this study is 
approximately 85 mL. The actual collection times of blood sampling may change. Additional 
blood samples may be taken for safety assessments at times specified by Pfizer, provided the 
total volume taken during the study does not exceed 550 mL during any period of 
56 consecutive days.
To prepare for study participation, participants will be instructed on the information in the 
Section 5.3 and 6.9 sections of the protocol.
8.2. Efficacy Assessments
Efficacy parameters are not evaluated in this study. 
8.3. Safety Assessments
Planned time points for all safety assessments are provided in the SoA. Unscheduled safety
measurements may be obtained at any time during the study to assess any perceived safety 
issues.
8.3.1. Physical Examinations
A complete physical examination will include, at a minimum, head, ears, eyes, nose, mouth, 
skin, heart and lung examinations, lymph nodes, and gastrointestinal, musculoskeletal, and 
neurological systems. 
A brief physical examination will include, at a minimum, assessments of general appearance, 
the respiratory and cardiovascular systems, and participant-reported symptoms.
Physical examinations may be conducted by a physician, trained physician’s assistant, or 
nurse practitioner as acceptable according to local regulation. 
Height and weight will also be measured and recorded as per the SoA. For measuring weight, 
a scale with appropriate range and resolution is used and must be placed on a stable, flat 
surface. Participants must remove shoes, bulky layers of clothing, and jackets so that only 
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light clothing remains. They must also remove the contents of their pockets and remain still 
during the measurement of weight. 
Physical examination findings collected during the study will be considered source record 
and will not be required to be reported, unless otherwise noted. Any untoward physical 
examination findings that are identified during the active collection period and meet the 
definition of an AE or SAE (Appendix 3) must be reported according to the processes in 
Sections 8.4.1 to 8.4.3.
8.3.2. Nasal Inspection
The nasal passages and turbinates will be visually inspected with a nasal speculum and light 
on Day -1 (to exclude participants with mucosal erythema, congestion, septal defects etc.), 
and 24 hours (± 30 minutes) postdose to detect evidence of nasal inflammation or edema. 
8.3.3. Vital Signs
8.3.3.1. Blood Pressure and Pulse Rate
Supine BP will be measured with the participant’s arm supported at the level of the heart and 
recorded to the nearest mm Hg after approximately 5 minutes of rest. The same arm 
(preferably the dominant arm) will be used throughout the study. Participants should be 
instructed not to speak during measurements.
The same properly sized and calibrated BP cuff will be used to measure BP each time. The 
use of an automated device for measuring BP and pulse rate is acceptable; however, when 
done manually, pulse rate will be measured in the brachial/radial artery for at least 
30 seconds. When the timing of these measurements coincides with a blood collection, BP 
and pulse rate should be obtained prior to the nominal time of the blood collection.
Additional collection times, or changes to collection times, of BP and pulse rate will be 
permitted, as necessary, to ensure the appropriate collection of safety data.
Any untoward vital sign findings that are identified during the active collection period and 
meet the definition of an AE or SAE (Appendix 3) must be reported according to the 
processes in Sections 8.4.1 to 8.4.3.
8.3.4. Electrocardiograms
Standard 12-lead ECGs will be collected at times specified in the SoA section of this
protocol using an ECG system that automatically calculates the HR and measures PR, QT, 
QTcF, and QRS intervals. All scheduled ECGs should be performed after the participant has 
rested quietly for at least 5 minutes in a supine position. 
In some cases, it may be appropriate to repeat abnormal ECGs to rule out improper lead 
placement as contributing to the ECG abnormality. It is important that leads be placed in the 
same positions each time in order to achieve precise ECG recordings. If a machine-read QTc 
value is prolonged, as defined above, repeat measurements may not be necessary if a 
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qualified medical provider’s interpretation determines that the QTcF values are in the 
acceptable range.
ECG values of potential clinical concern are listed in Appendix 8.
8.3.5. Clinical Safety Laboratory Assessments
See Appendix 2 for the list of clinical safety laboratory tests to be performed and the SoA for
the timing and frequency. All protocol-required laboratory assessments, as defined in
Appendix 2, must be conducted in accordance with the laboratory manual and the SoA.
Unscheduled clinical laboratory measurements may be obtained at any time during the study 
to assess any perceived safety issues.
The investigator must review the laboratory report, document this review, and record any 
clinically significant changes occurring during the study in the AE section of the CRF. 
Clinically significant abnormal laboratory test findings are those that are not associated with 
the underlying disease, unless judged by the investigator to be more severe than expected for 
the participant’s condition.
All laboratory tests with values considered clinically significant and abnormal during 
participation in the study or within 28 days after the last dose of study intervention should be 
repeated until the values return to normal or baseline or are no longer considered clinically 
significant by the investigator or study medical monitor.
If such values do not return to normal/baseline within a period of time judged reasonable by 
the investigator, the etiology should be identified and the sponsor notified.
See Appendix 6 for suggested actions and follow-up assessments in the event of potential 
DILI.
See Appendix 7 for instructions for laboratory testing to monitor kidney function and report 
laboratory test abnormalities.
8.3.6. Pregnancy Testing 
A urine or serum pregnancy test is required at screening. Following screening, pregnancy 
tests may be urine or serum tests, and must have a sensitivity of at least 25 mIU/mL. 
Pregnancy tests will be performed in WOCBP at the times listed in the SoA. Following a 
negative pregnancy test result at screening, appropriate contraception must be commenced,
and a second negative pregnancy test result will be required at the baseline visit prior to 
starting the study intervention. Pregnancy tests will also be done whenever 1 menstrual cycle 
is missed during the active treatment period (or when potential pregnancy is otherwise 
suspected) and at the end of the study. Pregnancy tests may also be repeated if requested by 
IRBs/ECs or if required by local regulations.
8.4. Adverse Events, Serious Adverse Events, and Other Safety Reporting
The definitions of an AE and an SAE can be found in Appendix 3.
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AEs may arise from symptoms or other complaints reported to the investigator by the 
participant (or, when appropriate, by a caregiver, surrogate, or the participant’s legally 
authorized representative), or they may arise from clinical findings of the investigator or 
other healthcare providers (clinical signs, test results, etc.).
The investigator and any qualified designees are responsible for detecting, documenting, and 
recording events that meet the definition of an AE or SAE and remain responsible to pursue 
and obtain adequate information both to determine the outcome and to assess whether the 
event meets the criteria for classification as an SAE or caused the participant to discontinue 
the study (see Section 7.1). 
During the active collection period as described in Section 8.4.1, each participant will be 
questioned about the occurrence of AEs in a nonleading manner.
In addition, the investigator may be requested by Pfizer Safety to obtain specific follow-up 
information in an expedited fashion.
8.4.1. Time Period and Frequency for Collecting AE and SAE Information
The time period for actively eliciting and collecting AEs and SAEs (“active collection 
period”) for each participant begins from the time the participant provides informed consent, 
which is obtained before undergoing any study -related procedure and/or receiving study 
intervention), through and including a minimum of 28 calendar days, except as indicated 
below, after the last administration of the study intervention.
Follow-up by the investigator continues throughout the active collection period and until the 
AE or SAE or its sequelae resolve or stabilize at a level acceptable to the investigator.
When a clinically important AE remains ongoing at the end of the active collection period, 
follow-up by the investigator continues until the AE or SAE or its sequelae resolve or 
stabilize at a level acceptable to the investigator and Pfizer concurs with that assessment.
For participants who are screen failures, the active collection period ends when screen failure 
status is determined.
If the participant withdraws from the study and also withdraws consent for the collection of 
future information, the active collection period ends when consent is withdrawn.
If a participant permanently discontinues or temporarily discontinues study because of an AE 
or SAE, the AE or SAE must be recorded on the CRF and the SAE reported using the PASS.
Investigators are not obligated to actively seek information on AEs or SAEs after the 
participant has concluded study participation. However, if the investigator learns of any SAE, 
including a death, at any time after a participant has completed the study, and they consider
the event to be reasonably related to the study intervention, the investigator must promptly 
report the SAE to Pfizer using the PSSA.
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8.4.1.1. Reporting SAEs to Pfizer Safety
All SAEs occurring in a participant during the active collection period as described in 
Section 8.4.1 are reported to Pfizer Safety on the PASS immediately upon awareness and 
under no circumstance should this exceed 24 hours, as indicated in Appendix 3. The 
investigator will submit any updated SAE data to the sponsor within 24 hours of its being 
available.
8.4.1.2. Recording Nonserious AEs and SAEs on the CRF
All nonserious AEs and SAEs occurring in a participant during the active collection period, 
which begins after obtaining informed consent as described in Section 8.4.1, will be recorded 
on the AE section of the CRF.  
The investigator is to record on the CRF all directly observed, and all spontaneously reported 
AEs and SAEs reported by the participant.
As part of ongoing safety reviews conducted by the sponsor, any nonserious AE that is 
determined by the sponsor to be serious will be reported by the sponsor as an SAE. To assist 
in the determination of case seriousness, further information may be requested from the 
investigator to provide clarity and understanding of the event in the context of the clinical 
study.
Reporting of AEs and SAEs for participants who fail screening are participant to the CRF
requirements as described in Section 5.4.
8.4.2. Method of Detecting AEs and SAEs
The method of recording, evaluating, and assessing causality of AEs and SAEs and the 
procedures for completing and transmitting SAE reports are provided in Appendix 3.
Care will be taken not to introduce bias when detecting AEs and/or SAEs. Open-ended and 
nonleading verbal questioning of the participant is the preferred method to inquire about 
AE occurrences.
8.4.3. Follow-Up of AEs and SAEs
After the initial AE or SAE report, the investigator is required to proactively follow each 
participant at subsequent visits/contacts. For each event, the investigator must pursue and 
obtain adequate information until resolution, stabilization, the event is otherwise explained, 
or the participant is lost to follow-up (as defined in Section 7.3).
In general, follow-up information will include a description of the event in sufficient detail to 
allow for a complete medical assessment of the case and independent determination of 
possible causality. Any information relevant to the event, such as concomitant medications 
and illnesses, must be provided. In the case of a participant death, a summary of available 
autopsy findings must be submitted as soon as possible to Pfizer Safety. 
Further information on follow--up procedures is provided in Appendix 3.
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8.4.4. Regulatory Reporting Requirements for SAEs
Prompt notification by the investigator to the sponsor of an SAE is essential so that legal 
obligations and ethical responsibilities toward the safety of participants and the safety of a 
study intervention under clinical investigation are met.
The sponsor has a legal responsibility to notify both the local regulatory authority and other 
regulatory agencies about the safety of a study intervention under clinical investigation. The 
sponsor will comply with country-specific regulatory requirements relating to safety 
reporting to the regulatory authority, IRBs/ECs, and investigators.
Investigator safety reports must be prepared for SUSARs according to local regulatory 
requirements and sponsor policy and forwarded to investigators as necessary.
An investigator who receives SUSARs or other specific safety information (eg, summary or 
listing of SAEs) from the sponsor will review and then file it along with the SRSD(s) for the 
study and will notify the IRB/EC, if appropriate according to local requirements.
8.4.5. Environmental Exposure, Exposure During Pregnancy or Breastfeeding, and 
Occupational Exposure
Environmental exposure occurs when a person not enrolled in the study as a participant 
receives unplanned direct contact with or exposure to the study intervention. Such exposure 
may or may not lead to the occurrence of an AE or SAE. Persons at risk for environmental 
exposure include healthcare providers, family members, and others who may be exposed. An 
environmental exposure may include EDP, EDB, and occupational exposure.
Any such exposures to the study intervention under study are reportable to Pfizer Safety 
within 24 hours of investigator awareness.
8.4.5.1. Exposure During Pregnancy
An EDP occurs if: 

A female participant is found to be pregnant while receiving or after discontinuing 
study intervention.

A male participant who is receiving or has discontinued study intervention
inseminates a female partner.

A female nonparticipant is found to be pregnant while being exposed or having been 
exposed to study intervention because of environmental exposure. Below are 
examples of environmental EDP:  

A female family member or healthcare provider reports that she is pregnant after 
having been exposed to the study intervention by ingestion, inhalation, or skin 
contact.
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
A male family member or healthcare provider who has been exposed to the study 
intervention by ingestion, inhalation, or skin contact then inseminates his female 
partner prior to or around the time of conception.
The investigator must report EDP to Pfizer Safety within 24 hours of the investigator’s 
awareness, irrespective of whether an SAE has occurred. The initial information submitted 
should include the anticipated date of delivery (see below for information related to 
termination of pregnancy). 

If EDP occurs in a participant/participant’s partner, the investigator must report this 
information to Pfizer Safety using the PSSA regardless of whether an SAE has 
occurred. Details of the pregnancy will be collected after the start of study 
intervention and until 28 days after the last dose.

If EDP occurs in the setting of environmental exposure, the investigator must report 
information to Pfizer Safety using the PSSA Since the exposure information does not 
pertain to the participant enrolled in the study, the information is not recorded on a 
CRF; however, a copy of the completed report is maintained in the investigator site 
file.
Follow-up is conducted to obtain general information on the pregnancy and its outcome for 
all EDP reports with an unknown outcome. The investigator will follow the pregnancy until 
completion (or until pregnancy termination) and notify Pfizer Safety of the outcome as a 
follow-up to the initial report. In the case of a live birth, the structural integrity of the neonate 
can be assessed at the time of birth. In the event of a termination, the reason(s) for 
termination should be specified and, if clinically possible, the structural integrity of the 
terminated fetus should be assessed by gross visual inspection (unless pre-procedure test 
findings are conclusive for a congenital anomaly and the findings are reported).
Abnormal pregnancy outcomes are considered SAEs. If the outcome of the pregnancy meets 
the criteria for an SAE (ie, ectopic pregnancy, spontaneous abortion, intrauterine fetal 
demise, neonatal death, or congenital anomaly in a liveborn baby, a terminated fetus, an 
intrauterine fetal demise, or a neonatal death), the investigator should follow the procedures 
for reporting SAEs. Additional information about pregnancy outcomes that are reported to 
Pfizer Safety as SAEs follows: 

Spontaneous abortion including miscarriage and missed abortion should be reported 
as an SAE;

Neonatal deaths that occur within 1 month of birth should be reported, without regard 
to causality, as SAEs. In addition, infant deaths after 1 month should be reported as 
SAEs when the investigator assesses the infant death as related or possibly related to 
exposure to the study intervention. 
Additional information regarding the EDP may be requested by the sponsor. Further 
follow-up of birth outcomes will be handled on a case-by-case basis (eg, follow-up on 
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preterm infants to identify developmental delays). In the case of paternal exposure, the 
investigator will provide the participant with the Pregnant Partner Release of Information 
Form to deliver to his partner. The investigator must document in the source documents that 
the participant was given the Pregnant Partner Release of Information Form to provide to his 
partner.
8.4.5.2. Exposure During Breastfeeding
An EDB occurs if: 

A female participant is found to be breastfeeding while receiving or after 
discontinuing study intervention.

A female nonparticipant is found to be breastfeeding while being exposed or having 
been exposed to study intervention (ie, environmental exposure). An example of 
environmental EDB is a female family member or healthcare provider who reports 
that she is breastfeeding after having been exposed to the study intervention by 
ingestion, inhalation, or skin contact.
The investigator must report EDB to Pfizer Safety within 24 hours of the investigator’s 
awareness, irrespective of whether an SAE has occurred. The information must be reported 
using the PSSA. When EDB occurs in the setting of environmental exposure, the exposure 
information does not pertain to the participant enrolled in the study, so the information is not 
recorded on a CRF. However, a copy of the completed report is maintained in the 
investigator site file.
An EDB report is not created when a Pfizer drug specifically approved for use in 
breastfeeding women (eg, vitamins) is administered in accordance with authorized use. 
However, if the infant experiences an SAE associated with such a drug, the SAE is reported 
together with the EDB.
8.4.5.3. Occupational Exposure
The investigator must report any instance of occupational exposure to Pfizer Safety within 
24 hours of the investigator’s awareness using the PSSA regardless of whether there is an 
associated SAE. Since the information about the occupational exposure does not pertain to a 
participant enrolled in the study, the information is not recorded on a CRF; however, a copy 
of the completed report is maintained in the investigator site file.
8.4.6. Cardiovascular and Death Events
Not applicable.
8.4.7. Disease-Related Events and/or Disease-Related Outcomes Not Qualifying as AEs 
or SAEs
Not applicable.
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8.4.8. Adverse Events of Special Interest
Not applicable.
8.4.8.1. Lack of Efficacy
This section is not applicable because efficacy is not expected in the study population.
8.4.9. Medical Device Deficiencies
Medical devices being provided for use in this study are those listed in Section 6.1.2. In order 
to fulfill regulatory reporting obligations worldwide, the investigator is responsible for the 
detection and documentation of events meeting the definitions of device deficiency that occur 
during the study with such devices.
The definition of a medical device deficiency can be found in Appendix 9.
Note: AEs and/or SAEs that are associated with a medical device deficiency will follow the 
same processes as other AEs or SAEs, as outlined in Section 8.4.1 through 8.4.4 and 
Appendix 3 of the protocol.
8.4.9.1. Time Period for Detecting Medical Device Deficiencies
Medical device deficiencies that result in an incident will be detected, documented, and 
reported during all periods of the study in which the medical device is used.
Importantly, reportable device deficiencies are not limited to problems with the device itself 
but also include incorrect or improper use of the device and even intentional misuse, etc.
If the investigator learns of any device deficiency at any time after a participant has been 
discharged from the study, and such deficiency is considered reasonably related to a medical 
device provided for the study, the investigator will promptly notify the sponsor.
Refer to Section 10.9.4 for instructions for documenting and reporting medical device 
deficiencies.
8.4.9.2. Regulatory Reporting Requirements for Device Deficiencies
The investigator will promptly report all device deficiencies occurring with any medical 
device provided for use in the study in order for the sponsor to fulfill the legal responsibility 
to notify appropriate regulatory authorities and other entities about certain safety information 
relating to medical devices being used in clinical studies.
The investigator, or responsible person according to local requirements (eg, the head of the 
medical institution), will comply with the applicable local regulatory requirements relating to 
the reporting of device deficiencies to the IRB/EC.
Note: There are additional reporting obligations for medical device deficiencies that are 
potentially related to SAEs (ie, an SADE) that must fulfill the legal responsibility to notify 
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appropriate regulatory authorities and other entities about certain safety information relating 
to medical devices being used in clinical studies.

Any device deficiency that is associated with an SAE must be reported to the sponsor 
within 24 hours after the investigator determines that the event meets the definition of 
a device deficiency.

The sponsor shall review all device deficiencies and determine and document in 
writing whether they could have led to an SAE. These shall be reported to the 
regulatory authorities and IRBs/ECs as required by national regulations.
8.4.10. Medication Errors
Medication errors may result from the administration or consumption of the study 
intervention by the wrong participant, or at the wrong time, or at the wrong dosage strength.
Medication errors are recorded and reported as follows:
Recorded on the 
Medication Error Page 
of the CRF
Recorded on the 
Adverse Event Page 
of the CRF
Reported on the PSSA to 
Pfizer Safety Within 
24 Hours of Awareness
All (regardless of whether 
associated with an AE)
Any AE or SAE associated 
with the medication error
Only if associated with an 
SAE
Medication errors include:

Medication errors involving participant exposure to the study intervention;

Potential medication errors or uses outside of what is foreseen in the protocol that do 
or do not involve the study participant.
Whether or not the medication error is accompanied by an AE, as determined by the 
investigator, such medication errors occurring to a study participant are recorded on the 
medication error page of the CRF, which is a specific version of the AE page and, if 
applicable, any associated serious and nonserious AE(s), are recorded on the AE page of the 
CRF.
In the event of a medication dosing error, the sponsor should be notified within 24 hours.
Medication errors should be reported to Pfizer Safety within 24 hours on a PSSA only when 
associated with an SAE.
8.5. Pharmacokinetics 
Venous blood samples of approximately 4 mL, to provide approximately 1.5 mL plasma, will 
be collected for measurement of plasma concentrations of zavegepant as specified in the 
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SoA. Prior to centrifugation of blood samples collected at the time points specified in the 
SoA, Table 2, a 500 µL portion of the PK blood sample will be aliquoted and used to 
determine the blood-to-plasma ratio of zavegepant. Determining the blood-to-plasma ratio 
will be crucial for converting the dried blood concentrations collected using Tasso-M20 to 
their equivalent plasma concentrations for adequate comparison between the 2 methods. For 
Tasso sampling, approximately 100 μL of blood will be collected from participants using the 
Tasso-M20 devices, while for Tasso-Plus, approximately 300-500 μL of blood will be 
collected to provide approximately 150 - 200 μL serum into appropriately labeled tubes for 
the measurement of zavegepant concentration as specified in the SoA, Table 2. Of note, both 
Tasso and venous PK samples will be collected at the same time. Instructions for the 
collection and handling of biological samples will be provided in the laboratory manual or by 
the sponsor. The actual date and time (24-hour clock time) of each sample will be recorded.  
All efforts will be made to obtain the samples at the exact nominal time relative to dosing. 
Collection of samples up to and including 10 hours after dose administration that are
obtained within 10% of the nominal time relative to dosing (eg, within 6 minutes of a 
60-minute sample) will not be captured as a protocol deviation, as long as the exact time of 
the collection is noted on the source document and the CRF. Collection of samples more than 
10 hours after dose administration that are obtained ≤1 hour away from the nominal time 
relative to dosing will not be captured as a protocol deviation, as long as the exact time of the 
collection is noted on the source document and the CRF. This protocol deviation window 
does not apply to samples to be collected more than 10 hours after dose administration at 
outpatient/follow-up visits with visit windows.
Samples will be used to evaluate the PK of zavegepant. Samples collected for analyses of 
zavegepant concentration may also be used to evaluate safety or efficacy aspects related to 
concerns arising during or after the study, for metabolite identification and/or evaluation of 
the bioanalytical method. The data may be used for other internal exploratory purposes. The 
exploratory results may not be reported in the CSR.
Genetic analyses will not be performed on the collected PK samples unless consent for this 
was included in the informed consent. Participant confidentiality will be maintained.
Samples collected for measurement of zavegepant concentrations will be analyzed using a 
validated analytical method in compliance with applicable SOPs.
The PK samples must be processed and shipped as indicated in the instructions provided to 
the investigator site to maintain sample integrity. Any deviations from the PK sample 
handling procedure (eg, sample collection and processing steps, interim storage or shipping 
conditions), including any actions taken, must be documented and reported to the sponsor. 
On a case-by-case basis, the sponsor may make a determination as to whether sample 
integrity has been compromised.
Any changes in the timing or addition of time points for any planned study assessments must 
be documented and approved by the relevant study team member and then archived in the 
sponsor and site study files, but will not constitute a protocol amendment. The IRB/EC will 
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be informed of any safety issues that require alteration of the safety monitoring scheme or 
amendment of the ICD.
8.6. Genetics
8.6.1. Specified Genetics
Specified genetic analyses are not evaluated in this study.
8.6.2. Retained Research Samples for Genetics
A 4-mL blood sample optimized for DNA isolation Prep D1 will be collected according to 
the SoA, as local regulations and IRBs/ECs allow.
Retained Research Samples may be used for research related to the study intervention. Genes 
and other analytes (eg, proteins, RNA, nondrug metabolites) may be studied using the 
retained samples. 
See Appendix 5 for information regarding genetic research. Details on processes for 
collection and shipment of these samples can be found in the laboratory manual and 
supporting documentation.
8.7. Biomarkers
Biomarkers are not evaluated in this study.
8.8. Immunogenicity Assessments
Immunogenicity assessments are not included in this study.
8.9. Health Economics
Health economics/medical resource utilization and health economics parameters are not 
evaluated in this study.
9. STATISTICAL CONSIDERATIONS
Detailed methodology for summary and statistical analyses of the data collected in this study 
is outlined here and further detailed in the SAP, which will be maintained by the sponsor. 
The SAP may modify what is outlined in the protocol where appropriate; however, any major 
modifications of the primary endpoint definitions or their analyses will also be reflected in a 
protocol amendment.
9.1. Statistical Hypotheses
There is no statistical hypothesis for this study.
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9.2. Analysis Sets
For purposes of analysis, the following analysis sets are defined:
Participant Analysis 
Set
Description
Enrolled 
“Enrolled” means a participant’s, or their legally authorized 
representative’s, agreement to participate in a clinical study 
following completion of the informed consent process and
assignment to study intervention. A participant will be 
considered enrolled if the informed consent is not withdrawn 
prior to participating in any study activity. Potential 
participants who are screened for the purpose of determining 
eligibility for the study, but do not participate in the study, are 
not considered enrolled, unless otherwise specified by the 
protocol.
PK Concentration 
Analysis Set
All enrolled participants who receive 1 single IN dose of 
zavegepant and provide at least 1 evaluable plasma 
concentration.
PK Parameter Analysis 
Set
All enrolled participants who receive 1 single IN dose of 
zavegepant and provide at least 1 evaluable PK parameters of 
interest.
Taste Assessment Set
All participants who receive at least 1 single IN dose of 
zavegepant and complete the Taste Assessment Questionnaire
Safety Analysis Set
All participants who take at least 1 dose of study intervention.
Participants will be analyzed according to the product they 
actually receive.
9.3. Statistical Analyses
The SAP will be developed and finalized before any analyses are performed and will 
describe the analyses and procedures for accounting for missing, unused, and spurious data.
This section is a summary of the planned statistical analyses of the primary and secondary 
endpoints.
9.3.1. General Considerations
No formal statistical tests will be performed. Descriptive summaries will be provided for all 
endpoints by each blood collection method. For the taste assessment in this study, the data 
used in the analysis will be transcribed and rescaled to a score from 0 to 100 from the raw 
measurements on the questionnaire. The sensory attributes (overall liking, bitterness, 
tongue/mouth burn, throat burn, sour taste, salty taste, and sweet taste) from the taste 
questionnaires (Appendix 11) will be listed and descriptively summarized by study 
intervention (zavegepant alone vs zavegepant + butterscotch candy) and time points. 
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Summary statistics (mean and 90% CI) will be calculated for the various questions. Radar
plots for each of 4 time points, summarizing all attributes for each intervention will be
generated. Boxplots of each attribute will be plotted against the time points. More details will 
be provided in the SAP.
9.3.2. Pharmacokinetic Analysis
9.3.2.1. Derivation of PK Parameters
Zavegepant PK parameters from samples collected using Tasso and venous phlebotomy will 
be derived from the concentration-time profile using non-compartmental methods, as detailed 
in Table 3. Actual PK sampling times will be used in the derivation of PK parameters. In the 
case that actual PK sampling times are not available, nominal PK sampling time will be used 
in the derivation of PK parameters.
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Table 3.
Plasma PK Parameters for Protocol C5301022
Parameter
Definition
Method of Determination
Cmax
Maximum plasma concentration
Observed directly from data
AUClast
Area under the plasma 
concentration-time profile from 
time 0 to the time of the last 
quantifiable concentration (Clast)
Linear/Log trapezoidal method
AUCinfa
Area under the plasma 
concentration-time profile from 
time 0 extrapolated to infinite 
time
AUClast + (Clast/kel), where Clast is the 
predicted plasma concentration at the 
last quantifiable time point estimated 
from the log-linear regression
analysis
Tmax
Time for Cmax
Observed directly from data as time 
of first occurrence
t1/2a
Terminal half-life
Loge(2)/kel, where kel is the terminal
phase rate constant calculated by a 
linear regression of the log-linear
concentration-time curve
CL/Fa
Apparent clearance
Dose/AUCinf
Vz/Fa
Apparent volume of distribution
Dose/(AUCinf × kel)
a. If data permits.
9.3.2.2. Statistical Methods for Pharmacokinetic Data
The plasma concentration of zavegepant will be listed and descriptively summarized by 
nominal sampling time, for each Tasso device by blood collection method (Tasso and 
venous), and by race (non-Japanese and Japanese), as data permit. Individual participant and 
summary profiles (mean and median plots) of the plasma concentration-time data will be 
plotted using actual and nominal sampling times, respectively. The correlations of paired 
Tasso-Plus versus venous phlebotomy concentrations and paired Tasso-M20 versus venous 
phlebotomy concentrations will be reported.
The PK parameters of zavegepant will be listed and summarized descriptively for each Tasso 
device by blood collection method (Tasso and venous), and by race (non-Japanese and 
Japanese), as data permits. For AUClast, AUCinf, and Cmax, box and whisker plots for 
individual participant parameters will be constructed for each Tasso device by blood 
collection method and overlaid with geometric means. The PK parameter analysis set will be 
used.
Additional specifications about the tables, listings, and figures will be outlined in the SAP.
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9.3.3. Safety Analyses
All safety analyses will be performed on the safety population.
AEs, ECGs, BP, pulse rate, and safety laboratory data will be reviewed and summarized to 
evaluate the safety of participants. Any clinical laboratory, ECG, BP, and pulse rate
abnormalities of potential clinical concern will be described. Safety data will be presented in 
tabular and/or graphical format and summarized descriptively, where appropriate.
Medical history and physical examination, and neurological examination information, as 
applicable, collected during the course of the study, will be considered source data and will 
not be required to be reported, unless otherwise noted. However, any untoward findings 
identified on physical and/or neurological examinations conducted during the active 
collection period will be captured as AEs, if those findings meet the definition of an AE. 
Data collected at screening that are used for inclusion/exclusion criteria, such as laboratory 
data, ECGs, and vital signs, will be considered source data, and will not be required to be 
reported, unless otherwise noted. Demographic data collected at screening will be reported.
9.4. Interim Analyses
No interim analysis will be conducted for this study. As this is an open-label study, the 
sponsor may conduct unblinded reviews of the data during the course of the study for the 
purpose of safety assessment, and/or supporting clinical development.
9.5. Sample Size Determination
Approximately 14 evaluable participants will be enrolled (7 for Tasso-Plus and 7 for 
Tasso-M20). There is no statistical hypothesis for this study. The sample size determination
for this study was based on the established scientific recommendation for having 30 to 40 PK 
data points to ensure adequate comparison between PCS (test) and venous sampling.36 With a 
sample size of 7 evaluable participants per each Tasso device, and 6 Tasso-venous paired PK 
samples collected, there will be sufficient PK data points (7 × 6 = 42 data points from each 
Tasso device) to meet the scientific community recommendation for having an adequate 
Tasso-venous phlebotomy PK bridging study. 
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10. SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS
10.1. Appendix 1: Regulatory, Ethical, and Study Oversight Considerations
10.1.1. Regulatory and Ethical Considerations
This study will be conducted in accordance with the protocol and with the following:

Consensus ethical principles derived from international guidelines, including the 
Declaration of Helsinki and CIOMS International Ethical Guidelines;

Applicable ICH GCP guidelines;

Applicable laws and regulations, including applicable privacy laws.
The protocol, protocol amendments, ICD, SRSD(s), and other relevant documents 
(eg, advertisements) must be reviewed and approved by the sponsor, submitted to an IRB/EC 
by the investigator, and reviewed and approved by the IRB/EC before the study is initiated.
Any amendments to the protocol will require IRB/EC approval before implementation of 
changes made to the study design, except for changes necessary to eliminate an immediate 
hazard to study participants.
Protocols and any substantial amendments to the protocol will require health authority 
approval prior to initiation except for changes necessary to eliminate an immediate hazard to 
study participants.
The investigator will be responsible for the following:

Providing written summaries of the status of the study to the IRB/EC annually or 
more frequently in accordance with the requirements, policies, and procedures 
established by the IRB/EC;

Notifying the IRB/EC of SAEs or other significant safety findings as required by 
IRB/EC procedures;

Providing oversight of the conduct of the study at the site and adherence to 
requirements of 21 CFR, ICH GCP guidelines, the IRB/EC, European regulation 
536/2014 for clinical studies, European Medical Device Regulation 2017/745 for 
clinical device research, and all other applicable local regulations.
10.1.1.1. Reporting of Safety Issues and Serious Breaches of the Protocol or ICH GCP
In the event of any prohibition or restriction imposed (ie, clinical hold) by an applicable 
regulatory authority in any area of the world, or if the investigator is aware of any new 
information that might influence the evaluation of the benefits and risks of the study 
intervention, Pfizer should be informed immediately.
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In addition, the investigator will inform Pfizer immediately of any urgent safety measures 
taken by the investigator to protect the study participants against any immediate hazard, and 
of any serious breaches of this protocol or of the ICH GCP guidelines that the investigator 
becomes aware of.
10.1.2. Financial Disclosure
Investigators and subinvestigators will provide the sponsor with sufficient, accurate financial 
information as requested to allow the sponsor to submit complete and accurate financial 
certification or disclosure statements to the appropriate regulatory authorities. Investigators 
are responsible for providing information on financial interests during the course of the study 
and for 1 year after completion of the study.
10.1.3. Informed Consent Process
The investigator or the investigator’s representative will explain the nature of the study, 
including the risks and benefits, to the participant and answer all questions regarding the 
study. The participant should be given sufficient time and opportunity to ask questions and to 
decide whether or not to participate in the trial.
Participants must be informed that their participation is voluntary. Participants will be 
required to sign a statement of informed consent that meets the requirements of 21 CFR 50, 
local regulations, ICH guidelines, privacy and data protection requirements, where 
applicable, and the IRB/EC or study center.
The investigator must ensure that each participant is fully informed about the nature and 
objectives of the study, the sharing of data related to the study, and possible risks associated 
with participation, including the risks associated with the processing of the participant’s 
personal data. 
The participant must be informed that their personal study-related data will be used by the 
sponsor in accordance with local data protection law. The level of disclosure must also be 
explained to the participant.
The participant must be informed that their medical records may be examined by Clinical 
Quality Assurance auditors or other authorized personnel appointed by the sponsor, by 
appropriate IRB/EC members, and by inspectors from regulatory authorities.
The investigator further must ensure that each study participant is fully informed about their 
right to access and correct their personal data and to withdraw consent for the processing of 
their personal data.
The medical record must include a statement that written informed consent was obtained 
before the participant was enrolled in the study and the date on which the written consent was 
obtained. The authorized person obtaining the informed consent must also sign the ICD.
Participants must be reconsented to the most current version of the IRB/EC-approved ICD(s) 
during their participation in the study as required per local regulations.
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A copy of the ICD(s) must be provided to the participant. Participants who are rescreened are 
required to sign a new ICD.
10.1.3.1. Electronic Consent 
Participants may be able to experience the informed consent process by electronic means 
(eConsent). The eConsent process includes an electronic presentation of the informed 
consent document (eICD), clinical trial educational components (as applicable), and 
electronic signatures (if allowed by local regulations). The use of eConsent does not replace 
or alter the ICD content or informed consent process as described above. The eConsent 
process complies with applicable regulations and sponsor policies to ensure reliability and 
data privacy. 
10.1.4. Data Protection
All parties will comply with all applicable laws, including laws regarding the implementation 
of organizational and technical measures to ensure protection of participant data.
Participants’ personal data will be stored at the study site in encrypted electronic and/or paper 
form and will be password protected or secured in a locked room to ensure that only 
authorized study staff have access. The study site will implement appropriate technical and 
organizational measures to ensure that the personal data can be recovered in the event of 
disaster. In the event of a potential personal data breach, the study site will be responsible for 
determining whether a personal data breach has in fact occurred and, if so, providing breach 
notifications as required by law.
To protect the rights and freedoms of participants with regard to the processing of personal 
data, participants will be assigned a single, participant-specific numerical code. Any 
participant records or data sets that are transferred to the sponsor will contain the numerical 
code; participant names will not be transferred. All other identifiable data transferred to the 
sponsor will be identified by this single, participant-specific code. The study site will 
maintain a confidential list of participants who participated in the study, linking each 
participant’s numerical code to their actual identity and medical record ID. In case of data 
transfer, the sponsor will protect the confidentiality of participants’ personal data consistent 
with the clinical study agreement and applicable privacy laws.
Information technology systems used to collect, process, and store study-related data are 
secured by technical and organizational security measures designed to protect such data 
against accidental or unlawful loss, alteration, or unauthorized disclosure or access.
The sponsor maintains SOPs on how to respond in the event of unauthorized access, use, or 
disclosure of sponsor information or systems.
10.1.5. Committees Structure
10.1.5.1. Data Monitoring Committee 
This study will not use an E-DMC.
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10.1.6. Dissemination of Clinical Study Data
Pfizer fulfills its commitment to publicly disclose clinical study results through posting the 
results of studies on www.clinicaltrials.gov (ClinicalTrials.gov), the EudraCT/CTIS, and/or 
www.pfizer.com, and other public registries and websites in accordance with applicable local 
laws/regulations. In addition, Pfizer reports study results outside of the requirements of local 
laws/regulations pursuant to its SOPs.
In all cases, study results are reported by Pfizer in an objective, accurate, balanced, and 
complete manner and are reported regardless of the outcome of the study or the country in 
which the study was conducted.
www.clinicaltrials.gov
Pfizer posts clinical trial results on www.clinicaltrials.gov for Pfizer-sponsored interventional 
studies (conducted in patients) that evaluate the safety and/or efficacy of a product, 
regardless of the geographical location in which the study is conducted. These results are 
submitted for posting in accordance with the format and timelines set forth by US law.
EudraCT/CTIS
Pfizer posts clinical trial results on EudraCT/CTIS for Pfizer-sponsored interventional studies 
in accordance with the format and timelines set forth by EU requirements.
www.pfizer.com
Pfizer posts CSR synopses and plain-language study results summaries on www.pfizer.com 
for Pfizer-sponsored interventional studies at the same time the corresponding study results 
are posted to www.clinicaltrials.gov. CSR synopses will have personally identifiable 
information anonymized.
Documents within marketing applications
Pfizer complies with applicable local laws/regulations to publish clinical documents included 
in marketing applications. Clinical documents include summary documents and CSRs 
including the protocol and protocol amendments, sample CRFs, and SAPs. Clinical 
documents will have personally identifiable information anonymized.
Data sharing
Pfizer provides researchers secure access to participant-level data or full CSRs for the 
purposes of “bona-fide scientific research” that contributes to the scientific understanding of 
the disease, target, or compound class. Pfizer will make data from these trials available 
18 months after study completion. Participant-level data will be anonymized in accordance 
with applicable privacy laws and regulations. CSRs will have personally identifiable 
information anonymized.
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Data requests are considered from qualified researchers with the appropriate competencies to 
perform the proposed analyses. Research teams must include a biostatistician. Data will not 
be provided to applicants with significant conflicts of interest, including individuals 
requesting access for commercial/competitive or legal purposes.
10.1.7. Data Quality Assurance
All participant data relating to the study will be recorded on printed or electronic CRF unless 
transmitted to the sponsor or designee electronically (eg, laboratory data). The investigator is 
responsible for verifying that data entries are accurate and correct by physically or 
electronically signing the CRF.
Guidance on completion of CRFs will be provided in the CRF Completion Requirements 
document.
The investigator must ensure that the CRFs are securely stored at the study site in encrypted 
electronic and/or paper form and are password-protected or secured in a locked room to 
prevent access by unauthorized third parties.
The investigator must permit study-related monitoring, audits, IRB/EC review, and 
regulatory agency inspections and provide direct access to source records and documents.
This verification may also occur after study completion. It is important that the 
investigator(s) and their relevant personnel are available during the monitoring visits and 
possible audits or inspections and that sufficient time is devoted to the process.
Monitoring details describing strategy, including definition of study-critical data items and 
processes (eg, risk-based initiatives in operations and quality, such as risk management and 
mitigation strategies and analytical risk-based monitoring), methods, responsibilities, and 
requirements, including handling of noncompliance issues and monitoring techniques 
(central, virtual, or on-site monitoring), are provided in the data management plan maintained 
and utilized by the sponsor or designee.
The sponsor or designee is responsible for the data management of this study, including 
quality checking of the data.
Records and documents, including signed ICDs, pertaining to the conduct of this study must 
be retained by the investigator for 15 years after study completion unless local regulations or 
institutional policies require a longer retention period. No records may be destroyed during 
the retention period without the written approval of the sponsor. No records may be 
transferred to another location or party without written notification to the sponsor. The 
investigator must ensure that the records continue to be stored securely for as long as they are 
maintained.
When participant data are to be deleted, the investigator will ensure that all copies of such 
data are promptly and irrevocably deleted from all systems.
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The investigator(s) will notify the sponsor or its agents immediately of any regulatory 
inspection notification in relation to the study. Furthermore, the investigator will cooperate 
with the sponsor or its agents to prepare the investigator site for the inspection and will allow 
the sponsor or its agent, whenever feasible, to be present during the inspection. The 
investigator site and investigator will promptly resolve any discrepancies that are identified 
between the study data and the participant’s medical records. The investigator will promptly 
provide copies of the inspection findings to the sponsor or its agent. Before response 
submission to the regulatory authorities, the investigator will provide the sponsor or its 
agents with an opportunity to review and comment on responses to any such findings.
10.1.8. Source Documents
Source documents provide evidence for the existence of the participant and substantiate the 
integrity of the data collected. Source documents are filed at the investigator site.
Data reported on the CRF or entered in the eCRF that are from source documents must be 
consistent with the source documents or the discrepancies must be explained. The 
investigator may need to request previous medical records or transfer records, depending on 
the study. Also, current medical records must be available.
In this study, the CRF will serve as the source document. A document must be available at 
the investigative site that identifies those data that will be recorded on the CRF and for which 
the CRF will be the source document.
Definition of what constitutes a source document and its origin can be found in the Source 
Document Locator, which is maintained by the sponsor’s designee (Pfizer CRU).
Description of the use of the computerized system is documented in the Data Management 
Plan, which is maintained by the sponsor’s designee (Pfizer CRU).
The investigator must maintain accurate documentation (source record) that supports the 
information entered in the CRF.
The sponsor or designee will perform monitoring to confirm that data entered into the CRF 
by authorized site personnel are accurate, complete, and verifiable from source documents; 
that the safety and rights of participants are being protected; and that the study is being 
conducted in accordance with the currently approved protocol and any other study 
agreements, ICH GCP guidelines, and all applicable regulatory requirements.
10.1.9. Use of Medical Records
There may be instances when copies of medical records for certain cases are requested by 
Pfizer Safety, where ethically and scientifically justified and permitted by local regulations, 
to ensure participant safety.
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Due to the potential for a participant to be re-identified from their medical records, the 
following actions must be taken when medical records are sent to the sponsor or sponsor 
designee:

The investigator or site staff must redact personal information from the medical 
record. The personal information includes, but is not limited to, the following:
participant names or initials, participant dates (eg, birth date, date of hospital 
admission/discharge, date of death), participant identification numbers (eg, Social 
Security number, health insurance number, medical record number, 
hospital/institution identifier), participant location information (eg, street address, 
city, country, postal code, IP address), participant contact information (eg, 
telephone/fax number, email address).

Each medical record must be transmitted to the sponsor or sponsor designee using 
systems with technical and organizational security measures to ensure the protection 
of personal data (eg, Florence is the preferred system if available). 
There may be unplanned situations where the sponsor may request medical records (eg, 
sharing medical records so that the sponsor can provide study-related advice to the 
investigator). The medical records should be submitted according to the procedure described 
above.
10.1.10. Study and Site Start and Closure
The study start date is the date of the first participant’s first visit.
The sponsor designee reserves the right to close the study site or terminate the study at any 
time for any reason at the sole discretion of the sponsor, including (but not limited to) 
regulatory authority decision, change in opinion of the IRB/EC, or change in benefit-risk 
assessment. Study sites will be closed upon study completion. A study site is considered 
closed when all required documents and study supplies have been collected and a study-site 
closure visit has been performed.
The investigator may initiate study-site closure at any time upon notification to the sponsor if 
requested to do so by the responsible IRB/EC or if such termination is required to protect the 
health of study participants.
Reasons for the early closure of a study site by the sponsor may include but are not limited 
to:

Failure of the investigator to comply with the protocol, the requirements of the 
IRB/EC or local health authorities, the sponsor’s procedures, or the ICH GCP 
guidelines;

Inadequate recruitment of participants by the investigator;

Discontinuation of further study intervention development.
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If the study is prematurely terminated or suspended, the sponsor shall promptly inform the 
investigators, the ECs/IRBs, the regulatory authorities, and any CRO(s) used in the study of 
the reason for termination or suspension, as specified by the applicable regulatory 
requirements. The investigator shall promptly inform the participant and should assure 
appropriate participant therapy and/or follow-up.
Study termination is also provided for in the clinical study agreement. If there is any conflict 
between the contract and this protocol, the contract will control as to termination rights.
10.1.11. Publication Policy
Investigators are free to publish individual center results that they deem to be clinically 
meaningful after publication of the overall results of the study or 12 months after primary 
completion date or study completion at all sites, whichever occurs first, participant to the 
other requirements described in this section.
The investigator agrees to refer to the primary publication in any subsequent publications. 
Pfizer will not provide any financial compensation for the investigator’s participation in the 
preparation of the primary congress abstract, poster, presentation, or primary manuscript for 
the study.
The investigator will provide Pfizer an opportunity to review any proposed publication or 
any other type of disclosure of the study results (collectively, “publication”) before it is 
submitted or otherwise disclosed and will submit all publications to Pfizer 30 days before 
submission. If any patent action is required to protect intellectual property rights, the 
investigator agrees to delay the disclosure for a period not to exceed an additional 60 days 
upon request from Pfizer. This allows Pfizer to protect proprietary information and to provide 
comments, and the investigator will, on request, remove any previously undisclosed 
confidential information before disclosure, except for any study-intervention or Pfizer-related 
information necessary for the appropriate scientific presentation or understanding of the 
study results. For joint publications, should there be disagreement regarding interpretation 
and/or presentation of specific analysis results, resolution of, and responsibility for, such 
disagreements will be the collective responsibility of all authors of the publication.
For all publications relating to the study, the investigator and Pfizer will comply with 
recognized ethical standards concerning publications and authorship, including those 
established by the International Committee of Medical Journal Editors. The investigator will 
disclose any relationship with Pfizer and any relevant potential conflicts of interest, including 
any financial or personal relationship with Pfizer, in any publications. All authors will have 
access to the relevant statistical tables, figures, and reports (in their original format) required 
to develop the publication.
10.1.12. Sponsor’s Medically Qualified Individual
The contact information for the sponsor’s MQI for the study is documented in the study 
contact list located in the CTMS.
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To facilitate access to their investigator and the sponsor’s MQI for study-related medical 
questions or problems from non-study healthcare professionals, participants are provided 
with an ECC at the time of informed consent. The ECC contains, at a minimum, (a) protocol 
and study intervention identifiers, (b) participant’s study identification number, and (c) site 
emergency phone number active 24 hours/day, 7 days per week.
The ECC is intended to augment, not replace, the established communication pathways 
between the participant and their investigator and site staff, and between the investigator and 
sponsor study team. The ECC is only to be used by healthcare professionals not involved in 
the research study, as a means of reaching the investigator or site staff related to the care of a 
participant. 
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10.2. Appendix 2: Clinical Laboratory Tests
The following safety laboratory tests will be performed at times defined in the SoA section of 
this protocol. Additional laboratory results may be reported on these samples as a result of 
the method of analysis or the type of analyzer used by the clinical laboratory, or as derived 
from calculated values. These additional tests would not require additional collection of 
blood. Unscheduled clinical laboratory measurements may be obtained at any time during the 
study to assess any perceived safety issues.
Table 4.
Protocol-Required Laboratory Assessments
Hematology
Chemistry
Urinalysis
Other
Hemoglobin
Hematocrit
RBC count
Platelet count
WBC count
Total neutrophils (Abs)
Eosinophils (Abs)
Monocytes (Abs)
Basophils (Abs)
Lymphocytes (Abs)
BUN
Creatinine
Cystatin Ca
eGFR, eCrClb
Glucose (fasting)
Calcium
Sodium
Potassium
Chloride
Total CO2 (bicarbonate)
AST, ALT
Total bilirubin
Alkaline phosphatase
Uric acid
Albumin
Total protein
For suspected 
DICI/DIKI: 
Creatinine (Screat) 
Cystatin Ca (Scys) 
eGFR (Screat only and 
combined Screat+Scys)
eCrClb
Urine albumin-to-
creatinine-ratio (UACR)
Local dipstick:
pH
Glucose (qual)
Protein (qual)
Blood (qual)
Ketones
Nitrites
Leukocyte esterase
Laboratory:
Microscopy and 
culturec
Pregnancy test (β-hCG)
Urine drug screeningd
Urine cotinine
At screening:

FSHe

HBcAb

HBsAbf

HBsAg

HCVAb

HIV
a.
Cystatin C (Scys): Screening or Baseline Scys is recommended to help differentiate post-baseline DIKI from DICI. 
Post-baseline, Scys is measured if and only if serum creatinine increase post-baseline is observed (see Section 7.1.1).
b.
Screening and Baseline eGFR or eCrCl is measured with Screat-based formula. Age-specific kidney function 
calculation (see Section 10.7.2) is recommended to assess presence or absence of post-baseline change in kidney 
function.
c.
Only if UTI is suspected and urine dipstick is positive for nitrites or leukocyte esterase or both.
d.
The minimum requirement for drug screening includes cocaine, THC, opiates/opioids, benzodiazepines, and 
amphetamines (others are site- and study-specific).
e.
For confirmation of postmenopausal status only in females <60 years old and not using hormonal or HRT only.
f.    This is a reflex test. HBsAb to be run if HBsAg and/or HBcAb are positive.
The investigator must review the laboratory report, document this review, and record any 
clinically relevant changes occurring during the study in the AE section of the CRF.
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10.3. Appendix 3: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-Up, and Reporting
10.3.1. Definition of AE
AE Definition

An AE is any untoward medical occurrence in a patient or clinical study 
participant, temporally associated with the use of study intervention, whether or 
not considered related to the study intervention.

Note: An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease (new or exacerbated) 
temporally associated with the use of study intervention.
Events Meeting the AE Definition

Any abnormal laboratory test results (hematology, clinical chemistry, or 
urinalysis) or other safety assessments (eg, ECG, radiological scans, vital sign 
measurements), including those that worsen from baseline, considered clinically 
significant in the medical and scientific judgment of the investigator. Any 
abnormal test results that meet any of the conditions below must be recorded as 
an AE:

Is associated with accompanying symptoms;

Requires additional diagnostic testing or medical/surgical intervention;

Leads to a change in study dosing (outside of any protocol-specified dose 
adjustments) or discontinuation from the study, significant additional 
concomitant drug treatment, or other therapy.

Exacerbation of a chronic or intermittent preexisting condition, including an 
increase in either frequency and/or intensity of the condition.

New condition detected or diagnosed after study intervention administration,
even though it may have been present before the start of the study.

Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction.

Signs, symptoms, or the clinical sequelae of a suspected overdose of either study 
intervention or a concomitant medication. Overdose per se will not be reported as 
an AE or SAE unless it is an intentional overdose taken with possible 
suicidal/self-harming intent. Such overdoses should be reported regardless of 
sequelae.
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Events NOT Meeting the AE Definition

Any clinically significant abnormal laboratory findings or other abnormal safety 
assessments that are associated with the underlying disease, unless judged by the 
investigator to be more severe than expected for the participant’s condition.

The disease/disorder being studied or expected progression, signs, or symptoms 
of the disease/disorder being studied, unless more severe than expected for the 
participant’s condition.

Medical or surgical procedure (eg, endoscopy, appendectomy): the condition that 
leads to the procedure is the AE.

Situations in which an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital).

Anticipated day-to-day fluctuations of preexisting disease(s) or condition(s) 
present or detected at the start of the study that do not worsen.
10.3.2. Definition of an SAE
An SAE is defined as any untoward medical occurrence that, at any dose, meets one 
or more of the criteria listed below:
a. Results in death
b. Is life-threatening
The term “life-threatening” in the definition of “serious” refers to an event in which 
the participant was at risk of death at the time of the event. It does not refer to an 
event that hypothetically might have caused death if it were more severe.
c.
Requires inpatient hospitalization or prolongation of existing hospitalization
In general, hospitalization signifies that the participant has been admitted (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. Complications that occur during hospitalization are AEs. 
If a complication prolongs hospitalization or fulfills any other serious criteria, the 
event is serious. When in doubt as to whether “hospitalization” occurred or was 
necessary, the AE should be considered serious.
Hospitalization for elective treatment of a preexisting condition that did not worsen 
from baseline is not considered an AE.
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An SAE is defined as any untoward medical occurrence that, at any dose, meets one 
or more of the criteria listed below:
d. Results in persistent or significant disability/incapacity

The term disability means a substantial disruption of a person’s ability to conduct 
normal life functions.

This definition is not intended to include experiences of relatively minor medical 
significance, such as uncomplicated headache, nausea, vomiting, diarrhea, 
influenza, and accidental trauma (eg, sprained ankle), that may interfere with or 
prevent everyday life functions but do not constitute a substantial disruption.
e.
Is a congenital anomaly/birth defect
f.
Is a suspected transmission via a Pfizer product of an infectious agent, 
pathogenic or non-pathogenic 
The event may be suspected from clinical symptoms or laboratory findings 
indicating an infection in a participant exposed to a Pfizer product. The terms 
“suspected transmission” and “transmission” are considered synonymous. These 
cases are considered unexpected and handled as serious expedited cases by 
pharmacovigilance personnel. Such cases are also considered for reporting as 
product defects, if appropriate.
g. Other situations:

Medical or scientific judgment should be exercised by the investigator in deciding 
whether SAE reporting is appropriate in other situations, such as significant 
medical events that may jeopardize the participant or may require medical or 
surgical intervention to prevent one of the other outcomes listed in the above 
definition. These events should usually be considered serious.

Examples of such events include invasive or malignant cancers, intensive 
treatment in an emergency room or at home for allergic bronchospasm, blood 
dyscrasias or convulsions that do not result in hospitalization, or development of 
drug dependency or drug abuse.
10.3.3. Recording/Reporting and Follow-Up of AEs and/or SAEs During the Active 
Collection Period
AE and SAE Recording/Reporting
The table below summarizes the requirements for recording AEs on the CRF and for 
reporting SAEs using the CT SAE Report Form or via PSSA to Pfizer Safety throughout 
the active collection period. These requirements are delineated for 3 types of events: 
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(1) SAEs; (2) nonserious AEs; and (3) exposure to the study intervention under study 
during pregnancy or breastfeeding, and occupational exposure. 
It should be noted that the CT SAE Report Form or the PSSA for reporting of SAE 
information is not the same as the AE page of the CRF. When the same data are 
collected, the forms must be completed in a consistent manner. AEs should be recorded 
using concise medical terminology and the same AE term should be used on both the 
CRF and the CT SAE Report Form or the PSSA for reporting of SAE information.
Safety Event
Recorded on the CRF
Reported on the CT SAE 
Report Form or PSSA to 
Pfizer Safety Within 24 
Hours of Awareness
SAE
All
All
Nonserious AE
All
None
Exposure to the study 
intervention under study 
during pregnancy or 
breastfeeding
All AEs/SAEs associated 
with EDP or EDB
Note: Instances of EDP or 
EDB not associated with an 
AE or SAE are not captured 
in the CRF
All instances of EDP are 
reported (whether or not 
there is an associated 
SAE)*
All instances of EDB are 
reported (whether or not 
there is an associated 
SAE)**
Environmental or 
occupational exposure 
to the product under 
study to a 
nonparticipant (not 
involving EDP or EDB)
None. Exposure to a study 
non-participant is not 
collected on the CRF
The exposure (whether or 
not there is an associated 
AE or SAE) must be 
reported***
*
EDP (with or without an associated SAE): is reported to Pfizer Safety using the PSSA. 
** EDB is reported to Pfizer Safety using the PSSA, which would also include details of any SAE 
that might be associated with the EDB. 
*** Environmental or occupational exposure: AEs or SAEs associated with occupational exposure 
are reported to Pfizer Safety using the PSSA.

When an AE or SAE occurs, it is the responsibility of the investigator to review 
all documentation (eg, hospital progress notes, laboratory reports, and diagnostic 
reports) related to the event.
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
The investigator will then record all relevant AE or SAE information in the CRF.

It is not acceptable for the investigator to send photocopies of the participant’s 
medical records to Pfizer Safety in lieu of completion of the CT SAE Report 
Form/AE or SAE CRF page.

There may be instances when copies of medical records for certain cases are 
requested by Pfizer Safety. In this case, all participant identifiers, with the 
exception of the participant number, will be redacted on the copies of the medical 
records before submission to Pfizer Safety. Refer to Section 10.1.9 for actions 
that must be taken when medical records are sent to the sponsor or sponsor 
designee.

The investigator 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 or SAE.
Assessment of Intensity
The investigator will make an assessment of intensity for each AE and SAE reported 
during the study and assign it to 1 of the following categories: 

Mild: A type of AE that is usually transient and may require only minimal 
treatment or therapeutic intervention. The event does not generally interfere with 
usual ADL.

Moderate: A type of AE that is usually alleviated with additional specific 
therapeutic intervention. The event interferes with usual ADL, causing 
discomfort, but poses no significant or permanent risk of harm to the research 
participant.

Severe: A type of AE that interrupts usual ADL, or significantly affects clinical 
status, or may require intensive therapeutic intervention.
An event is defined as “serious” when it meets at least 1 of the predefined outcomes as 
described in the definition of an SAE, NOT when it is rated as severe.
Assessment of Causality

The investigator is obligated to assess the relationship between study intervention 
and each occurrence of each AE or SAE. The investigator will use clinical 
judgment to determine the relationship.
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Assessment of Causality

A “reasonable possibility” of a relationship conveys that there are facts, 
evidence, and/or arguments to suggest a causal relationship, rather than a 
relationship cannot be ruled out.

Alternative causes, such as underlying disease(s), concomitant therapy, and other 
risk factors, as well as the temporal relationship of the event to study intervention 
administration, will be considered and investigated.

The investigator will also consult the IB and/or product information, for 
marketed products, in their assessment.

For each AE or SAE, the investigator must document in the medical notes that 
they have reviewed the AE or SAE and have provided an assessment of causality.

There may be situations in which an SAE has occurred and the investigator has 
minimal information to include in the initial report to the sponsor. However, it is 
very important that the investigator always make an assessment of causality 
for every event before the initial transmission of the SAE data to the 
sponsor.

The investigator may change their opinion of causality in light of follow-up 
information and send an SAE follow-up report with the updated causality 
assessment.

The causality assessment is one of the criteria used when determining regulatory 
reporting requirements.

If the investigator does not know whether or not the study intervention caused the 
event, then the event will be handled as “related to study intervention” for 
reporting purposes, as defined by the sponsor. In addition, if the investigator 
determines that an SAE is associated with study procedures, the investigator 
must record this causal relationship in the source documents and CRF, and report 
such an assessment in the dedicated section of the CT SAE Report Form and 
PSSA and in accordance with the SAE reporting requirements.
Follow-Up of AEs and SAEs

The investigator is obligated to perform or arrange for the conduct of 
supplemental measurements and/or evaluations, as medically indicated or as 
requested by the sponsor, to elucidate the nature and/or causality of the AE or 
SAE as fully as possible. This may include additional laboratory tests or 
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Follow-Up of AEs and SAEs
investigations, histopathological examinations, or consultation with other 
healthcare providers.

If a participant dies during participation in the study or during a recognized 
follow-up period, the investigator will provide Pfizer Safety with a copy of any 
postmortem findings, including histopathology.

New or updated information will be recorded in the originally submitted 
documents.

The investigator will submit any updated SAE data to the sponsor within 
24 hours of receipt of the information.
10.3.4. Reporting of SAEs
SAE Reporting to Pfizer Safety via an Electronic DCT

The primary mechanism for reporting an SAE to Pfizer Safety will be the 
electronic DCT (eg, eSAE or PSSA).

If the electronic system is unavailable, then the site will use the paper SAE 
report form (see next section) to report the event within 24 hours.

The site will enter the SAE data into the electronic DCT (eg, eSAE or PSSA) or 
paper form (as applicable) as soon as the data become available.

After the study is completed at a given site, the electronic DCT will be taken 
off-line to prevent the entry of new data or changes to existing data.

If a site receives a report of a new SAE from a study participant or receives 
updated data on a previously reported SAE after the electronic DCT has been 
taken off-line, then the site can report this information on a paper SAE form (see 
next section) or to Pfizer Safety by telephone.
SAE Reporting to Pfizer Safety via the CT SAE Report Form

Facsimile transmission of the CT SAE Report Form is one of the methods to 
transmit this information to Pfizer Safety.

Facsimile transmission of the CT SAE Report Form is the back-up method to 
transmit this information to Pfizer Safety in case PSSA is unavailable for more 
than 24 hours.
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SAE Reporting to Pfizer Safety via the CT SAE Report Form

In circumstances when the facsimile is not working, an alternative method should 
be used, eg, secured (Transport Layer Security) or password-protected email. If 
none of these methods can be used, notification by telephone is acceptable with a 
copy of the CT SAE Report Form sent by overnight mail or courier service.

Initial notification via telephone does not replace the need for the investigator to 
complete and sign the CT SAE Report Form pages within the designated 
reporting time frames.
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10.4. Appendix 4: Contraceptive and Barrier Guidance
10.4.1. Male Participant Reproductive Inclusion Criteria
Male participants are eligible to participate if they agree to the following requirements during 
the intervention period and for at least 28 days after the last dose of study intervention, which 
corresponds to the time needed to eliminate reproductive safety risk of the study intervention 
plus an additional 28 days (a spermatogenesis cycle): 

Refrain from donating sperm.
PLUS either:

Be abstinent from heterosexual intercourse as their preferred and usual lifestyle 
(abstinent on a long-term and persistent basis) and agree to remain abstinent.
OR

Must agree to use a male condom when engaging in any activity that allows for 
passage of ejaculate to another person.

The male participant should be advised of the benefit for a WOCBP partner using a 
highly effective method of contraception with a failure rate of <1% per year, as 
described in Section 10.4.4.
10.4.2. Female Participant Reproductive Inclusion Criteria
The criteria below are part of Inclusion Criterion 1 (Age and Sex; Section 5.1) and specify 
the reproductive requirements for including female participants. Refer to Section 10.4.4 for a 
complete list of contraceptive methods permitted in the study. 

A female participant is eligible to participate if she is not pregnant or breastfeeding 
and at least 1 of the following conditions applies:

Is not a WOCBP (see definition in Section 10.4.3).
            OR

Is a WOCBP and agrees to use a highly effective contraceptive method (failure rate of 
<1% per year) during the intervention period and for at least 28 days after the last 
dose of study intervention, which corresponds to the time needed to eliminate any 
reproductive safety risk of the study intervention. If a highly effective, 
user-dependent method is chosen, she agrees to concurrently use an effective barrier 
method of contraception. The investigator should evaluate the effectiveness of the 
contraceptive method in relationship to the first dose of study intervention.
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The investigator is responsible for review of medical history, menstrual history, and recent 
sexual activity to decrease the risk for inclusion of a woman with an early undetected 
pregnancy.
10.4.3. Woman of Childbearing Potential
A woman is considered fertile following menarche and until becoming postmenopausal 
unless permanently sterile (see below).
If fertility is unclear (eg, amenorrhea or oligomenorrhea) and a menstrual cycle cannot be 
confirmed before the first dose of study intervention, additional evaluation should be 
considered.
Women in the following categories are not considered WOCBP:
1. Premenopausal female with 1 of the following:

Documented hysterectomy;

Documented bilateral salpingectomy;

Documented bilateral oophorectomy.
For individuals with permanent infertility due to a medical cause other than the above
(eg, mullerian agenesis, androgen insensitivity), investigator discretion should be applied 
to determining study entry.
Note: Documentation for any of the above categories can come from the site personnel’s 
review of the participant’s medical records, medical examination, or medical history 
interview. The method of documentation should be recorded in the participant’s medical 
record for the study.
2. Postmenopausal female.

A postmenopausal state is defined as no menses for 12 months without an 
alternative medical cause. In addition:

A high FSH level in the postmenopausal range must be used to confirm a 
postmenopausal state in women under 60 years old and not using hormonal 
contraception or HRT. 

A female on HRT and whose menopausal status is in doubt will be required to 
use one of the highly effective nonestrogen hormonal contraception methods 
if she wishes to continue her HRT during the study. Otherwise, she must 
discontinue HRT to allow confirmation of postmenopausal status before study 
enrollment.
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10.4.4. Contraception Methods
Contraceptive use by men or women should be consistent with local availability/regulations 
regarding the use of contraceptive methods for those participating in clinical trials.
The following contraceptive methods are appropriate for this study:
Highly Effective Methods That Have Low User Dependency 
1. Implantable progestogen-only hormone contraception associated with inhibition of 
ovulation.
2. Intrauterine device.
3. Intrauterine hormone-releasing system.
4. Bilateral tubal occlusion.
5. Vasectomized partner:

Vasectomized partner is a highly effective contraceptive method provided that the 
partner is the sole sexual partner of the WOCBP and the absence of sperm has 
been confirmed. If not, an additional highly effective method of contraception 
should be used. The spermatogenesis cycle is approximately 90 days.
Highly Effective Methods That Are User Dependent 
6. Combined (estrogen- and progestogen-containing) hormonal contraception associated 
with inhibition of ovulation:

Oral + barrier*

Intravaginal + barrier*

Transdermal + barrier*
7. Progestogen-only hormone contraception associated with inhibition of ovulation:

Oral + barrier*

Injectable + barrier*
Sexual Abstinence
8. Sexual abstinence is considered a highly effective method only if defined as 
refraining from heterosexual intercourse during the entire period of risk associated 
with the study intervention. The reliability of sexual abstinence needs to be evaluated 
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in relation to the duration of the study and the preferred and usual lifestyle of the 
participant
* Acceptable barrier methods to be used concomitantly with options 6 or 7 for the study 
include any of the following:

Male or female condom, with or without spermicide;

Cervical cap, diaphragm or sponge with spermicide;

A combination of male condom with either cervical cap, diaphragm or sponge 
with spermicide (double-barrier methods).
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10.5. Appendix 5: Genetics
Use/Analysis of DNA

Genetic variation may impact a participant’s response to study intervention, 
susceptibility to, and severity and progression of disease. Therefore, where local 
regulations and IRBs/ECs allow, a blood sample will be collected for DNA analysis.

The scope of the genetic research may be narrow (eg, 1 or more candidate genes) or
broad (eg, the entire genome), as appropriate to the scientific question under 
investigation.

The samples may be analyzed as part of a multistudy assessment of genetic factors 
involved in the response to zavegepant or study interventions of this class to 
understand treatments for the disease(s) under study or the disease(s) themselves.

The results of genetic analyses may be reported in the CSR or in a separate study 
summary, or may be used for internal decision making without being included in a 
study report.

The sponsor will store the DNA samples in a secure storage space with adequate 
measures to protect confidentiality. 

The samples will be retained as indicated:

Retained samples will be stored indefinitely or for another period as per local 
requirements.

Participants may withdraw their consent for the storage and/or use of their Retained 
Research Samples at any time by making a request to the investigator; in this case, any 
remaining material will be destroyed. Data already generated from the samples will be 
retained to protect the integrity of existing analyses.

Samples for genetic research will be labeled with a code. The key between the code 
and the participant’s personally identifying information (eg, name, address) will be 
held securely at the study site.
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10.6. Appendix 6: Liver Safety: Suggested Actions and Follow-Up Assessments
Potential Cases of Drug-Induced Liver Injury
Humans exposed to a drug who show no sign of liver injury (as determined by elevations in 
transaminases) are termed “tolerators,” while those who show transient liver injury but adapt 
are termed “adaptors.” In some participants, transaminase elevations are a harbinger of a 
more serious potential outcome. These participants fail to adapt and therefore are 
“susceptible” to progressive and serious liver injury, commonly referred to as DILI. 
Participants who experience a transaminase elevation above 3 × ULN should be monitored 
more frequently to determine if they are “adaptors” or are “susceptible.”
In the majority of DILI cases, elevations in AST and/or ALT precede T bili elevations 
(>2 × ULN) by several days or weeks. The increase in T bili typically occurs while 
AST/ALT is/are still elevated above 3 × ULN (ie, AST/ALT and T bili values will be 
elevated within the same laboratory sample). In rare instances, by the time T bili elevations 
are detected, AST/ALT values might have decreased. This occurrence is still regarded as a 
potential DILI. Therefore, abnormal elevations in either AST OR ALT in addition to T bili 
that meet the criteria outlined below are considered potential DILI (assessed per Hy’s law 
criteria) cases and should always be considered important medical events, even before all 
other possible causes of liver injury have been excluded.
The threshold of laboratory abnormalities for a potential DILI case depends on the 
participant’s individual baseline values and underlying conditions. Participants who present 
with the following laboratory abnormalities should be evaluated further as potential DILI 
(Hy’s law) cases to definitively determine the etiology of the abnormal laboratory values:

Participants with AST/ALT and T bili baseline values within the normal range who 
subsequently present with AST OR ALT values ≥3 × ULN AND a T bili value ≥2 × ULN 
with no evidence of hemolysis and an alkaline phosphatase value <2 × ULN or not 
available.

For participants with baseline AST OR ALT OR T bili values above the ULN, the 
following threshold values are used in the definition mentioned above, as needed, 
depending on which values are above the ULN at baseline:

Preexisting AST or ALT baseline values above the normal range: AST or ALT 
values ≥2 times the baseline values AND ≥3 × ULN; or ≥8 × ULN (whichever is 
smaller).

Preexisting values of T bili above the normal range: T bili level increased from 
baseline value by an amount of ≥1 × ULN or if the value reaches ≥3 × ULN 
(whichever is smaller).
Rises in AST/ALT and T bili separated by more than a few weeks should be assessed 
individually based on clinical judgment; any case where uncertainty remains as to whether it 
represents a potential Hy’s law case should be reviewed with the sponsor. 
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The participant should return to the investigator site and be evaluated as soon as possible, 
preferably within 48 hours from awareness of the abnormal results. This evaluation should 
include laboratory tests, detailed history, and physical assessment. 
In addition to repeating measurements of AST and ALT and T bili for suspected Hy’s law 
cases, additional laboratory tests should include albumin, CK, direct and indirect bilirubin, 
GGT, PT/INR, eosinophils (%), and alkaline phosphatase. Consideration should also be
given to drawing a separate tube of clotted blood and an anticoagulated tube of blood for 
further testing, as needed, for further contemporaneous analyses at the time of the recognized 
initial abnormalities to determine etiology. A detailed history, including relevant information, 
such as review of ethanol, acetaminophen/paracetamol (either by itself or as a coformulated 
product in prescription or over-the-counter medications), recreational drug, or supplement 
(herbal) use and consumption, family history, sexual history, travel history, history of contact 
with a jaundiced person, surgery, blood transfusion, history of liver or allergic disease, and 
potential occupational exposure to chemicals, should be collected. Further testing for acute 
hepatitis A, B, C, D, and E infection, total bile acids, liver imaging (eg, biliary tract), and 
collection of serum samples for acetaminophen/paracetamol drug and/or protein adduct 
levels may be warranted. 
All cases demonstrated on repeat testing as meeting the laboratory criteria of AST/ALT and 
T bili elevation defined above should be considered potential DILI (Hy’s law) cases if no 
other reason for the LFT abnormalities has yet been found. Such potential DILI (Hy’s law) 
cases are to be reported as SAEs, irrespective of availability of all the results of the 
investigations performed to determine etiology of the LFT abnormalities.
A potential DILI (Hy’s law) case becomes a confirmed case only after all results of 
reasonable investigations have been received and have excluded an alternative etiology.
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10.7. Appendix 7: Kidney Safety: Monitoring Guidelines
10.7.1. Laboratory Assessment of Change in Kidney Function and Detection of Kidney 
Injury
Standard kidney safety monitoring requires assessment of baseline and postbaseline Screat 
measurement to estimate kidney function [Screat-based eGFR] or creatinine clearance 
[eCrCl]). Obtaining Screening or Baseline Scys and postbaseline reflex Scys (if confirmed 
Screat increase ≥0.3 mg/dL) makes it feasible to distinguish AKI from DICI. If Screat 
increase is confirmed after baseline, then reflex measurement of Scys is indicated.
ADULTS: Currently, 2021 CKD-EPI eGFR equations (Screat only-based and combined 
Screat plus Scys-based) are valid for use in adults only. At baseline Screat and Scys values 
are needed to calculate 2021 CKD-EPI eGFR by Screat only-based equation (see Table 
10.7.2.1.) and by combined Screat plus Scys-based equation. When post-baseline Screat 
increase ≥0.3 mg/dL is confirmed, then reflex Scys measurement is needed to enable post-
baseline comparison of eGFR changes (Screat only-based eGFR and combined Screat plus 
Scys eGFR). 
10.7.2. Age-Specific Kidney Function Calculation Recommendations
10.7.2.1. Adults (18 Years and Above)—2021 CKD-EPI Equations
eGFR (mL/min/1.73m²)39
2021 CKD-
EPI         
Screat Only
Screat
(mg/dL)
Scys
(mg/L)
Recommended eGFR Equation
Female
if ≤0.7
NA
eGFR = 143 × (Screat/0.7)-0.241  ×  (0.9938)Age
Female
if > 0.7
NA
eGFR = 143 × (Screat/0.7)-1.200  ×  (0.9938)Age
Male
if ≤0.9
NA
eGFR = 142 × (Screat/0.9)-0.302  ×  (0.9938)Age
Male
if > 0.9
NA
eGFR = 142 × (Screat/0.9)-1.200  ×  (0.9938)Age
2021 CKD-
EPI         
Screat-Scys
Combined
Screat
(mg/dL)
Scys
(mg/L)
Recommended eGFR Equation
Female
if ≤0.7
if ≤0.8
eGFR = 130 × (Screat/0.7)-0.219  × (Scys/0.8)-0.323  × (0.9961)Age
Female
if ≤0.7
if > 0.8
eGFR = 130 × (Screat/0.7)-0.219  × (Scys/0.8)-0.778  × (0.9961)Age
Female
if > 0.7
if ≤0.8
eGFR = 130 × (Screat/0.7)-0.544  × (Scys/0.8)-0.323  × (0.9961)Age
Female
if > 0.7
if > 0.8
eGFR = 130 × (Screat/0.7)-0.544  × (Scys/0.8)-0.778  × (0.9961)Age
Male
if ≤0.9
if ≤0.8
eGFR = 135 × (Screat/0.9)-0.144  × (Scys/0.8)-0.323  × (0.9961)Age
Male
if ≤0.9
if > 0.8
eGFR = 135 × (Screat/0.9)-0.144  × (Scys/0.8)-0.778  × (0.9961)Age
Male
if > 0.9
if ≤0.8
eGFR = 135 × (Screat/0.9)-0.544  ×  (Scys/0.8)-0.323  × (0.9961)Age
Male
if > 0.9
if > 0.8
eGFR = 135 × (Screat/0.9)-0.544  ×  (Scys/0.8)-0.778  × (0.9961)Age
10.7.3. Kidney Function Calculation Tools
The sponsor has provided the following resources to investigational sites when required to 
calculate age-specific kidney function at Screening, Baseline, and post-Baseline visits. Site 
calculations of kidney function can be performed manually, using the age appropriate 
formulae (see Section 10.7.2) and can use recommended online kidney function calculators 
to reduce the likelihood of a calculation error. 
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The United States National Kidney Foundation Online Calculators. 

Adults (18 years and above) - 2021 CKD-EPI Creatinine Online Calculator (eGFR): 
https://www.kidney.org/professionals/KDOQI/gfr_calculator
Investigational sites are responsible to ensure that the accurate age-specific equation is 
selected and that the correct units for serum creatinine (mg/dL only), serum cystatin C (mg/L 
only), total body weight (kg only), and age (years). Investigators are expected to (i) review 
and confirm correctness of the kidney function calculation results and (ii) evaluate the 
calculated value within the context of historical information available to them in the 
participant’s medical record. Investigators are responsible for the clinical oversight of the 
participant eligibility process, kidney function calculation, and dose selection and 
adjustments per study protocol. Investigators are encouraged to direct questions or 
uncertainties regarding kidney function and dosing to the Pfizer Clinical Team and Medical 
Monitor, if needed.
10.7.4. Adverse Event Grading for Kidney Safety Laboratory Abnormalities
AE grading for decline in kidney function (ie, eGFR or eCrCl) will be according to Kidney
disease: Improving Global Outcomes (KDIGO) criteria.
NON-ONCOLOGY Studies
KDIGO 
criteria
Grade 1
Grade 2
Grade 3
Grade 4
Grade 5
Decreased 
Kidney Function 
due to either 
Acute or 
Chronic Kidney 
Injury 
eGFR ≥90 
mL/min/1.73m² 
OR                
eCrCl ≥90 
mL/min 
eGFR ≥60 to 89 
mL/min/1.73m² 
OR                
eCrCl ≥60 to 89 
mL/min 
eGFR 30 to 59 
mL/min/1.73m² 
OR eCrCl 30 to 
59 mL/min
eGFR 15 to 29 
mL/min/1.73m² 
OR eCrCl 15 to 
29 mL/min
eGFR <15 
mL/min/1.73m² OR 
eCrCl <15 mL/min 
OR dialysis indicated
Albuminuria
Albuminuria 
<30 mg/g OR     
<3 mg/mmol
Albuminuria     
30 to 300 mg/g 
OR 3 to 30 
mg/mmol
Albuminuria 
>300 mg/gm OR 
<3 mg/mmol
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10.8. Appendix 8: ECG Findings of Potential Clinical Concern
ECG Findings That May Qualify as AEs

Marked sinus bradycardia (rate <40 bpm) lasting minutes.

New PR interval prolongation >280 ms.

New prolongation of QTcF to >480 ms (absolute).

New prolongation of QTcF by >60 ms from baseline.

New-onset atrial flutter or fibrillation, with controlled ventricular response rate: ie, 
rate <120 bpm.

New-onset type I second-degree (Wenckebach) AV block of >30-second duration.

Frequent PVCs, triplets, or short intervals (<30 seconds) of consecutive 
ventricular complexes.
ECG Findings That May Qualify as SAEs

QTcF prolongation >500 ms.

Absolute value of QTcF > 450 ms AND QTcF change from baseline >60 ms.

New ST-T changes suggestive of myocardial ischemia.

New-onset LBBB (QRS complex>120 ms).

New-onset right bundle branch block (QRS complex>120 ms).

Symptomatic bradycardia.

Asystole

In awake, symptom-free participants in sinus rhythm, with documented 
asystolic pauses ≥3 seconds or any escape rate <40 bpm, or with an escape 
rhythm that is below the AV node;

In awake, symptom-free participants with atrial fibrillation and bradycardia 
with 1 or more asystolic pauses of at least 5 seconds or longer. 

Atrial flutter or fibrillation, with rapid ventricular response rate: rapid = rate 
>120 bpm.
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
Sustained supraventricular tachycardia (rate >120 bpm) (“sustained” = short 
duration with relevant symptoms or lasting >1 minute).

Ventricular rhythms >30 seconds’ duration, including idioventricular rhythm (HR
<40 bpm), accelerated idioventricular rhythm (HR >40 bpm to <100 bpm), and 
monomorphic/polymorphic ventricular tachycardia (HR >100 bpm [such as
torsades de pointes]).

Type II second-degree (Mobitz II) AV block.

Complete (third-degree) heart block.
ECG Findings That Qualify as SAEs

Change in pattern suggestive of new myocardial infarction.

Sustained ventricular tachyarrhythmias (>30-seconds duration).

Second- or third-degree AV block requiring pacemaker placement.

Asystolic pauses requiring pacemaker placement.

Atrial flutter or fibrillation with rapid ventricular response requiring cardioversion.

Ventricular fibrillation/flutter.

At the discretion of the investigator, any arrhythmia classified as an adverse 
experience.
The major events of potential clinical concern listed above are recommended as “alerts” or notifications 
from the core ECG laboratory to the investigator and Pfizer study team, and not to be considered as all-
inclusive of what is reported as AEs/SAEs.
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10.9. Appendix 9: AEs, ADEs, SAEs, SADEs, USADEs, and Device Deficiencies: 
Definitions and Procedures for Recording, Evaluating, FollowUp, and Reporting in 
Medical Device Studies 
Definitions of a Medical Device Deficiency
The definitions and procedures detailed in this appendix are in accordance with ISO 14155 
and the European MDR 2017/745 for clinical device research (if applicable). 
Both the investigator and the sponsor will comply with all local reporting requirements for 
medical devices.
The detection and documentation procedures described in this protocol apply to all sponsor 
medical devices provided for use in the study (see Section 6) for the list of sponsor medical 
devices).
10.9.1. Definition of AE and ADE
AE and ADE Definition

An AE is defined in Appendix 3 (Section 10.3.1).

An ADE is defined as an AE related to the use of an investigational medical device. 
This definition includes any AEs resulting from insufficient or inadequate 
instructions for use, deployment, implantation, installation, or operation, or any 
malfunction of the investigational medical device as well as any event resulting 
from use error or from intentional misuse of the investigational medical device.
10.9.2. Definition of SAE, SADE, and USADE
SAE Definition

An SAE is defined in Appendix 3 (Section 10.3.2).
SADE Definition

An SADE is defined as an ADE that has resulted in any of the consequences 
characteristic of an SAE.

Any device deficiency that might have led to an SAE if appropriate action had not 
been taken, intervention had not occurred, or circumstances had been less fortunate.
USADE Definition
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
A USADE (also identified as UADE in US Regulations 21 CFR 813.3) is a SADE
that by its nature, incidence, severity, or outcome has not been identified in the 
current version of the risk analysis management file.
10.9.3. Definition of Device Deficiency
Device Deficiency Definition

A device deficiency is an inadequacy of a medical device with respect to its 
identity, quality, durability, reliability, safety, or performance. Device deficiencies 
include malfunctions, use errors, and inadequate information supplied by the 
manufacturer.
10.9.4. Recording/Reporting and Follow-Up of Medical Device Deficiencies
Device Deficiency Recording

When a device deficiency occurs, it is the responsibility of the investigator to 
review all documentation (e.g., hospital progress notes, laboratory reports, and 
diagnostic reports) related to the event.

The investigator will then record all relevant device deficiency information in the 
participant’s medical records, in accordance with the investigator’s normal clinical 
practice.  

If an AE (either serious or nonserious) associated with the device deficiency 
occurs, then the AE must be entered into the AE section of the CRF.

The investigator will notify the sponsor study team by email within 1 business day 
of determining that the incident meets the protocol definition of a medical device 
deficiency.

The sponsor study team will capture the required information on the Medical 
Device Complaint form along with any associated AE (either serious or 
nonserious) when applicable and send to the appropriate product quality complaint 
group.

If the investigator determines that the medical device deficiency may have injured 
the participant (ie, the medical device deficiency is associated with an AE or SAE), 
then the investigator will attempt to establish a diagnosis of the event based on 
signs, symptoms, and/or other clinical information. Whenever possible, the 
diagnosis will be documented in the participant’s medical record and recorded as 
the AE or SAE rather than the individual signs/symptoms.  All relevant details 
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Device Deficiency Recording
related to the role of the device in regard to the SAE must be included in via PSSA
as outlined in Sections 8.4.1.1 and 8.4.1.2. 

There may be instances when copies of medical records for certain cases are 
requested by Pfizer Safety. In this case, all participant identifiers, with the 
exception of the participant number, will be redacted on the copies of the medical 
records before submission to Pfizer Safety. Refer to Section 10.1.9 for actions that 
must be taken when medical records are sent to the sponsor or sponsor designee.

For device deficiencies, it is very important that the investigator describes any 
corrective or remedial actions taken to prevent recurrence of the incident.

A remedial action is any action other than routine maintenance or servicing of a 
medical device where such action is necessary to prevent recurrence of a device 
deficiency. This includes any amendment to the device design to prevent 
recurrence.
Assessment of Causality Occurring in Conjunction With a Medical Device Deficiency

If an AE or SAE has occurred in conjunction with a medical device deficiency, the 
investigator must assess the relationship between each occurrence of the AE or 
SAE and the medical device deficiency. The investigator will use clinical judgment 
to determine the relationship.

A “reasonable possibility” of a relationship conveys that there are facts, evidence, 
and/or arguments to suggest a causal relationship, rather than a relationship cannot 
be ruled out.

Alternative causes, such as underlying disease(s), concomitant therapy, and other 
risk factors, as well as the temporal relationship of the event to study intervention 
administration will be considered and investigated.

The investigator will also consult the IB in their assessment.

For each device deficiency, the investigator must document in the medical notes 
that they have reviewed the device deficiency and have provided an assessment of 
causality.

There may be situations in which an SAE has occurred and the investigator has 
minimal information to include in the initial report to the sponsor. However, it is 
very important that the investigator always make an assessment of causality for 
every event before the initial transmission of the SAE data to the sponsor.
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Assessment of Causality Occurring in Conjunction With a Medical Device Deficiency

The investigator may change their opinion of causality in light of follow-up 
information and send an SAE follow-up report with the updated causality 
assessment.

The causality assessment is one of the criteria used when determining regulatory 
reporting requirements.
Follow-Up of Medical Device Deficiency

Follow-up applies to all participants, including those who discontinue study 
intervention.

The investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations, as medically indicated or as requested by the 
sponsor to elucidate the nature and/or causality of the device deficiency as fully as 
possible. This may include additional laboratory tests or investigations, 
histopathological examinations, or consultation with other healthcare providers.

New or updated information regarding the nature of the device deficiency will be 
recorded in the originally completed Medical Device Complaint form by the 
sponsor study team.

New or updated information regarding any SAE that was potentially associated 
with the medical device deficiency will be submitted to Pfizer Safety via PSSA
within 24 hours of receipt of the information, according to the requirements 
provided in Appendix 3.
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10.10. Appendix 10: Prohibited Concomitant Medications That May Result in DDI
The prohibited concomitant medications listed below should not be taken with study 
intervention for a period of time at least equal to the required washout period listed in the 
table and throughout the study.  
The Pfizer study team is to be notified of any prohibited medications taken during the study. 
After consulting with the sponsor, the investigator will make a judgment on the ongoing 
participation of any participant with prohibited medication use during the study.
This list of drugs prohibited for potential DDI concerns with the IMP may be revised during 
the course of the study with written notification from the sponsor to include or exclude 
specific drugs or drug categories for various reasons (e.g., emerging DDI results for the IMP, 
availability of new information in the literature on the DDI potential of other drugs) if the 
overall benefit/risk assessment is not impacted or if the changes do not significantly impact 
the safety of participants or the scientific value of the trial.  
This is not an all-inclusive list. Site staff should consult with the sponsor or designee with 
any questions regarding potential DDI.
Drug 
Category 
Drugs 
Required Washout Period 
Requirement
OATP1B3 
inhibitors
atazanavir/ritonavir, clarithromycin, 
cyclosporine, gemfibrozil, lopinavir/ritonavir, 
rifampin
14 days or 5 half-lives, whichever is 
longer
Investigators should consult the SRSD for active comparator for information regarding 
medication prohibited for concomitant use. 
Investigators should consult the product label for any other medication used during the study 
for information regarding medication prohibited for concomitant use. 
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10.11. Appendix 11: Taste Assessment Questionnaire
1. Questionnaire should be administered to adult participants, preferably by the trained 
staff. The clinical staff is trained by the CRU clinical coordinator for performing the 
taste questionnaire and regarding the specific study restrictions.
2. Use colored copy of the questionnaire.
3. Do not alter (reduce or enlarge) the original size of the questionnaire.
4. Please gather the following background information: 
Background Information
Study #/Study Site
Period and Day
Participant ID (Rand ID)
Study Intervention
Collection Date
Collection Time
Name of trained staff
Questionnaire fully completed
Yes/No
Please answer the following questions and provide a mark () on the color bar at 
1 (immediately), 5, 10 and 20 minutes after dosing. Please ensure subject has access to these 
descriptions when completing the questionnaire. 
Q1: Overall liking – Please indicate how much you like or dislike the taste of the drug 
administered.
Q2: Bitterness – Please tell us about the degree of bitterness after drug administration.
Q3: Tongue/mouth burn – Please tell us about the degree of tongue/mouth burn after drug 
administration.
Q4: Throat burn – Please tell us about the degree of throat burn after drug administration.
Q5: Sour taste – Please tell us about the degree of sourness after drug administration.
Q6: Salty taste – Please tell us about the degree of saltiness after drug administration.
Q7: Sweet taste – Please tell us about the degree of sweetness after drug administration.
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Example: How to provide a mark (x) on the color bar

Good (score = 0)
Bad (score = 100)
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Within 1 minute (immediately) after dosing
Provide a mark ( ) on the color bar.
Overall 
Liking
Bitterness
Tongue/
Mouth 
Burn
Throat 
Burn
Sour 
Taste
Salty 
Taste
Sweet 
Taste
Good 
Bad 
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5 minutes after dosing
Provide a mark ( ) on the color bar.
Overall 
Liking
Bitterness
Tongue/
Mouth 
Burn
Throat 
Burn
Sour 
Taste
Salty 
Taste
Sweet 
Taste
Bad 
Good 
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10 minutes after dosing
Provide a mark ( ) on the color bar.
Overall 
Liking
Bitterness
Tongue/Mouth 
Burn
Throat 
Burn
Sour 
Taste
Salty 
Taste
Sweet 
Taste
Good 
Bad 
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20 minutes after dosing
Provide a mark ( ) on the color bar.
Overall 
Liking
Bitterness
Tongue/Mouth 
Burn
Throat 
Burn
Sour 
Taste
Salty 
Taste
Sweet 
Taste
Good 
Bad 
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Additional Feedback – After completing the “20 minute after dosing” taste questions, 
please provide any additional descriptive feedback in the box below regarding the taste 
experienced after drug administration.
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10.12. Appendix 12: Abbreviations
The following is a list of abbreviations that may be used in the protocol.
Abbreviation
Term
A1 to A3
albuminuria (Kidney Disease Improving Global Outcomes 
[KDIGO] albuminuria severity standardization)
Abs
absolute
ADE
adverse device effect
ADL
activity/activities of daily living
AE
adverse event
AKI
acute kidney injury
ALT
alanine aminotransferase
AST
aspartate aminotransferase
AUC
area under the curve
AUCinf
area under plasma concentration-time profile from time 0 
extrapolated to infinite time
AUClast
area under the plasma concentration-time profile from time 0 to the 
time of last quantifiable concentration (Clast)
AV
atrioventricular
AxMP
auxiliary medicinal product
-hCG
-human chorionic gonadotropin
BMI
body mass index
BP
blood pressure
BUN
blood urea nitrogen
bpm
beats per minute
CFR
Code of Federal Regulations
CGRP
calcitonin gene-related peptide
CIOMS
Council for International Organizations of Medical Sciences
CK
creatine kinase
CKD-EPI
chronic kidney disease epidemiology
CL/F
apparent clearance
Cmax
maximum plasma concentration
CO2
carbon dioxide (bicarbonate)
COVID-19
coronavirus disease 2019
CRF
case report form
CRO
contract research organization
CRU
clinical research unit
CSR
Clinical Study Report
CTIS
Clinical Trial Information System
CTMS
clinical trial management system
CYP
cytochrome P450
DCT
data collection tool
DDI
drug-drug interaction 
DICI
drug-induced creatinine increase
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Abbreviation
Term
DIKI
drug-induced kidney injury
DILI
drug-induced liver injury
EC
ethics committee
ECC
emergency contact card
ECG
electrocardiogram or electrocardiography
eCrCl
estimated creatinine clearance
eCRF
electronic case report form
EDB
exposure during breastfeeding
E-DMC
External Data Monitoring Committee
EDP
exposure during pregnancy
EE
ethinyl estradiol
eGFR
estimated glomerular filtration rate
eICD
electronic informed consent document
EOT
end of treatment
eSAE
electronic serious adverse event
EU
European Union
EudraCT
European Union Drug Regulating Authorities Clinical Trials 
(European Clinical Trials Database)
FDA
Food and Drug Administration
FSH
follicle-stimulating hormone
F/U
follow-up
GCP
Good Clinical Practice
GGT
gamma-glutamyl transferase
HBcAb
hepatitis B core antibody
HBsAb
hepatitis B surface antibody
HBsAg 
hepatitis B surface antigen
HCG
human chorionic gonadotropin
HCVAb
hepatitis C antibody
HIV
human immunodeficiency virus
HR
heart rate
HRT
hormone replacement therapy
IB
Investigator’s Brochure
ICD
informed consent document
ICH
International Council for Harmonisation of Technical 
Requirements for Pharmaceuticals for Human Use
ID
identification
IMP
investigational medicinal product
IN
intranasal
IND
Investigational New Drug 
INR
international normalized ratio
IP
interventional product
IPAL
Investigational Product Accountability Log
IPM
investigational product manual
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Abbreviation
Term
IRB
Institutional Review Board
ISO
International Organization for Standardization
IU/L
international units per liter
IV
intravenous(ly)
KDIGO
Kidney Disease Improving Global Outcomes
kel
elimination constant
LBBB
left bundle branch block
LFT
liver function test
LNG
levonorgestrel
MBS
modified barium swallow
MDR
medical device regulation
MQI
medically qualified individual
NA
not applicable
NIMP
non-investigational medicinal product
NTCP
sodium taurocholate co-transporting polypeptide
OATP
organic anion transporting polypeptide
OTC
over-the-counter
PCRU
Pfizer Clinical Research Unit
PCS
patient-centric sampling
PE
physical examination
P-gp
P-glycoprotein
PI
principal investigator
PK
pharmacokinetic(s)
PO
orally
PSSA
Pfizer's Serious Adverse Event Submission Assistant
PT
prothrombin time
PVC
premature ventricular contraction/complex
QD
once daily
QTc
corrected QT interval
QTcF
QTc corrected using Fridericia’s formula
qual
qualitative
RBC
red blood cell
RNA
ribonucleic acid
SADE
serious adverse device effect
SAE
serious adverse event
SAP
Statistical Analysis Plan
Screat
serum creatinine 
Scys
serum cystatin C
SoA
schedule of activities
SOP
standard operating procedure
SRSD
Single Reference Safety Document
SUSAR
Suspected Unexpected Serious Adverse Reaction
t½
terminal half-life
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Abbreviation
Term
T bili
total bilirubin
TEAE(s)
treatment-emergent adverse event(s)
THC
tetrahydrocannabinol
Tmax
time to Cmax
UACR
urine albumin-to-creatinine-ratio
UK
United Kingdom
ULN
upper limit of normal
USA
United States of America
USADE
unanticipated serious adverse device effect
US
United States
UTI
urinary tract infection
Vz/F
apparent volume of distribution
WBC
white blood cell
WOCBP
woman/women of childbearing potential
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Goadsby PJ, Edvinsson L. The trigeminovascular system and migraine: studies 
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