Clinical trial NCT05712460
Conditions: Respiratory Syncytial Viruses
Keywords: RSV respiratory syncytial virus
Sponsor: Pfizer
Start date: 2023-02-08; Completion date: 2023-04-28
Enrollment: 12 participants; Allocation: RANDOMIZED; Intervention model: CROSSOVER

Brief summary:
This study is seeking healthy participants who are:

1. Aged 18 to 65 years of age. All fertile participants must agree to use a highly effective method of contraception.
2. Male and female participants who are overtly healthy as determined by medical evaluation. This includes medical history, physical examination, blood pressure, pulse rate, standard 12-lead ECG (electrocardiogram), and laboratory tests.
3. BMI (body mass index) of 17.5 to 35 kg/m2; and a total body weight \>50 kg (110 lb).

This study will consist of up to 2 cohorts (groups of participants).:

Cohort 1 is a randomized, 2-part, crossover cohort. Part 1 has 3 periods. Periods 1 and 2 are to evaluate the safety and effects of sisunatovir. Participants will take sisunatovir tablets or placebo by mouth once every 12 hours. A placebo looks like the study medicine but does not contain any active medicine in it.

Period 3 is an open label period to evaluate the food effect of the planned higher dose of sisunatovir. Participants will take the planned higher dose sisunatovir tablets every 12 hours. In Part 2, participants will take sisunatovir prepared in 4 different vehicles (water, infant formula, apple juice, and saline) to assess how palatable each form is. Participants will complete a questionnaire after tasting each form of sisunatovir. The palatability questionnaire will be completed for each vehicle, the questionnaire asks participants to assess each vehicle at 4 different time increments after tasting. At least 60 minutes will pass between tasting each vehicle. Period 4 may start after the last PK draw of Period 3.

A minimum 7-day washout period will occur between the last dose of Periods 1 and 2 and the first dose of Periods 2 and 3. We will assess the safety of participants following each study period and doses and adjust the doses for subsequent study periods as needed.

Cohort 2 is an optional cohort; the design of Cohort 2 is the same as Part 1 of Cohort 1. Dose levels studied in Cohort 2 will be determined after the completion of Cohort 1.

Participants will take part in this study for approximately 2 months, excluding the screening period. During this time there are 3 separate 7-day in-patient stays at the study clinic and a follow-up phone call that takes place 28-35 days after the last dose of study medicine.

Detailed description:

Arms: arm 1: higher dose of sisunatovir dosed every 12 hours arm 2: Lower dose of sisunatovir dosed every 12 hours arm 3: Placebo for sisunatovir dosed every 12 hours arm 4: Higher dose of sisunatovir dosed every 12 hours under fasted conditions arm 5: Sisunatovir in 4 vehicles (water, saline, apple juice, infant formula) to assess the palatability of sisunatovir in each vehicle. sisunatovir will not be swallowed, participants will swirl and spit to assess various aspects of the taste.
Interventions: intervention 1: sisunatovir intervention 2: Placebo
Intervention descriptions: intervention 1: Sisunatovir is an orally administered RSV F-protein inhibitor being developed to target viral-host cell fusion for the treatment of adult and pediatric patients with RSV intervention 2: Placebo for sisunatovir

Protocol documents:
Prot_000.pdf: 
PF-07923568 
Protocol C5241006 
FINAL Protocol, 23 December 2022, Amendment 1 
PFIZER CONFIDENTIAL 
Page 1 
 
 
 
 
 
 
A PHASE 1, RANDOMIZED, SPONSOR OPEN, TWO-PART CROSSOVER STUDY 
TO ASSESS SAFETY, TOLERABILITY, PHARMACOKINETICS AND FOOD 
EFFECT OF MULTIPLE DOSES IN PART 1 AND PALATABILITY OF A SINGLE 
DOSE OF SISUNATOVIR IN PART 2, IN HEALTHY ADULT PARTICIPANTS 
 
 
Study Intervention Number: 
PF-07923568 
Study Intervention Name: 
Sisunatovir 
US IND Number: 
CCI  
EudraCT Number: 
2022-003426-53 
ClinicalTrials.gov ID: 
NA 
Pediatric Investigational Plan Number: 
NA 
Protocol Number: 
C5241006 
Phase: 
1 
Brief Title: A Study to Assess the Safety, Tolerability, Pharmacokinetics, Food Effect, and Palatability 
of Sisunatovir in Healthy Adult Participants 
 
 
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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Document History 
 
Document 
Version Date 
Original protocol 
29 November 2022 
Amendment 1 
23 December 2022 
 
This amendment incorporates all revisions to date, including amendments made at the 
request of country health authorities and IRBs/ECs and any global protocol 
administrative change letter(s). 
Protocol Amendment History 
The protocol amendment summary of changes table for the current amendment is located 
directly before the TOC. 
Amendment 1 (23 December 2022) 
Overall Rationale for the Amendment: The overall rationale for this amendment is to 
incorporate and clarify various protocol elements based upon FAMHP feedback. 
 
Section # and 
Name 
Description of Change 
Brief Rationale 
Section 1.1 Synopsis Updated to include review of PK 
analysis following Periods 1 and 2 in 
Cohort 1 and thresholds at which doses 
in subsequent periods would be capped 
prior to dosing in subsequent periods. 
To assure that NOAEL 
would not be exceeded ( 
in response to FAMHP 
feedback). 
Section 1.2 Schema 
Updated to reflect the possibility of 
dose changes in periods 2 and 3 
following PK analysis. 
Response to FAMHP 
feedback 
Section 1.3 
Schedule of 
Activities 
Added 5 hour PK and ECG timepoint to 
Table 2. 
To better characterize 
Tmax and in response to 
FAMHP feedback 
Section 2.2.2 
Nonclinical 
Pharmacokinetics 
and Metabolism 
Expanded descriptions of projected 
DDI risks for sinunatovir at the 400-mg 
BID dose based on EMA guidance. 
To clarify DDI risk for 
sisunatovir and in 
response to FAMHP 
feedback 
Section 4.1. Overall 
Design 
Updated to include review of PK 
analysis following Periods 1 and 2 in 
Cohort 1 and thresholds at which doses 
To assure that NOAEL 
would not be exceeded ( 


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Section # and 
Name 
Description of Change 
Brief Rationale 
in subsequent periods would be capped 
prior to dosing in subsequent periods. 
in response to FAMHP 
feedback). 
Section 4.2. 
Scientific Rationale 
for Study Design 
Added rationale for interim PK analysis 
after Periods 1 and 2 in Cohort 1 and 
criteria for capping the dose in 
subsequent periods if the planned doses 
are projected to exceed the rat NOAEL 
To assure NOAEL 
would not be exceeded 
in subsequent periods 
and response to FAMHP 
feedback 
Section 4.3. 
Justification for 
Dose 
Clarification that doses in Cohort 2 will 
not be a dose that is projected to exceed 
the rat NOAEL based on Cohort 1 PK 
data 
To assure NOAEL 
would not be exceeded 
in subsequent periods 
and response to FAMHP 
feedback 
Section 6.6. Dose 
Modification 
Update to allow for dose modifications 
in Cohort 1. 
To assure NOAEL 
would not be exceeded 
in subsequent periods 
and response to FAMHP 
feedback 
Section 10.9. 
Appendix 9: 
Prohibited 
Concomitant 
Medications That 
May Result in DDI 
Expansion of listed prohibited 
concomitant medications to include 
sensitive MATE1 substrates, sensitive 
CYP2B6 substrates, strong P-gp 
inhibitors, strong P-gp inducers and 
sensitive OCT1 substrates. Also added 
clarification that the sponsor will be 
consulted prior to the administration of 
any concomitant medications. 
Expanded list of 
excluded medications 
inresponse to FAMHP 
feedback 
Section 2.2.2 
Nonclinical 
Pharmacokinetics 
and Metabolism 
Correction of bioavailability and plasma 
protein binding data based on report 
Clarification 


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TABLE OF CONTENTS 
LIST OF TABLES ..................................................................................................................... 9 
1. PROTOCOL SUMMARY ................................................................................................... 10 
1.1. Synopsis ................................................................................................................... 10 
1.2. Schema ..................................................................................................................... 16 
1.3. Schedule of Activities .............................................................................................. 17 
2. INTRODUCTION ................................................................................................................ 22 
2.1. Study Rationale ........................................................................................................ 22 
2.2. Background .............................................................................................................. 22 
2.2.1. Nonclinical Pharmacology .......................................................................... 22 
2.2.2. Nonclinical Pharmacokinetics and Metabolism .......................................... 23 
2.2.3. Nonclinical Safety ....................................................................................... 24 
2.2.4. Clinical Overview ....................................................................................... 25 
CCI 
 
 
 
 
3. OBJECTIVES AND ENDPOINTS .................................................................................... 29 
4. STUDY DESIGN ................................................................................................................. 29 
4.1. Overall Design ......................................................................................................... 29 
4.2. Scientific Rationale for Study Design ..................................................................... 31 
4.2.1. Choice of Contraception/Barrier Requirements .......................................... 32 
4.2.2. Collection of Retained Research Samples ................................................... 32 
4.2.3. Collection of Retained Research Samples ................................................... 32 
4.3. Justification for Dose ............................................................................................... 32 
4.4. End of Study Definition ........................................................................................... 33 
5. STUDY POPULATION ...................................................................................................... 34 
5.1. Inclusion Criteria ..................................................................................................... 34 
5.2. Exclusion Criteria .................................................................................................... 34 
5.3. Lifestyle Considerations .......................................................................................... 37 
5.3.1. Contraception .............................................................................................. 37 


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5.3.2. Meals and Dietary Restrictions .................................................................. 37 
5.3.3. Caffeine, Alcohol, and Tobacco ................................................................. 38 
5.3.4. Activity ...................................................................................................... 38 
5.4. Screen Failures ........................................................................................................ 39 
6. STUDY INTERVENTION(S) AND CONCOMITANT THERAPY ................................. 39 
6.1. Intervention(s) Administered .................................................................................. 39 
6.1.1. Administration ............................................................................................ 40 
6.1.1.1. Period 1 and 2 ........................................................................... 40 
6.1.1.2. Period 3 ..................................................................................... 40 
6.1.1.3. Periods 4-7 (Cohort 1 only) ...................................................... 41 
6.2. Preparation, Handling, Storage, and Accountability .............................................. 41 
6.2.1. Preparation and Dispensing ........................................................................ 42 
6.3. Assignment to Study Intervention .......................................................................... 42 
6.4. Blinding .................................................................................................................. 42 
6.4.1. Blinding of Participants .............................................................................. 43 
6.4.2. Blinding of Site Personnel .......................................................................... 43 
6.4.3. Blinding of the Sponsor ............................................................................. 43 
6.4.4. Breaking the Blind ..................................................................................... 43 
6.5. Study Intervention Compliance .............................................................................. 43 
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 .............................................................................. 44 
7. DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL ........................................................................... 45 
7.1. Discontinuation of Study Intervention .................................................................... 45 
7.1.1. ECG Changes ............................................................................................. 45 
7.1.2. Potential Cases of Acute Kidney Injury ..................................................... 46 
7.1.3. COVID-19 .................................................................................................. 46 
7.2. Participant Discontinuation/Withdrawal From the Study ...................................... 47 
7.2.1. Withdrawal of Consent .............................................................................. 47 
7.3. Lost to Follow-up ................................................................................................... 48 


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8. STUDY ASSESSMENTS AND PROCEDURES ............................................................... 48 
8.1. Administrative and Baseline Procedures ................................................................. 48 
8.1.1. Baseline Procedures .................................................................................... 49 
8.2. Efficacy Assessments .............................................................................................. 49 
8.3. Safety Assessments .................................................................................................. 50 
8.3.1. Physical Examinations ................................................................................ 50 
8.3.2. Vital Signs ................................................................................................... 50 
8.3.2.1. Blood Pressure and Pulse Rate .................................................. 50 
8.3.3. Electrocardiograms ...................................................................................... 51 
8.3.4. Clinical Safety Laboratory Assessments ..................................................... 52 
8.3.5. COVID-19 Specific Assessments ............................................................... 52 
8.3.6. Pregnancy Testing ....................................................................................... 53 
8.4. Adverse Events, Serious Adverse Events, and Other Safety Reporting .................. 53 
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 ........................................................... 55 
8.4.3. Follow-Up of AEs and SAEs ...................................................................... 55 
8.4.4. Regulatory Reporting Requirements for SAEs ........................................... 55 
8.4.5. Environmental Exposure, Exposure During Pregnancy or 
Breastfeeding, and Occupational Exposure ..................................................... 56 
8.4.5.1. Exposure During Pregnancy ...................................................... 56 
8.4.5.2. Exposure During Breastfeeding ................................................. 57 
8.4.5.3. Occupational Exposure .............................................................. 58 
8.4.6. Cardiovascular and Death Events ................................................................ 58 
8.4.7. Disease-Related Events and/or Disease-Related Outcomes Not 
Qualifying as AEs or SAEs .............................................................................. 58 
8.4.8. Adverse Events of Special Interest ............................................................. 58 
8.4.8.1. Lack of Efficacy ........................................................................ 58 
8.4.9. Medical Device Deficiencies ...................................................................... 58 
8.4.10. Medication Errors ...................................................................................... 59 
8.5. Pharmacokinetics ..................................................................................................... 60 


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8.5.1. Palatability Questionnaire ........................................................................... 60 
8.6. Genetics ................................................................................................................... 61 
8.6.1. Specified Genetics ....................................................................................... 61 
8.6.2. Retained Research Samples for Genetics .................................................... 61 
CCI 
 
 
 
 
 
8.8. Immunogenicity Assessments ................................................................................ 62 
8.9. Health Economics ................................................................................................... 62 
9. STATISTICAL CONSIDERATIONS ................................................................................ 62 
9.1. Statistical Hypotheses ............................................................................................. 62 
9.2. Analysis Sets ........................................................................................................... 62 
9.3. Statistical Analyses ................................................................................................. 63 
9.3.1. General Considerations .............................................................................. 63 
9.3.2. Primary Endpoint(s) Analysis .................................................................... 63 
9.3.2.1. Electrocardiogram Analyses ..................................................... 63 
9.3.3. Secondary Endpoint(s) Analysis ................................................................ 64 
CCI 
 
9.4. Interim Analyses ..................................................................................................... 66 
9.5. Sample Size Determination .................................................................................... 66 
10. SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS .......................................................................................................... 67 
10.1. Appendix 1: Regulatory, Ethical, and Study Oversight Considerations ............... 67 
10.1.1. Regulatory and Ethical Considerations .................................................... 67 
10.1.1.1. Reporting of Safety Issues and Serious Breaches of the 
Protocol or ICH GCP ........................................................................ 67 
10.1.2. Financial Disclosure ................................................................................. 68 
10.1.3. Financial Disclosure ................................................................................. 68 
10.1.4. Informed Consent Process ....................................................................... 68 
10.1.5. Data Protection ......................................................................................... 69 


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10.1.6. Committees Structure ............................................................................... 69 
10.1.6.1. Data Monitoring Committee ................................................... 69 
10.1.7. Dissemination of Clinical Study Data ...................................................... 69 
10.1.8. Data Quality Assurance ............................................................................ 71 
10.1.9. Source Documents ................................................................................... 72 
10.1.10. Study and Site Start and Closure ............................................................ 72 
10.1.11. Publication Policy .................................................................................. 73 
10.1.12. Sponsor’s Medically Qualified Individual ............................................. 74 
10.2. Appendix 2: Clinical Laboratory Tests ................................................................ 75 
10.3. Appendix 3: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-Up, and Reporting ..................................................................... 77 
10.3.1. Definition of AE ....................................................................................... 77 
10.3.2. Definition of an SAE ................................................................................ 78 
10.3.3. Recording/Reporting and Follow-Up of AEs and/or SAEs During 
the Active Collection Period ........................................................................... 79 
10.3.4. Reporting of SAEs ................................................................................... 83 
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. Adverse Event Grading for Kidney Safety Laboratory 
Abnormalities .................................................................................................. 91 
10.8. Appendix 8: ECG Findings of Potential Clinical Concern ................................... 92 
10.9. Appendix 9: Prohibited Concomitant Medications That May Result in DDI ....... 94 


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10.10. Appendix 10 : Oral Solution or Suspension Palatability Questionnaire .............. 97 
10.11. Appendix 11: Abbreviations .............................................................................. 105 
11. REFERENCES ................................................................................................................. 109 
 
 
 
Table 1. 
Table 2. 
Table 3. 
Table 4. 
 
LIST OF TABLES 
Study Schedule of Assessment ................................................................. 17 
Periods 1-3 PK Days ................................................................................. 21 
Completed Sisunatovir Studies ................................................................. 25 
Plasma Sisunatovir PK Parameters Definitions ........................................ 64 
 
 
Table 6. 
Protocol-Required Safety Laboratory Assessments .................................. 75 


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1. PROTOCOL SUMMARY 
1.1. Synopsis 
Protocol Title: 
A Phase 1, Randomized, Sponsor Open, Two-Part Crossover Study to Assess Safety, 
Tolerability, Pharmacokinetics and Food Effect of Multiple Doses in Part 1 and Palatability 
of a Single Dose of Sisunatovir in Part 2, in Healthy Adult Participants 
Brief Title: A Study to Assess the Safety, Tolerability, Pharmacokinetics, Food Effect, and 
Palatability of Sisunatovir in Healthy Adult Participants 
Regulatory Agency Identification Number(s): 
 
US IND Number: 
143479 
EudraCT Number: 
2022-003426-53 
ClinicalTrials.gov ID: 
N/A 
Pediatric Investigational Plan Number: 
N/A 
Protocol Number: 
C5241006 
Phase: 
1 
Rationale: 
Sisunatovir (PF-07923568) is an orally administered RSV F-protein inhibitor being 
developed to target viral-host cell fusion for the treatment of adult and pediatric patients with 
RSV. This study is designed to assess safety and tolerability, pharmacokinetics, and food 
effect of multiple oral doses of sisunatovir. Additionally, the study is also designed to 
generate preliminary palatability data that will inform further development of formulations 
appropriate for pediatric Phase 2 and 3 studies. 
Objectives and Endpoints: 
 
Objectives 
Endpoints 
Primary: 
Primary: 
• 
To characterize the safety and 
tolerability of multiple oral doses of 
sisunatovir in healthy adult participants 
• 
Assessment of TEAEs, clinical laboratory abnormalities, vital signs, 
and 12-lead ECGs 
Secondary: 
Secondary: 
• 
To characterize the PK of multiple oral 
doses of sisunatovir 
• 
PK Parameters AUCtau, Cmax, Tmax, AUCtau(dn), Cmax(dn) for Day 1 
and AUCtau, Cmax, Tmax, AUCtau(dn), Cmax(dn), CL/F Rac, Rac,Cmax; 
and t1/2 and Vz/F (if data permits) post last dose on Day 5 
• 
To evaluate the effect of food on the PK 
of multiple oral doses of sisunatovir 
• 
The ratio of AUCtau and Cmax, on Day 5; Tmax on Day 5 
• 
To characterize the impact of liquid 
vehicles on the palatability of sisunatovir 
• 
Palatability Assessment Questionnaire Scoring Metrics: mouth feel, 
bitterness, sweetness, sourness, saltiness, tongue/mouth burn, 
overall liking 


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Overall Design: 
This is a Phase 1 study that will be conducted in up to two cohorts. 
Cohort 1 is a randomized, 2-part, crossover cohort. Part 1 has 3 periods, Periods 1 and 2 are 
double blind, sponsor open, placebo controlled crossover design to evaluate the safety and 
tolerability and PK of the planned 400 mg and 200 mg of sisunatovir given Q12 hours x 4 
days plus 1 dose as 50 mg capsules in a fed state. Period 3, is an open label period to evaluate 
the food effect of the planned 400 mg of sisunatovir given Q12 hours x4 days plus 1 dose in 
a fasted state. Part 2, Periods 4-7, is open label to assess the palatability of 50 mg of 
sisunatovir in 4 different vehicles (water, infant formula, apple juice, and saline) in a 
randomized crossover design. 
Cohort 1 will include approximately 12 participants that will be randomized into 4 sequences 
with 3 participants in each sequence. Each sequence will receive treatment in a pre-specified 
manner. 
Over the first 2 periods, all participants are planned to receive (A) 400 mg and either (B) 200 
mg plus matching placebo or (C) placebo dosed Q12 hours for 4 days plus 1 dose in the fed 
state. All participants in Period 3 will receive (D) 400 mg dosed Q12 hours for 4 days plus 1 
dose in the fasted state. A minimum 7-day washout period will occur between the last dose of 
Periods 1 and 2 and the first dose of Periods 2 and 3. 
Prior to proceeding to Period 2 of Cohort 1, the Period 1 Day 5 PK up to 12 hours post-dose 
will be assessed. If the mean exposures (AUC or Cmax) at 400 mg in Period 1 exceeds the 
rat (most sensitive species) NOAEL, the doses for the subsequent period(s) will be capped to 
a dose that is not expected to exceed the rat NOAEL. Similarly, prior to proceeding to 
Period 3 of Cohort 1, the Periods 1 and 2 Day 5 PK up to 12 hours post-dose will be 
assessed, and if the mean exposures (AUC or Cmax) at 400 mg exceeds the rat (most 
sensitive species) NOAEL, the doses for the subsequent period(s) will be capped to a dose 
that is not expected to exceed the rat NOAEL. Furthermore, safety will also be assessed 
following each period and doses for subsequent periods may be reduced if the safety and 
tolerability of the previous dose was not deemed sufficiently tolerated. 
During Periods 4-7 participants will taste sisunatovir 50 mg capsule content in different 
dosing vehicles ((E) water, (F) infant formula, (G) apple juice, and (H) saline) in a cross-over 
manner and then spit out the drug with the intention of assessing the palatability of 
sisunatovir in different dosing vehicles. The palatability questionnaire will be completed for 
each vehicle, the questionnaire asks participants to assess each vehicle at 4 different time 
increments after tasting. At least 60 minutes will pass between tasting each vehicle. Period 4 
may start after the last PK draw of Period 3. 
Cohort 2 is an optional randomized, crossover cohort with 3 periods. Periods 1-2 are double 
blind, sponsor open, placebo controlled crossover design evaluating the safety, tolerability, 
and PK of sisunatovir administered Q12 hours for 4 days plus 1 dose in a fed state. Period 3 
is an open label period to evaluate the food effect of sisunatovir given Q12 hours x 4 days 


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plus 1 dose in a fasted state. Doses will not exceed 400-mg Q12 hours x 4 days plus 1 dose. 
Note that if the mean Day 5 exposure exceeds the rat NOAEL in Cohort 1, the dose in Cohort 
2 will be capped at a dose that is not anticipated to exceed the rat NOAEL. Cohort 2 will be 
conducted at the discretion of the Sponsor after review of Cohort 1 data (including PK for at 
least periods 1 and 2), and there will be 2 sequences of 6 participants for Cohort 2. 
Participants who discontinue from the study for non-safety reasons may be replaced at the 
sponsor’s discretion in collaboration with the Investigator. 
Number of Participants: 
Approximately 12 participants will be enrolled in Cohort 1 in the study. Approximately 
12 additional participants may be enrolled in Cohort 2 in the study. 
Note: "Enrolled" means a participant, or their legally authorized representative’s, agreement 
to participate in a clinical study following completion of the informed consent process and 
randomization to study intervention. A participant will be considered enrolled if the informed 
consent is not withdrawn prior to participating in any study activity after screening. 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. 
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. Participants aged 18 to 65 years of age, inclusive, at the time of signing of the ICD. 
• All fertile participants must agree to use a highly effective method of 
contraception. 
2. Male and female participants who are overtly healthy as determined by medical 
evaluation including medical history, physical examination, including blood pressure, 
pulse rate, standard 12-lead ECG, and laboratory tests. 
3. BMI of 17.5 to 35 kg/m2; and a total body weight >50 kg (110 lb). 


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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. 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. 
3. Use of prescription or nonprescription drugs and dietary and herbal supplements 
within 7 days or 5 half-lives (whichever is longer) prior to the first dose of study 
intervention with the exception of moderate/strong CYP3A inducers or 
time-dependent inhibitors which are prohibited within 14 days plus 5 half-lives prior 
to the first dose of study intervention. 
4. A positive urine drug test, confirmed by a repeat test, if deemed necessary. 
5. Screening supine BP ≥140 mm Hg (systolic) or ≥90 mm Hg (diastolic), following at 
least 5 minutes of supine rest. If BP is ≥140 mm Hg (systolic) or ≥90 mm Hg 
(diastolic), 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. 
6. 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 the uncorrected QT 
interval is >450 ms, this interval should be rate-corrected using the Fridericia method 
only and the resulting QTcF should be used for decision making and reporting. 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. 
7. 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: 
• GFR <60 mL/min/1.73m2 based on CKD-EPI equation; 


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• AST or ALT level ≥1.5 x ULN; 
• Gamma-GT> ULN; 
• Alkaline phosphatase > 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. 
Study Arms and Duration: 
 
Study Intervention(s) 
Intervention Name 
PF-07923568 
(sisunatovir) 
Placebo for PF-07923568 
(sisunatovir) 
PF-07923568 
(sisunatovir) Palatability 
in Liquid Vehicles 
Unit Dose Strength(s) 
50 mg 
Placebo 
Content of 50 mg 
capsule 
Dose Formulation 
Capsule 
capsule 
Capsule content 
dispensed in liquid 
vehicles 
Dosage Level(s) 
Planned doses are 
200 mg and 400 mg 
BID for 5 days in 
Cohort 1. 
Doses in Cohort 2 will 
not exceed 400 mg 
0 mg 
Planned doses are the 
content of a 50 mg 
capsule of sisunatovir, 
dispensed in 7 ml of the 
following liquid 
vehicles: 
• 
Water 
• 
Infant formula 
• 
Apple juice 
• 
Saline 
Route of 
Administration 
Oral 
Oral 
Oral/”Swirl and Spit” 
Use 
Experimental 
Placebo 
Experimental 
IMP or NIMP/AxMP 
IMP 
IMP 
IMP 
Sourcing 
Provided centrally by 
the sponsor 
Provided centrally by the 
sponsor 
Sisunatovir: Provided 
centrally by the sponsor 
Liquid vehicles: 
Provided locally by the 
CRU 
Packaging and 
Labeling 
The PF-07923568 
50 mg capsules will be 
provided in bulk. CRU 
Staff will prepare 
individual doses for 
administration 
The placebo capsules will 
be provided in bulk. CRU 
Staff will prepare 
individual doses for 
administration 
The PF-07923568 50 mg 
capsules will be 
provided in bulk. CRU 
Staff will prepare 
individual doses (capsule 
content + liquid) for 
administration 


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Study Intervention(s) 
Current/former 
Sisunatovir 
Placebo 
Sisunatovir 
Name(s) or Alias(es) 
PF-07923568 
PF-07923568 
RV521 
RV521 
Liquid vehicles: As 
available locally. 
Statistical Methods: 
A sufficient number of participants will be screened to achieve 12 participants randomized to 
study intervention in Cohort 1. Approximately 12 additional participants may be enrolled in 
Cohort 2 in the study. The sample size is empirically selected and is not based on statistical 
power calculation. 
Safety Analysis: 
All safety analyses will be performed on the safety analysis set, which is defined as all 
participants randomly assigned to study intervention and who take at least 1 dose of study 
intervention. Participants will be analyzed according to the product they actually received. 
AEs, ECGs, BP, pulse rate and safety laboratory data will be reviewed and summarized on an 
ongoing basis during the study 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. 
Pharmacokinetic Analysis: 
The plasma concentrations of sisunatovir will be listed and descriptively summarized by 
treatment and nominal PK sampling time. PK parameters for sisunatovir will be analyzed 
using standard noncompartmental method of analysis. Actual PK sampling times will be used 
in the derivation of sisunatovir PK parameters when available, otherwise nominal times will 
be used. In the food effect evaluation, natural log transformed AUCtau and Cmax of sisunatovir 
will be analyzed using a mixed effect model with treatment and sequence as fixed effects and 
participant within sequence as a random effect. For the food effect evaluation, estimates of 
the adjusted mean differences (Test-Reference) and corresponding 90% confidence intervals 
will be obtained from the model. The adjusted mean differences and 90% confidence 
intervals for the differences will be exponentiated to provide estimates of the ratio of adjusted 
geometric means (Test/Reference) and 90% confidence intervals for the ratios. Individual 
participant and summary profiles (mean and median plots) of the plasma concentration-time 
data will be plotted by treatment using actual and nominal times, respectively. 
Palatability Assessment: 
For palatability 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 palatability 


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attributes (mouth feel, bitterness, sweetness, sourness, saltiness, tongue/mouth burn, overall 
liking ) from the palatability questionnaires will be listed and descriptively summarized. 
Ethical Considerations: 
Sisunatovir is not expected to provide any clinical benefit to healthy participants. This study 
is designed primarily to generate safety, tolerability, palatability and pharmacokinetic data 
for further clinical development. 
1.2. Schema 
 
 


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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 infonnation 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 paiiicipant. 
 
Table 1. 
Study Schedule of Assessment 
 
Visit Identifier· 
Abbreviations used in 
this table may be found 
in Annendix 11 . 
Scl'een
Periods 1-3 
Periods 
4-7 
F/U 
28-35 days 
aftel' last dose 
ET 
Notes 
Days Relative to Day 1 
for·each period 
Day- 
28 to
Day-2 
Day-1 Dayl Day2 Day3 Day4 Day5 Day6 Day7 
Dayl 
• 
Screening '.S28 days before the first dose. 
•  Follow-up may occur via telephone 
contact and 28 to 35 days after final dose. 
• 
Periods 4-7 apply only to Cohort I. 
• 
Periods 4-7 of Cohort 1 will occur on 
Day 7 of Period 3. 
. 
Hom·s Aftel' Dose 
0 
24 
48 
Informed consent 
X 
Informed consent must be obtained prior 
to undergoing any study-specific 
procedures. 
CRU confinement 
X 
➔ 
➔ 
➔ 
➔ 
➔ 
➔ 
X 
X 
Inclusion/exclusion 
criteria 
X 
X 
Medical/medication 
historv 
X 
X 
Physical exam 
X 
X 
. PE at Screening or Period 1 Day -1 only. 
A brief PE at other times at the discretion 
. 
of the investigator. 
Including height and weight at screening 
onlv. 
Safety laboratory 
X 
X 
X 
X 
X 
X 
Participants should fast for at least 4 how-s 
.
before safety labs are drawn. 
Includes minalysis. 


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Table 1. 
Study Schedule of Assessment 
 
 
 
 
 
 
. 
Visit Identifier· 
Abbreviations used in 
this table may be found 
in Aooendix 11 . 
Scl'een
Periods 1-3 
Periods 
4-7 
F/U 
28-35 days 
aftel' last dose 
ET 
Notes 
Days Relative to Day 1 
for·each period 
Day- 
28 to 
Day-2 
Day-1 Dayl Day2 Day3 Day4 Day5 Day6 Day7 
Dayl 
• 
Screening gg days before the first dose. 
•  Follow-up may occur via telephone 
contact and 28 to 35 days after final dose. 
• 
Periods 4-7 apply only to Cohort I. 
• 
Periods 4-7 of Cohort I will occur on 
Day 7 of Period 3. 
Hom·s Aftel' Dose 
0 
24 
48 
Demo,mmhv 
X 
Pregnancy test (WOCBP 
only) 
X 
X 
X . ET pregnancy testing only if participant 
withdraws while not admitted to the CRU. 
Contraception check 
X 
X 
X 
X 
X 
Contraception check will occtu· with 
dischar,ze activities at the end of Period 7. 
FSH (post-menopausal 
women only) 
X 
Urine drug testing 
X 
X 
12-Lead ECG (triplicate) 
X 
X 
X 
X 
X 
X . 
Single ECG for Screening. 
Pre-dose ECGs are triplicate of triplicates 
at 30 min, 20 min, and IO min before the 
pre-dose meal in Periods I and 2, and 
30 min, 20 min, and IO min pre-dose in 
. 
Period 3. 
All other ECGs are triplicate. 
DI and D5 schedule in Table 2. 
Blood pressm·e and pulse 
rate 
X 
X 
X 
X 
X 
DI and D5 schedule in Table 2. 
HIV, HBsAg, HBsAb, 
HBcAbHCVAb 
X 
COVID-19 related 
orocedm·es 
X 
X 
➔ 
➔ 
➔ 
➔ 
➔ 
➔ 
X 
X 
X .  Performed per local procedm·es. 


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Table 1. 
Study Schedule of Assessment 
 
Visit Identifier· 
Abbreviations used in 
this table may be found 
in Aooendix 11 . 
Scl'een 
Periods 1-3 
Periods 
4-7 
F/U 
28-35 days 
aftel' last dose 
ET 
Notes 
Days Relative to Day 1 
for·each period 
Day- 
28 to 
Day-2 
Day-1 Dayl Day2 Day3 Day4 Day5 Day6 Day7 
Dayl 
• 
Screening gg days before the first dose. 
•  Follow-up may occur via telephone 
contact and 28 to 35 days after final dose. 
• 
Periods 4-7 apply only to Cohort I. 
• 
Periods 4-7 of Cohort 1 will occur on 
Day 7 of Period 3. 
Hom·s Aftel' Dose 
0 
24 
48 
Study intervention 
administration 
X 
X 
X 
X 
X 
X 
•  For Periods 1-3: Ql2 hours on Days 1-4; 
on Day 5 only the moming dose of study 
. 
dmg will be administered. 
The washout between last dose in 
previous period ?.7 days (Periods 2 and 3 
. 
only). 
Periods 1 and 2 are dosed in the fed state 
and Period 3 is dosed in the fasted state. 
Palatability Assessments 
X 
Palatability assessments will be completed 
at 1 min (immediately following dose), 
5 min, IOmin, and 20 min after tasting 
dose in vehicle. 
• 
There is an at least 60 minutewashout 
between tasting each dose in vehicle. 
Pharmacokinetic blood 
sampling 
X 
X 
X 
X 
X 
X 
X 
X 
D2, D3, and D4 PK samples to be drawn 
before AM dosing. 
DI and D5 PK schedule in Table 2. 
Retained Research 
Sample for Genetics 
(Prep DI) 
X 
Prep DI Retained Research Samples for 
Genetics: If not collected on the 
designated collection day, collect at the 
next available time point when 
biospecimens are being collected in 
.
conjunction with a pa1ticipant visit. 
To be collected dming Period I onlv. 


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Hom·s Aftel' Dose 
 
Follow-up may occur via telephone 
contact and 28 to 35 days after final dose. 
Periods 4-7 apply only to Cohort I. 
 
. 
 
 
 
Participants will discharge from the unit 
 
After the last PK draw for Period 3 
participants will immediately sta1t 
Period 4. 
Participants will discharge from Period 7 
after completing the final palatability 
assessment. 
See Se-ction 8.4.3 for follow-up AE and 
SAE assessments. 
 
 
X 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Serious and nonserious 
AE monitoring 
CRU discharge 
 
 
0 
Day 1 
Day 7 
Day 6 
Day 5 
Day 4 
Day 3 
Day 2 
Day 1 
Day -1 
 
Days Relative to Day 1 
for·each period 
Notes 
 
 
 
Periods 
4-7 
Periods 1-3 
Scl'een 
Visit Identifier· 
Abbreviations used in 
this table may be found 
in A endix 11 . 
 
Table 1. 
Study Schedule of Assessment 
 


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Table 2. 
Periods 1-3 PK Days 
 
Visit Identifier 
For Periods 1-3 only 
Notes 
Study Day 
Day 1 and Day 5 
6 
7 
Hours After Morning Dose 
0 
1 
2 
3 
4 
5 
6 
8 
12 
16 
24 
36 
48 
Hour 0 = predose sample collection 
Study intervention administration 
X 
X 
• 
H12 dose should be given 12 hours ±1 hour after 
H0 dose. 
• 
On D5 only the H0 dose will be given. 
PK blood sampling 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
• 
H12 PK draw on D1 should be completed prior to 
evening dosing. 
• 
H16 sample day 5 only. 
CCI 
Triplicate ECGs 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
• 
Pre-dose ECGs are triplicate of triplicates at 30 min, 
20 min, and 10 min before the pre-dose meal in 
Periods 1 and 2, and 30 min, 20 min, and 10 min pre- 
dose in Period 3. 
• 
All other ECGs are triplicate. 
Vitals 
X 
X 
X 
X 


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2. INTRODUCTION 
Sisunatovir is an orally administered RSV F-protein inhibitor being developed to target 
viral-host cell fusion for the treatment of adult and pediatric patients with RSV. Sisunatovir 
(formerly RV521) is an inhibitor of RSV fusion (F) protein mediated fusion that is currently 
being investigated for the treatment of RSV infection. 
2.1. Study Rationale 
The purpose of the study is to assess the safety, tolerability, and PK of multiple oral doses of 
sisunatovir when administered with food or fasting. Palatability assessments will be 
conducted to aid in the development of pediatric formulations of sisunatovir. 
2.2. Background 
RSV, a member of the Pneumovirus family, is a significant pathogen of the very young, 
immunocompromised, and the elderly. RSV is ubiquitous and is known to infect almost all 
children by 2 years of age.1 The clinical manifestation of RSV infection is typically mild 
upper respiratory tract illness. However, in infants, young children, the immunocompromised 
and the elderly, it can cause serious LRTI. Infants <6 months of age are at the highest risk of 
severe RSV infection which can lead to hospitalization, ICU admission and even death.2,3,4 
The current management of RSV infection includes a combination of preventative and 
limited treatment measures, primarily consisting of supportive care. Ribavirin, a nucleoside 
analogue, is currently the only licensed antiviral for the treatment of RSV in children 
(Virazole®).5 There is no approved antiviral for the treatment of RSV in other age groups. 
Most current guidelines make either no recommendation or do not recommend routine use of 
ribavirin due to its weak antiviral capacity, inherent toxicity and teratogenic potential.6 Thus, 
a placebo controlled design is considered appropriate for trials of new antiviral agents for the 
treatment of RSV. Palivizumab (Synagis®) is a prophylactic monoclonal antibody that has 
been shown to protect infants against RSV disease and is used in specified high risk infant 
groups. Despite the availability of these agents, their limited use means that treatment of 
RSV infection remains an area of unmet need. 
Sisunatovir is a potent inhibitor of RSV F protein mediated cell-to-cell fusion. The RSV 
F protein is essential for the entry of the virus to the host cell. Cell surface expression of the 
F protein also causes cell-to-cell fusion, leading to the giant syncytia characteristic of RSV 
infection. 
The sisunatovir preclinical profile, as well as the safety and tolerability data from the first 
human dosing studies, provide a strong rationale for the clinical development of sisunatovir. 
2.2.1. Nonclinical Pharmacology 
• In vitro, sisunatovir has demonstrated potent inhibition of RSV F protein-mediated 
cell-cell fusion, and of infection by a panel of RSV laboratory and clinical isolates of 
both A and B strains in the RSV plaque assay. Sisunatovir treatment resulted in a 
significant reduction in RSV infection in a human airway epithelial cell model. 


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• In vivo, sisunatovir resulted in a marked reduction in lung virus titer in a Balb/C 
mouse model of RSV infection. 
• An in vitro secondary pharmacology study did not reveal any significant off-target 
activity for sisunatovir. 
• Refer to the sisunatovir IB for further details. 
2.2.2. Nonclinical Pharmacokinetics and Metabolism 
• In animal pharmacokinetic studies sisunatovir showed slow oral absorption, 
moderate-high CL, high volume of distribution, and oral bioavailability of 46%, 42- 
132%, and 44% in mouse, rat, and dog, respectively. 
• Plasma protein binding of sisunatovir was low to moderate across species, with 
average fraction unbound of 67%, 38%, 52%, 27%, and 48% in human, mouse, rat, 
dog and guinea pig, respectively. Repeat dosing studies in the rat show that extensive 
distribution of sisunatovir to the lungs occurs, resulting in high lung to plasma ratio. 
This effect is greater than dose proportional from 50 mg/kg to 150 mg/kg. 
• Consistent with the results of the midazolam DDI study (C5421004), in vitro studies 
indicate that CYP3A4 is the main CYP isoform that metabolizes sisunatovir with 
minor contribution from CYPs 2C9 and 2D6. 
• Based on EMA guidance, in vitro studies indicate a DDI risk exists for 
OATP1B1/1B3, OCT1, MATE1, OCT2, and OAT3. However, ratios of unbound 
hepatic inlet concentrations relative to Ki values are low, and DDI risk is considered 
unlikely for OATPs, OCT2, and OAT3. The pharmacokinetics of OCT1 and MATE1 
substrates may be altered when co-administered with sisunatovir, and therefore 
sensitive OCT1 and MATE1 substrates are prohibited in this protocol (Appendix 9). 
• Based on calculations from EMA guidance in vitro studies indicate there is a risk of 
inhibition of CYPs 1A2, 2B6, 2C9, 2C19, and 3A4. The DDI with CYPs 1A2, 2C9, 
and 2C19 is predicted to be minimal (predicted less than 25% increase in AUC of a 
sensitive substrate) and DDI with CYP2B6 is predicted to be weak. A DDI study 
conducted with sisunatovir (200 mg BID) and midazolam as a sensitive CYP3A4 
probe substrate (C5241004) indicate that sisunatovir is a moderate 3A4 inhibitor. 
There is also a possibility that the pharmacokinetics of CYP2B6 substrates may be 
altered when coadministered with sisunatovir. Based on these findings sensitive or 
narrow therapeutic index 3A4 substrates and narrow TI CYP2B6 substrates are 
prohibited in this protocol (Appendix 9) . 
• In vitro studies indicate that sisunatovir is a Pgp substrate; therefore, 
co-administration of inhibitors for the transporter (P-gp) may result in increased 
exposure to sisunatovir (approximately 2-fold). 'A clinical DDI study (C5241004) 
indicated that verapamil (a P-gp and CYP3A4 inhibitor) coadministration produced 


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an approximately 2.5-fold increase in exposure to sisunatovir. Based on these 
findings, strong inhibitors or inducers are prohibited in this protocol (Appendix 9). 
• The major metabolites produced in all species appeared to be hydroxylated 
metabolites although some Phase 2 metabolites were also detected in all species. The 
in vitro metabolite profile in the rat, mouse, dog, guinea pig, and human were similar 
with the exception of M4, an apparent double hydroxylation only apparent in human 
at low levels. 
2.2.3. Nonclinical Safety 
• In the repeat dose toxicity studies in adult (up to 28 days) and neonatal/juvenile rats 
and dogs, the MTDs were defined by body weight loss and reduced food consumption 
accompanied by adverse clinical observation of varying severity. In dogs, there was 
dose-related incidence of emesis and liquid feces at ≥15 mg/kg/day. The key target 
organ for toxicity in adult animals was the hepatobiliary system, which included both 
degenerative and inflammatory changes in bile duct, in rats (≥60 mg/kg/day) and 
dogs (≥45 mg/kg/day). In dogs, the hepatobiliary findings correlated with elevated 
plasma levels of ALP, ALT and GGT. In addition, the findings observed only in rats 
were in kidney (degeneration/regeneration of medullary tubules) at ≥120 mg/kg/day, 
lung (vascular degeneration/necrosis) at 240 mg/kg/day (non-tolerated dose) and 
trachea (epithelial degeneration and subepithelial inflammation [predominantly in 
females]) at 120 mg/kg/day in 14 and/or 28-day studies. In the 28-day dog repeat 
dose toxicity study, the NOAEL was 15 mg/kg/day corresponding to Cmax of 729 
ng/mL and AUCtau of 9510 ng.h/mL. In the 28-day rat repeat dose toxicity study, the 
NOAEL was 60 mg/kg/day corresponding to Cmax of 322 ng/mL and AUCtau of 
4725 ng.h/mL. 
• In the embryo-fetal toxicity studies in rat (GD6-17) and rabbit (GD6-18), there were 
no effects on pregnancy or embryo-fetal development. In rat, the NOAEL for 
maternal toxicity was 45 mg/kg/day based on the transient initial body weight loss 
followed by dose-related decreased body weight gain at ≥45 mg/kg/day. The NOAEL 
for embryo-fetal toxicity in rat was 60 mg/kg/day, corresponding to systemic 
maternal exposure (AUC24) of 9830 ng.h/mL on Day 15 of gestation. In rabbit, 
maternal toxicity was limited to lower body weight gain and food intake at 
45 mg/kg/day. The NOAEL for embryo-fetal development in rabbit was 
45 mg/kg/day, corresponding to a systemic maternal exposure (AUC24) of 
220 ng.h/mL on Day 16 of gestation. 


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2.2.4. Clinical Overview 
Table 3. 
Completed Sisunatovir Studies 
 
Study Number 
(Status) 
Study Type/Key 
Design Features 
Study Population 
Dose, Dosing 
Regimen 
Formulation Used 
C5241001 
(previously 
REVC001a) 
(completed) 
Phase 1, 
randomized, double 
blind, placebo 
controlled, safety, 
tolerability, PK, 
food-effect of SAD 
and MAD 
Healthy participants Dose range: 10 mg – 
525 mg (SAD); 
36 participants 
Dose range: 175 mg 
– 350 mg; BID 
(MAD), Food effect; 
24 participants 
Liquid Formulation 
DIC 
C5241002 
(previously 
REVC002) 
(completed) 
Phase 2a, 
randomised, double 
blind, placebo 
controlled 
Healthy participants 
inoculated with RSV 
CV 
200 mg or 350 mg 
BID for a total 
10 doses; 
66 Participants 
DIC 
C5241004 
(previously 
REVC004) 
(completed) 
Phase 1, adaptive, 
part randomised, 
part open-label, drug 
interactions, safety, 
tolerability 
Healthy participants 200 mg; BID; 
62 Participants 
DIC 
C5241005 
(previously 
REVC005) 
(completed) 
Phase 1, open-label, 
single-dose, PK, 
safety, and 
tolerability study 
Healthy participants 200 mg, 4 single 
doses total; 
9 Participants 
1 ×: DIC (fed) 
DIC 
DPB 
1 ×: DPB (fed) 
1 ×: DPB dispersed 
in H2O (fed) 
1 ×: DPB dispersed 
in H2O (fasted) 
[wash-out: 3 days 
between each of the 
4 dosing days] 
a. 
A total of 8 participants received the liquid dosage formulation of sisunatovir in a solution, at a 
concentration of 5 mg/mL, containing HBP cyclodextrin, Lycasin, flavoring agent (strawberry), benzoic 
acid and water) and 68 subjects received DIC in the study. 
 
A total of 201 adult healthy participants have received sisunatovir in 4 completed clinical 
studies (C5241001, C5241002, C5241004 and C5241005) investigating the PK profile, 
effects of food on PK, effects of formulation on PK (C5241001, C5241005), DDIs 
(C5241004), and the efficacy in an RSV Viral Challenge Study (C5241002) at doses ranging 
from 10 mg to 525 mg. In addition, as of 03 October 2021, 45 pediatric patients hospitalized 
due to RSV LRTI have been enrolled into the ongoing C5241003 study. 
The administration of sisunatovir was well tolerated at all doses, dosage forms and dosing 
regimens tested. In the adult healthy participants treated to date, the occurrence of TEAEs 
considered related to sisunatovir has been low. Most commonly reported treatment-related 


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TEAEs were in the GI disorders SOC; nausea, diarrhea and abdominal pain. These TEAEs 
have been mild to moderate in intensity and resolved without sequelae. Most events 
attributed to IMP involved the gastrointestinal tract with nausea, diarrhea, and abdominal 
pain/discomfort/distension being the most common and occurring more commonly with the 
350 mg dose of sisunatovir than with the 200 mg sisunatovir dose, where the number of 
participants reporting these events were lower and similar to those on placebo. In children, 
sisunatovir is required to be suspended in a solution to enable oral administration, there has 
been evidence of poor tolerability when sisunatovir was suspended in water as a single dose 
of 2.0 mg/kg in children aged 6-36 months, resulting in expulsion of the oral dose. 
Suspension in breast milk, formula milk or saline appeared to improve the palatability, with 
all doses being successfully administered to children aged 1 to 36 months in study 
C5241003. 
As of 28 October 2022, there have been no SAEs attributable to sisunatovir and no deaths in 
the clinical studies. 
In adults, sisunatovir is slowly absorbed reaching maximum plasma concentrations (tmax) at 
5-6 hours (hrs) with a relatively moderate clearance, resulting in a half-life of 7-10 hours in 
healthy participants. Dosing to steady state resulted in steady state concentrations being 
reached after approximately 2 days of dosing resulting in 2-4 fold accumulation of exposure. 
AUC and Cmax values increased in a greater than dose proportional manner across single and 
multiple dose studies. Following 5 days of dosing, the variability in PK parameters was high, 
with % CV ranging from 67.4-84% for Cmax and 71.9-144% for AUC12. 
The effect of food on the single dose pharmacokinetics was assessed for the DIC and DPB 
dispersed in water. For the DIC the extent of systemic exposure to sisunatovir (geometric 
mean AUCinf under fed and fasted conditions) was 357 and 221 ng.h/mL respectively, with 
the between-subject variability being lower under fed conditions (CV 64.1% compared with 
198%). The ratio of fed/fasted was 218% (90% CI 94.2 - 502%) for Cmax and 162% (90% CI 
83.0 – 316%) for AUC0-inf. For the DPB dispersed in water the extent of systemic exposure to 
sisunatovir (geometric mean AUC0-∞) under fed and fasted conditions was 371 and 
337 ng.h/mL respectively, with the between-subject variability being slightly lower under 
fasted conditions (CV 49.0% compared with 61.6%). The ratio of fed/fasted was 
107.7% (90% CI 78.0 – 148.8%) for Cmax and 110.0% (90% CI 85.6 – 141.4%) for AUC0-inf. 
Inter-individual variability as illustrated by the %CV geometric mean suggests this was 
greater following administration of DPB in the fed state. 
Clinical DDI Study C5241004 demonstrated that the disposition of sisunatovir is expected to 
be affected by moderate to strong inhibitors and inducers of CYP3A4. Furthermore, 
sisunatovir was demonstrated to be a moderate inhibitor of CYP3A4, so dose adjustments for 
compounds that are sensitive substrates for CYP3A4 may need to be considered. 
In an RSV challenge study, sisunatovir treatment resulted in a statistically significant 
reduction in AUC of RSV viral load compared with placebo; 55.25% (p=0.007) and 
63.05% (p=0.002) for the 200 mg and 350 mg sisunatovir dose groups respectively (dosed 
Q12 hours for 5 days). Results for the AUC of total symptom score were consistent with the 


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viral load AUC. Geometric mean AUCs of total symptom score were 195.56, 30.79 and 
31.76 hours x score for placebo, 200 mg sisunatovir and 350 mg sisunatovir, respectively. 
The reduction in AUCs of total symptom score compared with placebo was statistically 
significant for both sisunatovir treatment groups; p=0.009 (70.84%) and p=0.002 (74.42%), 
(Wilcoxon Rank-Sum test) for the 200 mg and 350 mg sisunatovir dose groups, respectively. 
More detailed information about results of clinical studies for sisunatovir may be found in the 
IB, which is the SRSD for this study. 
2.3. Benefit/Risk Assessment 
Sisunatovir is not expected to provide any clinical benefit to healthy participants. This study 
is designed primarily to generate safety, tolerability, and pharmacokinetic data for further 
clinical development. 
For healthy participants participating in this study, no clinical benefit is expected. The 
purpose of the study is to provide the basis for further clinical development of sisunatovir as 
a potential new, pharmacological agent for the treatment of RSV. As of 14 September 2022, 
no specific human risks have been identified; postulated risks based on nonclinical studies 
are summarized in Section 2.2.1. The clinical impact of these potential risks will be 
minimized through standard, intensive, inpatient monitoring of the participants following 
administration of multiple oral doses of the study intervention. 
More detailed information about the known and expected benefits and risks and reasonably 
expected AEs of sisunatovir may be found in the IB, which is the SRSD for this study. 
2.3.1. Risk Assessment 
 
Potential Risk of 
Clinical 
Significance 
Summary of Data/Rationale for Risk 
Mitigation Strategy 
Study Intervention: sisunatovir 
Hepatobiliary 
system effects 
Degenerative and inflammatory changes in the 
bile duct of both rats (≥60 mg/kg/day) and dogs 
(≥45 mg/kg/day) in studies of up to 28 days, 
with elevated plasma levels of ALP, ALT and 
GGT in dogs only. Evidence of recovery for all 
findings following a 14-day treatment-free 
period. 
Standard monitoring including 
laboratory (ie, transaminases, ALP, 
GGT) and AE monitoring. 
Gastrointestinal 
effects 
Transient dose-related incidence of emesis and 
liquid feces in dogs at doses ≥15 mg/kg/day in 
studies up to 28 days. Additionally, 
inflammation in duodenum, gall bladder, and 
liver at 45 mg/kg/day noted in 28-day dog 
study. 
In previous clinical studies sisunatovir has been 
associated with mild GI AEs. 
As this is an investigational agent, 
there is some risk that is mitigated 
by close observation of AEs, etc. 
Participants will be closely 
evaluated in an inpatient setting to 
monitor for GI AEs. If needed, 
palliative alleviating measures such 
care as antiemetics may be 
provided. 


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Potential Risk of 
Clinical 
Significance 
Summary of Data/Rationale for Risk 
Mitigation Strategy 
Renal effects 
Degeneration/regeneration of medullary tubules 
was noted in rats at ≥120 mg/kg/day in studies 
of up to 28 days; considered non-adverse based 
on lack of clinical pathology changes. 
Standard monitoring including 
laboratory and AE monitoring. 
Cardiovascular 
effects 
Myocardial degeneration and necrosis was 
noted at 240 mg/kg/day (non-tolerated dose) in 
a 14-day rat study. 
No similar effect in rats at 120 mg/kg/day in the 
28-day study, or in dogs at any dose, for 14 or 
28 days. 
Monitoring will include vital signs, 
including heart rate, and ECG 
assessments. 
Pulmonary effects 
Vascular degeneration/necrosis in lung at 240 
mg/kg/day and epithelial degeneration/necrosis 
in trachea at 120 mg/kg/day in 14-day rat study. 
No similar effect in rats at 120 mg/kg/day in the 
28-day study, or in dogs at any dose, for 14 or 
28 days. 
Phase 1 FIH study (C5241001) showed no 
adverse clinically significant changes in safety 
laboratory parameters (including troponin), 
ECGs and vital signs. 
There will be standard safety 
monitoring including vital signs 
and of adverse events. 
Thymus effects 
Lymphoid atrophy and decreased thymus 
weight and reduced size of thymus in both rats 
(≥120 mg/kg/day) and dogs ≥15 mg/kg/day) in 
studies of up to 28 days. 
Evidence of recovery following a 14-day 
treatment-free period. 
These findings are secondary to stress and not 
directly sisunatovir related 
Standard monitoring including 
laboratory (ie, complete blood 
count with differential) and AE 
monitoring. Brief 5-day course 
regimen should further limit this 
potential risk. 
Other 
The COVID-19 
pandemic may pose 
risks to study 
participation. 
Participants may have increased risk of 
SARS-CoV-2 infection by undergoing a study 
procedure at a study facility. 
Inclusion of COVID-19 specific 
assessments according to the 
Schedule of Activities. 
2.3.2. Benefit Assessment 
For healthy participants participating in this study, no clinical benefit is expected. 
2.3.3. Overall Benefit/Risk Conclusion 
Sisunatovir is not expected to provide any clinical benefit to healthy participants in this 
study. 
Taking into account the measures to minimize risk to study participants, the potential risks 
identified in association with sisunatovir are justified by the anticipated benefits that may be 
afforded to participants with RSV. 


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3. OBJECTIVES AND ENDPOINTS 
 
Objectives 
Endpoints 
P1imary: 
Primary: 
• 
To characterize the safety and tolerability of multiple 
oral doses of sisunatovir in healthy adult participants 
• 
Assessment ofTEAEs, clinical laboratory 
abnonualities, vital signs, and 12-lead ECGs 
Secondary: 
Secondary: 
• 
To characterize the PK of multiple oral doses of 
sisunatovir 
• 
 PK Parameters AUCtau, Cmax., Tmax, AUCtau(dn), 
Cmax(dn) for Day 1 and AUCtau, Cmax, Tmax, AUCtau(dn), 
Cmax(dn), CL/F, Rae, Rac,Cmax; and t112 and V,/F (if data 
penuits) post last dose on Day 5 
• 
To evaluate the effect of food on the PK of multiple 
oral doses sisunatovir 
• 
The ratio of AUCtau and Cma...,on Day 5; Tmax on Day 5 
• 
To characterize the impact ofliquid vehicles on the 
palatability of sisunatovit· 
• 
 Palatability Assessment Questionnait·e Scoring Metrics: 
mouth feel, bitterness, sweetness, sourness, saltiness, 
tongue/mouth burn, overall liking 
 
 
 
 
4. STUDY DESIGN 
4.1. Overall Design 
This is a Phase 1 study that will be conducted in up to two coho1ts. 
Coho1t 1 is a randomized, 2-part, crossover design. Pait 1 has 3 periods, Periods 1 and 2 ai·e 
double blind, sponsor open, placebo controlled crossover design to evaluate the safety and 
tolerability and PK of the planned 400 mg and 200 mg of sisunatovir given Q12 hours x 4 
days plus 1 dose as 50 mg capsules in a fed state. Period 3, is an open label period to evaluate 
the food effect of the planned 400 mg of sisunatovir given Q12 hours x 4 days plus 1 dose in 
a fasted state. Pait 2, Periods 4-7, is open label to assess the palatability of 50 mg of 
sisunatovir in 4 different vehicles (water, infant fo1mula, apple juice, and saline) in a 
randomized crossover design. 
Coho1t 1 will include approximately 12 paiticipants that will be randomized into 4 sequences 
with 3 paiticipants in each sequence. Each sequence will receive treatment in a pre-specified 
manner (Section 1.2 Schema). 
Paiticipants will be admitted to the CRU on Day -1 to undergo baseline procedures. Over the 
first 2 periods, all paiticipants ai·e planned to receive (A) 400 mg and either (B) 200 mg plus 
matching placebo or (C) placebo dosed Q12 hours for 4 days plus 1 dose in the fed state. All 
paiticipants in Period 3 will receive (D) 400 mg dosed Q12 hours for 4 days plus 1 dose in 
the fasted state. Note that the dose levels for Periods 2 and 3 ai·e dependent upon the PK in 
the previous periods as described below. 


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Prior to proceeding to Period 2 of Cohort 1, the Period 1 Day 5 PK up to 12 hours post-dose 
will be assessed. If the mean exposures (AUC or Cmax) at 400 mg in Period 1 exceeds the 
rat (most sensitive species) NOAEL, the doses for the subsequent period(s) will be capped to 
a dose that is not expected to exceed the rat NOAEL. Similarly, prior to proceeding to 
Period 3 of Cohort 1, the Periods 1 and 2 Day 5 PK up to 12 hours post-dose will be 
assessed, and if the mean exposures (AUC or Cmax) at 400 mg exceeds the rat (most 
sensitive species) NOAEL, the doses for the subsequent period(s) will be capped to a dose 
that is not expected to exceed the rat NOAEL. Furthermore, safety will also be assessed 
following each period and doses for subsequent periods may be reduced if the safety and 
tolerability of the previous dose was not deemed sufficiently tolerated. 
A minimum 7-day washout period will occur between the last dose of Periods 1 and 2 and 
the first dose of Periods 2 and 3. 
Periods 4-7 will consist of a palatability assessment where participants will taste sisunatovir 
50 mg capsule content in different dosing vehicles ((E) water, (F) infant formula, (G) apple 
juice, and (H) saline) in a cross-over manner and then spit out the drug with the intention of 
assessing the palatability of sisunatovir in different dosing vehicles. The palatability 
questionnaire will be completed for each vehicle, the questionnaire asks participants to assess 
each vehicle at 4 different time increments after tasting. For each of the palatability 
assessments, at least 60 minutes will pass between tasting each vehicle. Period 4 may start 
after the last PK draw of Period 3. 
Cohort 2 is an optional randomized, crossover cohort with 3 periods. Periods 1-2 are double 
blind, sponsor open, placebo controlled crossover design evaluating the safety, tolerability, 
and PK of sisunatovir administered Q12 hours for 4 days plus 1 dose in a fed state. Period 3, 
is an open label period to evaluate the food effect of sisunatovir given Q12 hours x 4 days 
plus 1 dose in a fasted state. Doses will not exceed 400 mg Q12 hours x 4 days plus 1 dose 
and the projected exposure based on emerging data from Cohort 1 for the dose selected for 
Cohort 2 will not exceed the rat NOAEL. Cohort 2 will be conducted at the discretion of the 
Sponsor after review of Cohort 1 data (including PK for at least Periods 1 and 2) and there 
will be 2 sequences of 6 participants for Cohort 2. 
Participants who discontinue from the study for non-safety reasons may be replaced at the 
sponsor’s discretion in collaboration with the Investigator. 


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4.2. Scientific Rationale for Study Design 
The primary purpose of this study is to assess the safety and tolerability of 400 mg 
sisunatovir when dosed Q12 hours for 4 days plus 1 dose. In a clinical study evaluating the 
effect of sisunatovir on RSV viral load following a viral challenge in healthy participants 
indicated that both 200 and 350 mg Q12 for 5 days robustly decreased viral load relative to 
placebo (C5241002). The effect at the 350 mg dose was numerically superior to the 200 mg 
dose; however, the 350 mg dose was associated with GI-related AEs, which was also 
consistent with data from the MAD study (C5241001) indicating an increase in GI AEs at 
higher doses, the majority of GI-related AEs were mild. Since sisunatovir was dosed in the 
fasted state in these studies, it is not known if food will ameliorate these GI AEs. To fill this 
knowledge gap, the first 2 periods of Cohort 1 are designed to assess the safety and 
tolerability of 400 mg Q12 hours (n=12) versus 200 mg Q12 hours (n=6) and placebo (n=6). 
As a secondary objective, the effect of food on the safety, tolerability and PK of sisunatovir 
at the 400 mg Q12 hours dose will be compared. Thus, the data from the first 3 periods of 
Cohort 1 are designed to assess the highest well-tolerated dose of sisunatovir that can be 
assessed in future clinical studies and if food can ameliorate any potential GI AEs. 
Since the projected exposure at the 400-mg dose is expected to provide approximately 1.2x 
margins for AUC and Cmax using the rat NAOEL as the most sensitive species, the PK from 
each of Period 1 and Period 2 will be assessed prior to dosing the subsequent period. If the 
Day 5 exposure at the 400-mg dose exceeds the rat NOAEL (most sensitive species), then the 
dose in subsequent periods will be capped at a dose that is not projected to exceed the rat 
NOAEL. Note doses in Periods 2 and 3 may be adjusted based on safety findings from the 
previous dosing periods (see Section 4.1). 
Optional Cohort 2 is included and will only be conducted at the discretion of the sponsor 
after reviewing data from at least the first 2 periods of Cohort 1. This cohort could potentially 
be used to collect data at a lower dose (e.g., 300 mg) or collect additional data at a dose that 
does not exceed 400 mg Q12 hours, depending on the exposures observed in Cohort 1. 
In Cohort 1 only, the palatability of sisunatovir will be assessed to aid in development of 
pediatric formulations. These assessments will be conducted at least 48 hours after the last 
dose in Period 3, to allow for collection of the final PK sample and complete assessment of 
and AEs associated with the multiple dosing scheme. Palatability will be assessed by all 
participants in 4 different vehicles with a minimum of 1 hour between each vehicle, 1 hour 
washout has been used for the palatability assessment of other compounds. In each case, the 
drug in vehicle will be swirled in the mouth and spat out since it is not necessary to consume 
the drug to assess palatability. API blend in Pharmacopeial grade water will be used to assess 
the taste of the API blend. API blend in formula milk and apple juice will inform whether 
food vehicles are likely to improve palatability. API blend in saline will enable understanding 
of whether saline reduces bitter perception and improves palatability. 
The highest dose planned in this study (400 mg Q12 hours x 4 days plus 1 dose) is slightly 
higher than the previous highest multiple oral dose tested (350 mg Q12 hours x 5 days). For 


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this reason, in addition to AE monitoring, labs, vitals and ECGs will also be assessed. In 
order to facilitate possible PK/QTc modeling, ti·iplicate ECG measures will be taken. 
As this is healthy paiiicipant study, the use of concomitant medications in this study is 
expected to be minimal. Nevertheless, according to the DDI risk assessment for sisunatovir 
as described in Section 2.2.2, sisunatovir is a moderate inhibitor of CYP3A4 and is projected 
to be a weak inhibitor of CYP2B6. For this reason sensitive and naiTow TI CYP3A4 
subsu-ates and sensitive naiTow TI CYP2B6 substi·ates ai·e prohibited in this study. Since 
sisunatovir is a Pgp and CYP3A4 subsu-ate, su-ong and moderate CYP3A4 inhibitors and 
sti·ong Pgp inhibitors ai·e also prohibited. Lastly, due to risk ofMATEl and OCTl 
inhibition, sensitive substi·ates of these ti·anspo1iers ai·e prohibited. 
 
4.2.1. Choice of Contraception/Barrier Requirements 
There is no suspicion of human teratogenicity based on the intended phaimacology of the 
compound. Human reproductive safety data are limited for sisunatovir, therefore the use of a 
highly effective method of conti·aception is required for all fe1iile paiiicipants (see 
Appendix 4). 
4.2.2. Collection of Retained Research Samples 
Retained Reseai·ch Samples will be collected and stored for further analyses which may, for 
example, provide greater understanding of the study intervention. 
4.2.3. Collection of Retained Research Samples 
Retained Research Samples will be collected and stored for fmiher analyses which may, for 
example, provide greater understanding of the study intervention. 
4.3. Justification for Dose 
To investigate the effect of sisunatovir on clinical activity following RSV infection, a viral 
challenge clinical study in healthy pa1iicipants was conducted where doses of200 mg or 
350 mg Q12 x 5 days were administered following inoculation of an RSV infection. In this 
study, at both does evaluated, sisunatovir robustly decreased viral load and alleviated RSV 
symptoms relative to placebo. While statistically significant differences were not observed 
between the two dose levels, the 350 mg dose was numerically superior to the 200 mg dose. 
While these data do demonsu-ate phaimacological activity, effects in the viral challenge study 
have not ti·anslated to robust effects in clinical ti·ials evaluating patient populations (ie, in 
ti·eatment of RSV). One possible reason for this is that in the ti·eatment of RSV dmg 
intervention occurs several days after infection whereas the proximity of staii of ti·eatment to 
infection in the viral challenge study is much sooner. For this reason, it is desired to dose 
sisunatovir Phase 2/3 efficacy studies at doses that maximize coverage over EC90 at a safe 


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and well tolerated dose. Additionally, dosing at higher multiples over EC90 may confer 
protection against resistance. 
Sisunatovir was generally well tolerated in the viral challenge study as well as other Phase 1 
studies conducted to date. However, an increased incidence of GI AEs were observed at the 
350 mg dose relative to the 200 mg dose. Higher rates of GI AEs were also observed at 
higher doses within the Phase 1 program. In these studies, sisunatovir was dosed in a fasted 
state. Although improved GI tolerability has been observed for some anti-infective agents 
when dosed with food, it is not clear if GI tolerability of sisunatovir will improve with food. 
The primary purpose of Cohort 1 of this study is to evaluate the safety and tolerability of the 
400 mg Q12 hours x 4 days plus one dose dosing regimen and if any potential GI AEs can be 
mitigated with food. Therefore, within the first 2 periods of Cohort 1, each participant will 
receive 400 mg Q12 hours x 4 days plus 1 dose of sisunatovir with food (compared to 
placebo or 200 mg Q12hours). In Period 3 of Cohort 1, participants will receive 400 mg 
Q12 hours x 4 days plus 1 dose fasted to directly compare PK, safety and tolerability in the 
same participants dosed fed at the same dose level. Note doses in Periods 2 and 3 may be 
adjusted based on PK and safety findings from the previous dosing periods (see Section 4.1). 
The effect of food on the pharmacokinetics of sisunatovir has been variable in Phase 1 
studies. However, the effect of food on the pharmacokinetics of sisunatovir using the 
formulation to be used in this study (dry powder blend in capsules) showed minimal food 
effect. 
As the exposure of sisunatovir increases in a greater than dose proportional manner, the 
steady state exposure at the planned dose in Cohort 1 (400 mg Q12 hours) is expected to be 
~40% greater than the exposure at the highest dose studied to date (350 mg Q12 hours). At 
this dose, the anticipated safety margin over rat (most sensitive species) NOAEL AUC and 
Cmax in the 28-day toxicology study are 1.2-fold. 
Cohort 2 in this study is optional and will only be conducted at the discretion of the sponsor 
after reviewing data from Cohort 1. The dose assessed in Cohort 2 will not exceed 400 mg 
Q12 hours x 5 days or a dose that is projected to exceed the rat NOAEL based on Cohort 1 
PK data. This cohort may be used to assess a lower dose (e.g., 300 mg) or may be used to 
collect additional data at the same dose that has been tested in Cohort 1 and is viewed as safe. 
These data may then be used to define the dose and dosing instructions in Phase 2/3. 
The dose for the palatability cohort (50 mg in a 7 mL dosing solution) was selected to be 
close to the anticipated drug concentration in pediatric studies. 
4.4. End of Study Definition 
The end of the study is defined as the date of the last visit of the last participant in the study. 
A participant is considered to have completed the study if they have completed all periods of 
the study, including the last visit. 


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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. Use of 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, and race, and ethnicity. The following eligibility 
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. Participants aged 18 to 65 years of age, inclusive, at the time of signing of the ICD. 
• All fertile participants must agree to use a highly effective method of 
contraception. 
• Refer to Appendix 4 for reproductive criteria for male (Section 10.4.1) and female 
(Section 10.4.2) participants. 
2. Male and female participants who are overtly healthy as determined by medical 
evaluation including medical history, physical examination, including blood pressure, 
pulse rate, standard 12-lead ECG, and laboratory tests. 
Other Inclusion Criteria: 
3. BMI of 17.5 to 35 kg/m2; and a total body weight >50 kg (110 lb). 
4. Capable of giving signed informed consent as described in Appendix 1: Regulatory, 
Ethical, and Study Oversight Considerations which includes compliance with 
requirements and restrictions listed in the ICD and in this protocol. 
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 


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allergic disease (including drug allergies, but excluding untreated, asymptomatic, 
seasonal allergies at the time of dosing). 
• Any condition possibly affecting drug absorption (eg, gastrectomy, 
cholecystectomy). 
• History of HIV infection, hepatitis B, or hepatitis C; positive testing for HIV, 
HBsAg, or HCVAb. Hepatitis B vaccination is allowed. 
• Positive test result for SARS-CoV-2 infection on Day -1. 
2. 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: 
3. Use of prescription or nonprescription drugs and dietary and herbal supplements 
within 7 days or 5 half-lives (whichever is longer) prior to the first dose of study 
intervention with the exception of moderate/strong CYP3A inducers or 
time-dependent inhibitors which are prohibited within 14 days plus 5 half-lives prior 
to the first dose of study intervention. (Refer to Section 6.9 for additional details). 
4. Current use of any prohibited concomitant medication(s) or participant 
unwilling/unable to use a permitted concomitant medication(s). 
5. Female participants taking hormonal contraceptives or hormone replacement therapy 
within 28 days of the first dose of study treatment. 
• Injectable hormone therapy (eg, DepoProvera®) must be discontinued at least 
6 months prior to the first dose of study treatment. 
Prior/Concurrent Clinical Study Experience: 
6. Previous administration with an investigational product (drug or vaccine) within 
30 days (or as determined by the local requirement) or 5 half-lives preceding the first 
dose of study intervention used in this study (whichever is longer). 
Diagnostic Assessments: 
7. A positive urine drug test, confirmed by a repeat test, if deemed necessary. 
8. Screening supine BP ≥140 mm Hg (systolic) or ≥90 mm Hg (diastolic), following at 
least 5 minutes of supine rest. If BP is ≥140 mm Hg (systolic) or ≥90 mm Hg 


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(diastolic), 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. 
9. 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 the uncorrected QT 
interval is >450 ms, this interval should be rate-corrected using the Fridericia method 
only and the resulting QTcF should be used for decision making and reporting. 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. 
10. 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: 
• eGFR <60 mL/min/1.73m2 based on CKD-EPI equation; 
• AST or ALT level ≥1.5 x ULN; 
• Gamma-GT> ULN; 
• Alkaline phosphatase > 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. 
Other Exclusion Criteria: 
11. 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). 
12. Blood donation (excluding plasma donations) of approximately 1 pint (500 mL) or 
more within 60 days prior to dosing. 
13. History of sensitivity to sisunatovir or any of the formulation components. 
14. Use of tobacco or nicotine-containing products in excess of the equivalent of 
5 cigarettes/day or 2 chews of tobacco/day. 


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15. Unwilling or unable to comply with the criteria in the Lifestyle Considerations 
section of this protocol. 
16. 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. 
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 
and their partner(s) from the permitted list of contraception methods (see Appendix 4, 
Section 10.4.3) and will confirm that the participant has been instructed in its consistent and 
correct use. 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 evaluations. 
• On Dosing days in periods 1 and 2, participants will consume a standard meal 
approximately 30 minutes prior to dosing. They should be encouraged to complete 
their meals on Day 1 and Day 5 (PK sampling days) by approximately 10 minutes 
prior to anticipated dosing. 
• During Period 3, lunch will be the first meal after an overnight fast of approximately 
10 hours. 
• During the palatability assessment periods, there will be at least 60 minutes between 
meals and palatability assessments. 


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• Lunch will be provided approximately 4 hours after dosing. 
• In Period 3, dinner will be provided approximately 13 hours after AM dosing (1 hour 
after PM dosing). 
• In Period 3, an afternoon snack may be permitted approximately 7.5 hours after AM 
dosing. 
• An evening snack may be permitted, for all periods. 
• 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 collection of the final PK sample of each study period. 
• 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 collection 
of the final PK sample of each study period. Participants may undergo an alcohol 
breath test or blood alcohol test at the discretion of the investigator. 
• Participants will abstain from the use of tobacco- or nicotine-containing products for 
24 hours prior to dosing 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. 
• In order to standardize the conditions on PK sampling days, participants will be 
required to refrain from lying down (except when required for BP, pulse rate, and 
ECG measurements), eating, and drinking beverages other than water during the first 
4 hours after dosing. These criteria only apply to the AM doses on Days 1 and 5 
(Periods 1-3). 


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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. 
6. STUDY INTERVENTION(S) AND CONCOMITANT THERAPY 
Study interventions are all prespecified investigational and non-investigational 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 sisunatovir and placebo. 
6.1. Intervention(s) Administered 
 
Study Intervention(s) 
Intervention Name 
PF-07923568 
(sisunatovir) 
Placebo for PF-07923568 
(sisunatovir) 
PF-07923568 
(sisunatovir) Palatability 
in Liquid Vehicles 
Unit Dose Strength(s) 
50 mg 
Placebo 
Content of 50 mg capsule 
Dose Formulation 
capsule 
Capsule 
Capsule content dispensed 
in liquid vehicles 
Dosage Level(s) 
Planned doses are 200 mg 
and 400 mg BID for 4 days 
plus 1 dose in Cohort 1. 
Doses in Cohort 2 will not 
exceed 400 mg Q12 hours. 
0 mg 
Planned doses are the 
content of a 50 mg capsule 
of sisunatovir, dispensed in 
7 ml of the following liquid 
vehicles: 
• 
Water 
• 
Infant formula 
• 
Apple juice 
• 
Saline 
Route of Administration 
Oral 
Oral 
Oral/”Swirl and Spit” 
Use 
Experimental 
Placebo 
Experimental 
IMP or NIMP/AxMP 
IMP 
IMP 
IMP 
Sourcing 
Provided centrally by the 
sponsor 
Provided centrally by the 
sponsor 
Sisunatovir: Provided 
centrally by the sponsor 
Liquid vehicles: Provided 
locally by the CRU 
Packaging and Labeling 
The PF-07923568 50 mg 
capsules will be provided in 
bulk. CRU Staff will 
prepare individual doses for 
administration 
The placebo capsules will 
be provided in bulk. CRU 
Staff will prepare 
individual doses for 
administration 
The PF-07923568 50 mg 
capsules will be provided in 
bulk. CRU Staff will 
prepare individual doses 
(capsule content + liquid) 
for administration 


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Study Intervention(s) 
Current/former Name(s) 
Sisunatovir 
Placebo 
Sisunatovir 
or Alias(es) 
PF-07923568 
PF-07923568 
RV521 
RV521 
Liquid vehicles: As 
available locally. 
Study intervention will be supplied by Pfizer as 50-mg capsules. 
Matching placebo capsules will also be provided. 
Capsules will be supplied to the CRU in bulk along with individual dosing containers for unit 
dosing. 
6.1.1. Administration 
6.1.1.1. Period 1 and 2 
During Periods 1 and 2 for Cohorts 1 and 2, participants will receive study intervention at 
approximately 0800 hours (plus or minus 2 hours) approximately 30 minutes after the start of 
a standard breakfast that will be consumed over approximately 20 minutes. Participants will 
receive the evening dose of study intervention 12 hours after the morning dose (plus or minus 
1 hour) approximately 30 minutes after the start of a standard dinner that will be consumed 
over approximately 20 minutes. On Day 5 in each period only the morning dose of study 
intervention will be administered. Investigator site personnel will administer study 
intervention during each period with ambient temperature water to a total volume of 
approximately 240 mL. Participants may receive additional ambient temperature water up to 
100 mL, if needed. This will be documented by the site. Participants will swallow the study 
intervention whole and will not manipulate or chew the study intervention prior to 
swallowing. 
6.1.1.2. Period 3 
During Period 3 for Cohorts 1 and 2, participants will receive morning study intervention at 
approximately 0800 hours (plus or minus 2 hours). For the Day 1 morning and Day 5 
morning doses, the pre-dose fasting period is 10 hours and post-dose fasting period is a 
minimum of 4 hours. For all Days 2, 3, and 4 morning doses, the pre-dose fasting period is 
8 hours and the post-dose fasting period is a minimum of 1 hour. For evening doses, the 
pre-dose fasting period is 4 hours, and the post-dose fasting period is a minimum of 1 hour. 
On Day 5 only the morning dose of study intervention will be administered. For all doses, 
participants will have nothing to drink (including water) for 1 hour pre-dose and 1 hour post- 
dose. Investigator site personnel will administer study intervention during each period with 
ambient temperature water to a total volume of approximately 240 mL. Participants may 
receive additional ambient temperature water up to 100 mL, if needed. This will be 
documented by the site. Participants will swallow the study intervention whole and will not 
manipulate or chew the study intervention prior to swallowing. 


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On Day 1 and Day 5 for morning doses, in order to standardize the conditions on PK 
sampling days, all participants will be required to refrain from lying down (except when 
required for BP, pulse rate, and ECG measurements), eating, and drinking beverages other 
than water during the first 4 hours after dosing. 
6.1.1.3. Periods 4-7 (Cohort 1 only) 
During Periods 4-7, participants will be assessing the taste of sisunatovir in a variety of 
vehicles using the questionnaire in Appendix 10 . Participants will taste 50 mg of sisunatovir 
in 7 ml of the following vehicles: water, saline, apple juice, and infant formula, given in a 
randomized order. Participants will swirl the study intervention in their mouth for 10 seconds 
and then spit it out. Participants will assess various aspects of the taste using the 
questionnaire in Appendix 10: Oral Solution or Suspension Palatability Questionnaire at 
approximately 1 minute, 5 minutes, 10 minutes, and 20 minutes after spitting. There will be 
at least 60 minutes between tasting each study intervention, and at least 60 minutes after 
meals. Participants may eat plain crackers and water to cleanse their palate between 
assessments. 
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 CRU procedures. 
5. Any storage conditions stated in the SRSD will be superseded by the storage 
conditions stated on the label. 
6. Study interventions should be stored in their original containers. 


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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 CRU’s 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 as described in the IPM. 
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. 
Sisunatovir and placebo will be prepared by qualified unblinded site personnel according to 
the IPM. Blinded study intervention will be administered in a blinded fashion to the 
participant. See the IPM for instructions on how to prepare the study intervention for 
administration or palatability assessment. Capsules will be prepared at the CRU in the 
individual dosing containers by 2 operators, 1 of whom is an appropriately qualified and 
experienced member of the study staff (eg, physician, nurse, physician’s assistant, nurse 
practitioner, pharmacy assistant/technician, or pharmacist). 
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 
The first 2 periods of each cohort are double blind (sponsor open) design. 
Study intervention administrated in Periods 3 to 7 of the study will be open to the participant, 
Investigator and Sponsor or Sponsor-designate personnel responsible for study monitoring 
activities (including all site monitoring activities). 


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6.4.1. Blinding of Participants 
Participants will be blinded to their assigned study intervention. Study intervention 
administrated in Periods 3 to 7 of the study will be open to participant. 
6.4.2. Blinding of Site Personnel 
Investigators and other site staff will be blinded to participants’ assigned study intervention. 
Study intervention administrated in Periods 3 to 7 of the study will be open to Investigator 
and other site staff. 
Participants will be assigned to receive study intervention according to the assigned treatment 
group from the randomization scheme. 
In the first 2 periods, in order to maintain the blind, an otherwise uninvolved third party will 
be responsible for the preparation and dispensing of all study intervention and will endeavor 
to ensure that there are no differences in time taken to dispense or visual presentation, 
following randomization or dispensing. 
In the event of a Quality Assurance audit, the auditor(s) will be allowed access to unblinded 
study intervention records at the site(s) to verify that randomization/dispensing has been done 
accurately. 
6.4.3. Blinding of the Sponsor 
As this is a sponsor open study, a limited number of the sponsor’s team members (excluding 
site staff) may conduct unblinded reviews of the data during the course of the study for the 
purpose of safety and tolerability assessment, facilitating PK/PD modeling, and/or supporting 
clinical development. 
6.4.4. Breaking the Blind 
Blood specimens will be obtained from all participants for PK analysis to maintain the study 
blind at the investigator site. Only the investigator site staff and blinded study monitor, if 
assigned, will be blinded to study treatment for Periods 1 and 2. Other Pfizer personnel will 
be unblinded to participant treatments in order to permit real-time interpretation of the safety 
and PK data; and provide information necessary to further clinical development. The blinded 
study monitor, if assigned, will remain blinded to treatment until all monitoring for the study 
has been completed. Specimens from participants randomized to placebo will not be 
routinely analyzed. To minimize the potential for bias, treatment randomization information 
for Periods 1 and 2 will be kept confidential by Pfizer unblinded personnel and will not be 
released to the blinded investigator or blinded investigator site personnel until the study 
database has been locked or the investigator requests unblinding for safety reasons. 
6.5. Study Intervention Compliance 
When the individual dose for a participant is prepared from a bulk supply, the preparation of 
the dose will be confirmed by a second qualified member of the study site staff. 


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When participants are dosed, 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. 
The dose of study intervention and study participant identification will be confirmed at the 
time of dosing by a member of the study site staff. Study site personnel will examine each 
participant’s mouth to ensure that the study intervention was ingested. 
6.6. Dose Modification 
Dose in Periods 2 and 3 of Cohort 1 may be reduced based on safety and PK observations in 
previous periods (see Section 4.1). The dose for Cohort 2 (if conducted) will be chosen based 
on data from Cohort 1 and will not exceed 400 mg Q12 hours. 
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 
For this study, any dose of sisunatovir greater than 1200 mg 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 at least until the next scheduled follow-up. 
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 if requested by the study medical monitor 
(determined on a case-by-case basis). 
Decisions regarding dose interruptions or modifications will be made by the investigator in 
consultation with the study medical monitor as needed based on the clinical evaluation of the 
participant. 
6.9. Prior and Concomitant Therapy 
Use of prescription or nonprescription drugs and dietary and herbal supplements are 
prohibited within 7 days or 5 half-lives (whichever is longer) prior to the first dose of study 
intervention. Limited use of nonprescription medications that are not believed to affect 
participant safety or the overall results of the study may be permitted on a case-by-case basis 


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following approval by the sponsor. Acetaminophen/paracetamol may be used at doses of 
≤1 g/day. 
Females using hormonal contraceptives or taking hormone replacement therapy may be 
eligible to participate in this study if they are willing to discontinue therapy at least 28 days 
prior to the first dose of study treatment and remain off hormonal therapy for the duration of 
the study. DepoProvera® must be discontinued at least 6 months prior to the first dose of 
study treatment. 
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 requiring discontinuation in investigator’s view. 
• Pregnancy. 
If study intervention is permanently discontinued, the participant will not remain in the study 
for further evaluation. See the SoA for data to be collected at the time of discontinuation of 
study intervention. 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, 
posttreatment study follow-up, and/or future collection of additional information. 
7.1.1. ECG Changes 
A participant who meets either bulleted criteria based on the average of triplicate ECG 
readings will be withdrawn from the study intervention. 
• QTcF >500 ms. 
• Change from baseline: QTcF >60 ms. 
 
 
 
 
 
PFIZER CONFIDENTIAL 
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If a clinically significant finding is identified (including, but not limited to, changes from 
baseline in QTcF after enrollment), the investigator or qualified designee will determine if 
the participant can continue in the study and if any change in participant management is 
needed. This review of the ECG printed at the time of collection must be documented. Any 
new clinically relevant finding should be reported as an AE. 
7.1.2. Potential Cases of Acute Kidney Injury 
Abnormal values in SCr concurrent with presence or absence of increase in BUN that meet 
the criteria below, in the absence of other causes of kidney injury, are considered potential 
cases of acute kidney injury and should be considered important medical events. 
An increase of ≥0.3 mg/dL (or ≥26.5 µmol/L) in SCr level relative to the participant’s own 
baseline measurement should trigger another assessment of SCr as soon as practically 
feasible, preferably within 48 hours from awareness. 
If the second assessment (after the first observations of ≥0.3 mg/dL [or ≥26.5 µmol/L] in SCr 
relative to the participant’s own baseline measurement) is ≥0.4 mg/dL (or ≥35.4 µmol/L), the 
participant should be discontinued from the study and adequate, immediate, supportive 
measures taken to correct apparent acute kidney injury. 
Participants should return to the investigator site and be evaluated as soon as possible, 
preferably within 48 hours from awareness of the second assessment confirming abnormal 
SCr result. This evaluation should include laboratory tests, detailed history, and physical 
assessment. In addition to repeating SCr, laboratory tests should include serum BUN, serum 
creatine kinase, and serum electrolytes (including at a minimum potassium, sodium, 
phosphate/phosphorus, and calcium), in addition to urinary dipstick, urine microscopic 
examination, and urinary indices. All cases confirmed on repeat testing as meeting the 
laboratory criteria for acute kidney injury, with no other cause(s) of laboratory abnormalities 
identified, should be considered potential cases of drug-induced kidney injury irrespective of 
availability of all the results of the investigations performed to determine etiology of the 
abnormal SCr. If ≥2 healthy participants in a given period are noted to have 2 consecutive 
SCr results of ≥0.3 mg/dL (or ≥26.5 µmol/L), an assessment of whether the finding may be 
considered an adverse drug reaction should be undertaken. 
7.1.3. COVID-19 
If a participant has COVID-19 during the study, this should be reported as an AE or SAE (as 
appropriate) and appropriate medical intervention provided. Temporary discontinuation of 
the study intervention may be medically appropriate until the participant has recovered from 
COVID-19. 
It is recommended that the investigator discuss temporary or permanent discontinuation of 
study intervention with the study medical monitor. 


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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; 
• Lost to follow-up; 
• Death; 
• Study terminated by sponsor; 
• Pregnancy; 
• Behavioral, compliance, or administrative reasons. 
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 


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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. 
The following actions must be taken if a participant fails to return to the clinic for a required 
study visit: 
• The site must attempt to contact the participant and reschedule the missed visit as 
soon as possible. 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 and Baseline 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 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 


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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 eligibility criteria for this study. In 
addition, other clinical assessments or specimen collections, eg, retained research samples, 
may be used without repeat collection, 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 
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. 
Safety/laboratory/analyte results that have been collected for the purposes of this study and 
could unblind the study will not be reported to investigative sites or other blinded personnel 
until the study has been unblinded. 
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 individual participants in this study is approximately 
340 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 
Lifestyle Considerations and Concomitant Therapy sections of the protocol. 
8.1.1. Baseline Procedures 
Planned timepoints for medical history and demography are provided in the SoA. 
8.2. Efficacy Assessments 
Not Applicable. 


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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 
light clothing remains. They must also remove the contents of their pockets and remain still 
during measurement of weight. 
Physical examination findings collected during the study will be considered source data 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. Vital Signs 
8.3.2.1. 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 appropriate collection of safety data. 


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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. 
8.3.3. Electrocardiograms 
Standard 12-lead ECGs utilizing limb leads (with a 10-second rhythm strip) should be 
collected at times specified in the SoA section of this protocol using an ECG machine that 
automatically calculates the HR and measures PR interval, QT interval, QTcF, and QRS 
complex. Alternative lead placement methodology using torso leads (eg, Mason-Likar) 
should not be used given the potential risk of discrepancies with ECGs acquired using 
standard limb lead placement. All scheduled ECGs should be performed after the participant 
has rested quietly for at least 5 minutes in a supine position. 
3 baseline pre-dose measurements are needed for CQT analysis, these ECGs will be done 
approximately 30 min, 20 min, and 10 min before the pre-dose meal in Periods 1 and 2, and 
approximately 30 min, 20 min, and 10 min pre-dose in Period 3. The average of the triplicate 
ECGs over the 3 pre-dose measurements (total of 9 ECGs) will serve as each participant’s 
baseline QTc value. Triplicate 12-lead ECGs will be obtained approximately 2 to 4 minutes 
apart. 
To ensure safety of the participants, a qualified individual at the investigator site will make 
comparisons to baseline measurements. Additional ECG monitoring will occur if a) a 
postdose QTcF interval is increased by ≥60 ms from the baseline and is >450 ms; or b) an 
absolute QT value is ≥500 ms for any scheduled ECG. If either of these conditions occurs, 
then 2 additional ECGs will be collected approximately 2 to 4 minutes apart to confirm the 
original measurement. If the QTcF values from these repeated ECGs remain above the 
threshold value, then a single ECG must be repeated at least hourly until QTc values from 
2 successive ECGs fall below the threshold value that triggered the repeat measurement. 
To ensure safety of the participants, a qualified individual at the investigator site will make 
comparisons to baseline measurements. Additional ECG monitoring will occur if a) the mean 
value from the triplicate measurements for any postdose QTcF interval is increased by 
≥60 ms from the baseline and is >450 ms; or b) an absolute QT value is ≥500 ms for any 
scheduled ECG. If either of these conditions occurs, then a single ECG measurement must be 
repeated at least hourly until QTcF values from 2 successive ECGs fall below the threshold 
value that triggered the repeat measurement. 
If a) a postdose QTcF interval remains ≥60 ms from the baseline and is >450 ms; or b) an 
absolute QT value is ≥500 ms for any scheduled ECG for greater than 4 hours (or sooner, at 
the discretion of the investigator); or c) QTcF value get progressively longer, the participant 
should undergo continuous ECG monitoring. A cardiologist should be consulted if QTcF 
values do not return to less than the criteria listed above after 8 hours of monitoring (or 
sooner, at the discretion of the investigator). 


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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 
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. 
8.3.4. 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 48 hours after the last dose of study 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 
reporting laboratory test abnormalities. 
Participants may undergo random urine drug testing at the discretion of the investigator. 
Drug testing conducted prior to dosing must be negative for participants to receive study 
intervention. 
8.3.5. COVID-19 Specific Assessments 
Participants will be tested for COVID-19 infection per CRU SOPs. Additional testing may be 
required by local regulations or by the PI. 


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8.3.6. Pregnancy Testing 
A 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 the participant’s receiving 
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. If a urine test cannot be confirmed as negative 
(eg, an ambiguous result), a serum pregnancy test is required. In such cases, the participant 
must be excluded if the serum pregnancy result is positive. 
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. 
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 intervention (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 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. 


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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 intervention 
because of an AE or SAE, the AE or SAE must be recorded on the CRF and the SAE 
reported using the CT SAE Report Form. 
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 CT SAE Report Form. 
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 CT SAE Report Form 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 subject to the CRF 
requirements as described in Section 5.4. 


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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. 
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. 


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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 until the follow-up visit (28-35 days after last dose of study drug). 
• A male participant who is receiving or has discontinued study intervention 
inseminates a female partner until the follow-up visit (28-35 days after last dose of 
study drug) for the participant. 
• 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. 
• 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 on the CT SAE Report Form and an EDP Supplemental 
Form, regardless of whether an SAE has occurred. Details of the pregnancy will be 
collected after the start of study intervention and until the follow-up visit (28-35 days 
after last dose of study drug) for the participant. 


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• If EDP occurs in the setting of environmental exposure, the investigator must report 
information to Pfizer Safety using the CT SAE Report Form and EDP Supplemental 
Form. 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 CT SAE Report Form 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 EDP Supplemental Form. 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 
preprocedure 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 live-born 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 
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. 


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• 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 CT SAE Report Form. 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 CT SAE Report 
Form 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 CT SAE Report Form 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 CT SAE Report Form must be maintained in the 
investigator site file. 
8.4.6. Cardiovascular and Death Events 
This section is not applicable for this study. 
8.4.7. Disease-Related Events and/or Disease-Related Outcomes Not Qualifying as AEs 
or SAEs 
This section is not applicable for this study. 
8.4.8. Adverse Events of Special Interest 
This section is not applicable for this study. 
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 
This section is not applicable because there are no medical devices included in the study. 


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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 CT SAE 
Report Form 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. 
Other examples include, but are not limited to: 
• The administration of expired study intervention; 
• The administration of an incorrect study intervention; 
• The administration of an incorrect dosage; 
• The administration of study intervention that has undergone temperature excursion 
from the specified storage range, unless it is determined by the sponsor that the study 
intervention under question is acceptable for use. 
Such medication errors occurring to a study participant are to be captured on the medication 
error page of the CRF, which is a specific version of the AE page. 
Whether or not the medication error is accompanied by an AE, as determined by the 
investigator, the medication error is recorded on the medication error page of the CRF and, if 
applicable, any associated AE(s), serious and nonserious, 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 CT SAE Report 
Form only when associated with an SAE. 


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8.5. Pharmacokinetics 
Blood samples of approximately 2 mL, to provide approximately 0.8 mL plasma, will be 
collected for measurement of plasma concentrations of sisunatovir as specified in the SoA. 
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. 
The actual times may change, but the number of samples will remain the same. 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. 
CCI 
. Participant confidentiality 
will be maintained. 
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. 
Drug concentration information that may unblind the study will not be reported to 
investigator sites or blinded personnel until the study has been unblinded. 
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 
be informed of any safety issues that require alteration of the safety monitoring scheme or 
amendment of the ICD. 
8.5.1. Palatability Questionnaire 
Participants will be asked to fill out the Palatability Questionnaire after sisunatovir 
administration for treatments E, F, G, and H. The Palatability Questionnaire will be 
administered at 1 (immediately after sisunatovir administration), 5, 10, and 20 minutes after 
sisunatovir administration. 
Details of the Palatability Questionnaire are provided in Appendix 10. 


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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. 
 
See Appendix 5: Genetics for infonnation regarding genetic research. Details on processes 
for collection and shipment of these samples can be found in the Laborato1y Manual and 
suppo1ting documentation. 
 
 
8.7.1. Specified Gene Expression (RNA) Research 
Specified gene expression (RNA) research is not included in this study. 
8.7.2. Specified Protein Research 
Specified protein research is not included in this study. 
8.7.3. Specified Metabolomic Research 
Specified metabolomic research is not included in this study. 
 
I 
 
 


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See Appendix 5: Genetics for infonnation regarding genetic research. Details on processes 
for collection and shipment of these samples can be found in the Laborato1y Manual and 
suppo1ting documentation. 
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 summaiy 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 primaiy endpoint definitions or their analyses will also be reflected in a 
protocol amendment. 
9.1. Statistical Hypotheses 
No fonnal statistical hypothesis will be tested in this study. 
9.2. Analysis Sets 
For pmposes of analysis, the following analysis sets are defined: 
 
Participant Analysis 
Set 
Description 
Emolled 
"Emolled" means a paiticipant, or their legally authorized 
representative's, agreement to paiticipate in a clinical study 
following completion of the info1med consent process and 
randomization to study intervention. A paiticipant will be 
considered enrolled if the info1med consent is not withdrawn 
prior to paiticipating in any study activity after screening. 
Potential paiticipants who ai·e screened for the pmpose of 
dete1mining eligibility for the study, but do not paiticipate in 
the study, are not considered enrolled, unless othe1wise 
specified by the protocol. 
Safety analysis set 
All paiticipants randomly assigned to study intervention and 
who take at least 1 dose of study intervention. Pa1ticipants will 
be analyzed according to the product they actually received. 


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Participant Analysis 
Set 
Description 
PK Concentration 
Population 
All participants randomly assigned to study intervention and 
who take at least 1 dose of study intervention and in whom at 
least 1 concentration value can be reported. 
PK Parameter Analysis 
Population 
All participants randomly assigned to study intervention and 
who take at least 1 dose of study intervention and in whom at 
least 1 of the PK parameters of interest can be reported. 
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 
Details of the analyses will be provided in the Statistical Analysis Plan. 
All treatment arms and placebo will be reported separately. 
9.3.2. Primary Endpoint(s) Analysis 
All safety analyses will be performed on the safety population. 
AEs, ECGs, BP, pulse rate, and safety laboratory data will be reviewed and summarized on 
an ongoing basis during the study 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. 
9.3.2.1. Electrocardiogram Analyses 
Changes from baseline for the ECG parameters HR, QTcF , PR interval, and QRS complex 
will be summarized by treatment and time. The frequency of uncorrected QT values above 
500 ms will be tabulated. 


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The number (%) of participants with maximum postdose QTcF values and maximum 
increases from baseline in the following categories will be tabulated by treatment: 
 
Safety QTcF Assessment 
 
Degree of Prolongation 
Mild (ms) 
Moderate (ms) 
Severe (ms) 
Absolute value 
>450-480 
>480-500 
>500 
Increase from baseline 
30-60 
>60 
If more than 1 ECG is collected at a nominal time after dose administration (for example, 
triplicate ECGs), the mean of the replicate measurements will be used to represent a single 
observation at that time point. If any of the 3 individual ECG tracings has a QTcF value 
>500 ms, but the mean of the triplicates is not >500 ms, the data from the participant’s 
individual tracing will be described in a safety section of the CSR in order to place the 
>500 ms value in appropriate clinical context. However, values from individual tracings 
within triplicate measurements that are >500 ms will not be included in the categorical 
analysis unless the average from the triplicate measurements is also >500 ms. Changes from 
baseline will be defined as the change between the post-dose QTcF value and the average of 
the predose triplicate values on Day 1. 
9.3.3. Secondary Endpoint(s) Analysis 
Plasma PK parameters of sisunatovir will be derived from the concentration-time data using 
standard noncompartmental methods of analysis as outlined in Table 4. Actual PK sampling 
times will be used in the derivation of sisunatovir PK parameters when available. In the case 
that actual PK sampling times are not available, nominal PK sampling time will be used in 
the derivation of PK parameters. 
 
Table 4. 
Plasma Sisunatovir PK Parameters Definitions 
 
Parameter 
Definition 
Method of Determination 
AUCtau 
Area under the concentration-time profile 
from time zero to time tau (the dosing 
interval), where tau = 12 hours for BID 
dosing. 
Linear/Log trapezoidal method. 
AUCtau(dn) 
Dose normalized AUCtau 
AUCtau/Dose 
Cmax 
Maximum observed plasma concentration 
Observed directly from data 
Cmax(dn) 
Dose normalized maximum plasma 
concentration 
Cmax/Dose 
Tmax 
Time to reach Cmax 
Observed directly from data as time of first 
occurrence 
t½* 
Terminal elimination half-life 
Loge(2)/kel, where kel is the terminal phase 
rate constant calculated by a linear 
regression of the loglinear concentration- 
time curve. Only those data points judged 
to describe the terminal loglinear decline 
will be used in the regression. 


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Table 4. 
Plasma Sisunatovir PK Parameters Definitions 
 
Parameter 
Definition 
Method of Determination 
CL/F 
Apparent clearance 
Dose/AUC1au 
Vz/F* 
Apparent volume of distribution 
Dose/(AUCtau • ke1) 
Rae 
Observed accumulation ratio for AUC 
AUCtau Day5/AUCtau Dayl 
Rac,Cmax 
Observed accumulation ratio for Cmax 
Cmax Day5/CmaxDayl 
* If data permit. 
 
The plasma concentrntions of sisunatovir will be listed and descriptively summarized by 
nominal PK sampling time and treatment. Individual paiiicipant and summaiy profiles (mean 
and median plots) of the plasma concentrntion-time data will be plotted by treatment using 
actual and nominal times, respectively. Mean and median profiles will be presented on both 
lineai·and semi-log scales. 
 
For the food effect evaluation, natural log transfo1med AUC1au, and Cmax of sisunatovir will 
be analyzed using a mixed effect model with sequence, and treatment as fixed effects and 
paiiicipant within sequence as a random effect. Estimates of the adjusted mean differences 
(Test-Reference) and co1Tesponding 90% Cls will be obtained from the model. The adjusted 
mean differences and 90% Cls for the differences will be exponentiated to provide estimates 
of the ratio of adjusted geometric means (Test/Reference) and 90% CI for the ratios. 
Treatment D (sisunatovir 400 mg Q12 hours administered under fasted condition) is the 
Reference treatment and Treatment A (sisunatovir 400 mg Q12 hours administered under fed 
condition) is the Test treatment. For the food effect compai·ison only the data from treatment 
A and D will be included in the model. 
The data collected for palatability assessment using the sponsor-provided palatability 
questionnaire will be numerically derived by measuring length (using a scale with gradations 
of at least 0.1 cm) of the "x" mai·ked by the paiticipant relative to the "good trait". For 
palatability 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 palatability 
attributes (mouth feel, bitterness, sweetness, sourness, saltiness, tongue/mouth bmn, overall 
liking) from the palatability questionnaire (Appendix 10) will be listed and descriptively 
smnmai·ized and appropriate plots may be generated. 
 


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- 
 
 
9.4. Interim Analyses 
No interim analysis will be conducted for this study. As this is a sponsor open study, the 
sponsor may conduct unblinded reviews of the data during the course of the study for the 
pmpose of safety assessment, facilitating PK/PD modeling, and/or suppo1iing clinical 
development. 
9.5. Sample Size Determination 
A sufficient number of paiiicipants will be screened to achieve 12 paiiicipants randomized to 
study intervention in Coho1i 1 in the study. Approximately 12 additional paiiicipants may be 
emolled in Coho1i 2 in the study. The sample size is empirically selected and is not based on 
statistical power calculation. Paiiicipants who discontinue from the study for non-safety 
reasons may be replaced at the sponsor's discretion in collaboration with the Investigator. 
 


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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 
Not applicable. 
10.1.3. Financial Disclosure 
Not applicable. 
10.1.4. 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. 
A participant who is rescreened is not required to sign another ICD if the rescreening occurs 
within 28 days from the previous ICD signature date. 
10.1.5. 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 standard operating procedures on how to respond in the event of 
unauthorized access, use, or disclosure of sponsor information or systems. 
10.1.6. Committees Structure 
10.1.6.1. Data Monitoring Committee 
This study will not use an E-DMC. 
10.1.7. 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. 


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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 
24 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. 
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. 


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10.1.8. 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 data 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 [and 
monitoring 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. 
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 


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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. 
10.1.9. 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 source data 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 data) 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. 
10.1.10. Study and Site Start and Closure 
The study start date is the date on which the clinical study will be open for recruitment of 
participants. 
The first act of recruitment is the date of the first participant’s first visit and will be the study 
start date. 
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. 


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The investigator may initiate study-site closure at any time upon notification to the sponsor’s 
designee (Pfizer CRU)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. 
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 
For multicenter trials, the primary publication will be a joint publication developed by the 
investigator and Pfizer reporting the primary endpoint(s) of the study covering all study sites. 
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. 
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, subject to the other 
requirements described in this section. 
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 


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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 
To facilitate access to their investigator and the sponsor’s MQI for study-related medical 
questions or problems from nonstudy 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. 


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10.2. Appendix 2: Clinical Laboratory Tests 
The following safety laborato1y tests will be perfo1med at times defined in the Schedule of 
Activities section of this protocol. Additional laborato1y results may be repo1ted on these 
samples as a result of the method of analysis or the type of analyzer used by the clinical 
laborato1y, or as derived from calculated values. These additional tests would not require 
additional collection of blood. Unscheduled clinical laborato1y measurements may be 
obtained at any time during the study to assess any perceived safety issues. 
 
Table 6. 
Protocol-Required Safety Laboratory Assessments 
 
Hematolo!!V 
Chemistrv 
Urinalvsis 
Other 
Hemoglobin 
Hematocrit 
RBC count 
Platelet count 
WBCcount 
Total neutrophils (Abs) 
BUN and creatinine, 
CystC 
eGFR 
Glucose (fasting) 
Calcium 
Sodium 
Local di12stick: 
Urine chug screening< 
Pregnancy test (P-hCGl 
SARS-CoV-2 RT-PCR 
At screening: 
• FSHb 
•  Hepatitis B swface 
antigen 
•  Hepatitis B swface 
antibody 
• Hepatitis B core antibody 
• Hepatitis C antibody 
• Human 
immunodeficiency vims 
pH• 
Glucose (qual) 
Protein (qual) 
Blood (qual) 
Ketones 
Eosinophils (Abs) 
Monocytes (Abs) 
Basophils (Abs) 
Lymphocytes (Abs) 
Potassium 
Chloride 
Total CO2 (bicarbonate) 
AST,ALT 
GGT 
Total bilirnbin 
Nitrites 
Leukocyte esterase 
Laborato1 : 
Microscopy and 
culture• 
Alkaline phosphatase 
Uric acid 
Albumin 
Total protein 
a. Urina1y culture only if deemed appropriate by the investigator. 
b. For confinnation of postmenopausal status only. 
c. The minimum requirement for chug screening includes cocaine, THC, opiates/opioids, benzodiazepines, 
and amphetamines (others are site and study specific). 
d. Local urine testing will be standard for the protocol unless sernm testing is required by local regulation 
or IRB/EC. Sernm or urine P-hCG for female participants of childbearing potential. 
e. Can be performed on dipstick or pH meter device. 
f. 
Only if urine dipstick is positive for blood, protein, nitrites, or leukocyte esterase. 
 
The investigator must review the laborato1y repo1t, document this review, and record any 
clinically relevant changes occuning during the study in the AE section of the CRF. 
Laborato1y results that could unblind the study and have been collected for the pmpose of the 
study will not be repo1ted to investigator sites or other blinded personnel until the study has 
been unblinded. 
Any remaining senun/plasma from samples collected for clinical safety laborato1y 
measurements at baseline and at all times after dose administration ma be retained and 


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purpose will be shipped to either a Pfizer-approved BBS facility or other designated 
laboratory and retained for up to 1 year following the completion of the study. 


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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 occmTence in a patient or clinical study 
pa1ticipant, 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 
abnonnal laborato1y finding), symptom, or disease (new or exacerbated) 
temporally associated with the use of study intervention. 
 
 
Events Meeting the AE Definition 
• 
Any abnonnal laborato1y test results (hematology, clinical chemistiy, or minalysis) 
or other safety assessments (eg, ECG, radiological scans, vital sign measmements), 
including those that worsen from baseline, considered clinically significant in the 
medical and scientific judgment of the investigator. Any abnonnal laborato1y 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/smgical intervention; 
• 
 Leads to a change in study dosing (outside of any protocol-specified dose 
adjustinents) or discontinuation from the study, significant additional 
concomitant dmg ti·eatinent, or other therapy. 
• 
 Exacerbation of a chronic or intennittent preexisting condition, including an 
increase in either frequency and/or intensity of the condition. 
• 
 New condition detected or diagnosed after study intervention administi·ation, even 
though it may have been present before the start of the study. 
• 
Signs, symptoms, or the clinical sequelae of a suspected dmg-dmg 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 repo1ted as 
an AE or SAE unless it is an intentional overdose taken with possible 
suicidal/self-hanning intent. Such overdoses should be repo1ted regardless of 
sequelae. 


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Events 
Meeting the AE Definition 
• 
Any clinically significant abnonnal laborato1y findings or other abnonnal safety 
assessments that are associated with the underlying disease, unless judged by the 
investigator to be more severe than expected for the paiiicipant'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 
paiticipant'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 occmTence 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 sta1i 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 tenn "life-threatening" in the definition of "serious" refers to an event in which the 
paiticipant 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 paiiicipant has been admitted (usually 
involving at least an overnight stay) at the hospital or emergency wai·d 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" occmTed or was necessaiy, 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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d. Results in persistent or significant disability/incapacity 
• The te1m disability means a substantial disrnption of a person's ability to conduct 
n01mal life functions. 
• This definition is not intended to include experiences of relatively minor medical 
significance, such as uncomplicated headache, nausea, vomiting, diaIThea, 
influenza, and accidental trauma (eg, sprained ankle), that may interfere with or 
prevent eve1yday life functions but do not constitute a substantial disrnption. 
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 laborato1y findings indicating 
an infection in a paiiicipant exposed to a Pfizer product. The te1ms "suspected 
transmission" and "transinission" ai·e considered synonymous. These cases are 
considered unexpected and handled as serious expedited cases by phannacovigilance 
personnel. Such cases ai·e 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 repo1iing is appropriate in other situations, such as significant 
medical events that may jeopai·dize the pa1iicipant 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. 
•  Exainples 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 diug 
dependency or di11g 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 
repo1iing SAEs on the CT SAE Repo1i Fonn to Pfizer Safety throughout the active 
collection period. These requirements ai·e delineated for 3 types of events: (1) SAEs; 


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(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 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 for reporting of SAE information. 
* 
EDP (with or without an associated AE or SAE): any pregnancy information is reported to Pfizer 
Safety using the CT SAE Report Form and EDP Supplemental Form; if the EDP is associated with 
an SAE, then the SAE is reported to Pfizer Safety using the CT SAE Report Form. 
** EDB is reported to Pfizer Safety using the CT SAE Report Form, 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 CT SAE Report Form. 
• 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. 
• The investigator will then record all relevant AE or SAE information in the CRF. 
Safety Event 
Recorded on the CRF 
Reported on the CT SAE 
Report Form 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*** 


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• 
 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 
Fonn/AE or SAE CRF page. 
• 
There may be instances when copies of medical records for ce1iain cases are 
requested by Pfizer Safety. In this case, all paiiicipant identifiers, with the 
exception of the paiiicipant number, will be redacted on the copies of the medical 
records before submission to Pfizer Safety. 
• 
The investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical infonnation. 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 repo1ied 
dming 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 
usualADL. 
• 
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 pennanent risk of haim to the reseai·ch participant. 
• 
Severe: A type of AE that inte1n1pts 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 inte1vention 
and each occmTence of each AE or SAE. The investigator will use clinical 
judgment to dete1mine 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 mled out. 


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• 
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 infonnation, 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 occuned and the investigator has 
minimal infonnation 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 
infonnation and send an SAE follow-up repo1i with the updated causality 
assessment. 
• 
The causality assessment is one of the criteria used when detennining regulato1y 
repo1iing 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 repo1iing 
purposes, as defined by the sponsor. In addition, if the investigator detennines that 
an SAE is associated with study procedures, the investigator must record this 
causal relationship in the source documents and CRF, and repo1i such an 
assessment in the dedicated section of the CT SAE Report Fonn and in accordance 
with the SAE repo1iing requirements. 
 
 
Follow-Up of AEs and SAEs 
• 
The investigator is obligated to perfo1m or anange 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 laborato1y tests or investigations, 
histopathological examinations, or consultation with other healthcare providers. 
• 
 If a paiiicipant dies during paiiicipation 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. 


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• 
New or updated infonnation 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 info1mation. 
10.3.4. Reporting of SAEs 
 
SAE Reporting to Pfizer Safety via an Electronic DCT 
• 
The prima1y mechanism for repo1iing an SAE to Pfizer Safety will be the 
electronic DCT. 
• 
 If the electronic system is unavailable, then the site will use the paper SAE DCT 
(see next section) to repo1i the event within 24 hours. 
• 
The site will enter the SAE data into the electronic DCT (eg, eSAE or PSSA) or 
paper f01m (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 entiy of new data or changes to existing data. 
• 
 If a site receives a repo1i of a new SAE from a study participant or receives updated 
data on a previously repo1ied SAE after the electi·onic DCT has been taken off-line, 
then the site can repo1i this info1mation on a paper SAE f01m (see next section) or 
to Pfizer Safety by telephone. 
 
 
SAE Reporting to Pfizer Safety via the CT SAE Report Form 
• 
Facsimile ti·ansmission of the CT SAE Report Fonn is the prefe1Ted method to 
transmit this info1mation to Pfizer Safety. 
• 
 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 Fonn 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 Repo1i Fonn pages within the designated repo1iing 
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(s): 
• Refrain from donating sperm. 
PLUS either: 
• Be abstinent from heterosexual intercourse as their preferred and usual lifestyle 
(abstinent on a longterm and persistent basis) and agree to remain abstinent. 
OR 
• Must agree to use contraception/barrier as detailed below: 
• Agree to use a male condom[,and should also be advised of the benefit for a 
female partner to use a highly effective method of contraception, as a condom 
may break or leak,] when having sexual intercourse with a WOCBP who is not 
currently pregnant. 
• In addition to male condom use, a highly effective method of contraception may be 
considered in WOCBP partners of male participants (refer to the list of highly 
effective methods below 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(s). If a highly effective, 
user-dependent method is chosen, she agrees to concurrently use an effective barrier 


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method of contraception. The investigator should evaluate the effectiveness of the 
contraceptive method in relationship to the first dose of study intervention. 
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 in adolescents or athletes) 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 


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discontinue HRT to allow confirmation of postmenopausal status before study 
enrollment. 
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. Progestogen only hormone contraception associated with inhibition of ovulation: 
• Oral + barrier*. 
• Injectable + barrier*. 
Sexual Abstinence 
7. 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 
in relation to the duration of the study and the preferred and usual lifestyle of the 
participant. 


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* Acceptable barrier methods to be used concomitantly with option 6 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 sisunatovir 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.” 
LFTs are not required as a routine safety monitoring procedure in this study. However, 
should an investigator deem it necessary to assess LFTs because a participant presents with 
clinical signs/symptoms, such LFT results should be managed and followed as described 
below. 
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). 


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• 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. 
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, total bile acids, 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, 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 serum 
creatinine (Scr measurement to estimate glomerular filtration rate [Scr-based eGFR] or 
creatinine clearance [eCrCl]). Baseline and postbaseline serum Scys makes it feasible to 
distinguish AKI from other causes of Scr increase. If Scr increase is confirmed after baseline, 
then reflex measurement of Scys is indicated to estimate the combined Scr-Scys eGFR 
calculation (for adults only). 
Regardless of whether kidney function monitoring tests are required as a routine safety 
monitoring procedure in the study, if the investigator or sponsor deems it necessary to further 
assess kidney safety and quantify kidney function, then these test results should be managed 
and followed per standard of care. 
10.7.2. Age-Specific Kidney Function Calculation Recommendations 
10.7.2.1. Adults (18 Years and Above)—2021 CKD-EPI Equations 
 
2021 CKD- 
EPI 
Scr Only 
Scr 
(mg/dL) 
Scys 
(mg/L) 
Recommended eGFR Equation 
Female 
if ≤0.7 
NA 
eGFR = 143 × (Scr/0.7)-0.241 × (0.9938)Age 
Female 
if >0.7 
NA 
eGFR = 143 × (Scr/0.7)-1.200 × (0.9938)Age 
Male 
if ≤0.9 
NA 
eGFR = 142 × (Scr/0.9)-0.302 × (0.9938)Age 
Male 
if >0.9 
NA 
eGFR = 142 × (Scr/0.9)-1.200 × (0.9938)Age 
2021 CKD- 
EPI 
Scr-Scys 
Combined 
Scr 
(mg/dL) 
Scys 
(mg/L) 
Recommended eGFR Equation 
Female 
if ≤0.7 
if ≤0.8 
eGFR = 130 × (Scr/0.7)-0.219 × (Scys/0.8)-0.323 × (0.9961)Age 
Female 
if ≤0.7 
if >0.8 
eGFR = 130 × (Scr/0.7)-0.219 × (Scys/0.8)-0.778 × (0.9961)Age 
Female 
if >0.7 
if ≤0.8 
eGFR = 130 × (Scr/0.7)-0.544 × (Scys/0.8)-0.323 × (0.9961)Age 
Female 
if >0.7 
if >0.8 
eGFR = 130 × (Scr/0.7)-0.544 × (Scys/0.8)-0.778 × (0.9961)Age 
Male 
if ≤0.9 
if ≤0.8 
eGFR = 135 × (Scr/0.9)-0.144 × (Scys/0.8)-0.323 × (0.9961)Age 
Male 
if ≤0.9 
if >0.8 
eGFR = 135 × (Scr/0.9)-0.144 × (Scys/0.8)-0.778 × (0.9961)Age 
Male 
if >0.9 
if ≤0.8 
eGFR = 135 × (Scr/0.9)-0.544 × (Scys/0.8)-0.323 × (0.9961)Age 
Male 
if >0.9 
if >0.8 
eGFR = 135 × (Scr/0.9)-0.544 × (Scys/0.8)-0.778 × (0.9961)Age 
10.7.3. Adverse Event Grading for Kidney Safety Laboratory Abnormalities 
AE grading for decline in kidney function (ie, eGFR or eCrCl) will be according to KDIGO 
criteria. 


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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) or by60 ms from baseline. 
• 
 New-onset ati·ial flutter or fibrillation, with conh'olled venti·icular response rate: ie, 
rate <120 bpm. 
• 
New-onset type I second-degree (Wenckebach) AV block of>30 seconds' 
duration. 
• 
Frequent PVCs, triplets, or sho1i intervals (<30 seconds) of consecutive venh'icular 
complexes. 
ECG Findings That May Qualify as SAEs 
• 
QTcF prolongation >500 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 periods 
of asystole3.0 seconds or any escape rate <40 bpm, or with an escape rhythm 
that is below the AV node. 
• 
 In awake, symptom-free pa1iicipants with ati·ial fibrillation and bradycardia 
with 1 or more pauses of at least 5 seconds or longer. 
• 
Ati·ial flutter or fibrillation, with rapid ventricular response rate: rapid = rate 
>120bpm. 
• 
Sustained supraventi·icular tachycardia (rate >120 bpm) ("sustained" = sho1i 
duration with relevant symptoms or lasting>1 minute). 


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• Venti·icular rhythms >30 seconds' dmation, including idiovenu-icular rhythm (HR 
<40 bpm), accelerated idioventi·icular rhythm (HR >40 bpm to <l 00 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) heali block. 
ECG Findings That Qualify as SAEs 
• Change in pattern suggestive of new myocardial infarction. 
• Sustained venti·icular tachyarrhythmias (>30 seconds' dmation). 
• Second- or third-degree AV block requiring pacemaker placement. 
• Asystolic pauses requiring pacemaker placement. 
• Au-ial flutter or fibrillation with rapid venti·icular response requiring cardioversion. 
• Venti·icular fibrillation/flutter. 
• At the discretion of the investigator, any aiThythmia classified as an adverse 
expenence. 
The enumerated list of major events of potential clinical concem are recommended as "alerts" or 
notifications from the core ECG laborato1y to the investigator and Pfizer study team, and not to be 
considered as all-inclusive of what to be repo1ted as AEs/SAEs. 


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10.9. Appendix 9: Prohibited Concomitant Medications That May Result in DDI 
The prohibited concomitant medications listed below should not be taken with sisunatovir for 
the period of time at least equal to the required washout period listed in the table, and 
throughout the conduct of 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 sponsor, to include or exclude specific 
drugs or drug categories for various reasons (eg, emerging DDI results for the IMP, 
availability of new information in literature on the DDI potential of other drugs). 
The Sponsor must be consulted for any concomitant medications given to participants 
enrolled in this study. 
Strong and moderate CYP3A4 and P-gp inhibitors or inducers are prohibited, as these 
medications may have meaningful impact on the pharmacokinetics of sisunatovir. 
Sisnunatovir is a CYP3A4 inhibitor and therefore sensitive and narrow therapeutic index 
CYP3A4 substrates are also prohibited in this study. Since based on in vitro data sisunatovir 
may be a weak inhibitor of CYP2B6, sensitive narrow TI substrates of CYP2B6 are 
excluded. 
Sisunatovir also may be an inhibitor of OCT1 and MATE1 transporters; therefore, sensitive 
substrates of these transporters are excluded. 
Although his is not all-inclusive, a list of medications that are prohibited in this study is 
provided below . Site staff should consult with the sponsor or designee with any questions 
regarding potential DDI. 
Prohibited Concomitant Medications 
 
CYP3A Inhibitors 
CYP3A Inducers 
Moderate 
Strong 
Moderate 
Strong 
Aprepitant 
Boceprevir 
Bosentan 
Apalutamide 
Ciprofloxacin 
Cobicistat 
Efavirenz 
Carbamazepine 
Conivaptan 
Danoprevir 
Etravirine 
Enzalutamide 
Crizotinib 
Dasabuvir 
Phenobarbital 
Mitotane 
Cyclosporine 
Elvitegravir 
Primidone 
Phenytoin 
Diltiazem 
Indinavir 
Rifampin 
Dronedarone 
Itraconazole 
St. John’s wort 
Erythromycin 
Ketoconazole 
Fluconazole 
Lopinavir 
Fluvoxamine 
Paritaprevir 
Imatinib 
Ombitasvir 
Tofisopam 
Posaconazole 
Verapamil 
Ritonavir 


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Saquinavir 
Telaprevir 
Tipranavir 
Telithromycin 
Troleandomycin 
Voriconazole 
Sensitive CYP3A Substrates 
CYP3A Substrates 
with Narrow Therapeutic Index 
Alfentanil 
Lovastatin 
Alfentanil 
Atorvastatin 
Lurasidone 
Astemizole 
Avanafil 
Maraviroc 
Cisapride 
Budesonide 
Midazolam 
Cyclosporine 
Buspirone 
Naloxegol 
Dihydroergotamine 
Darifenacin 
Nisoldipine 
Ergotamine 
Darunavir 
Quetiapine 
Fentanyl 
Dasatinib 
Sildenafil 
Pimozide 
Dronedarone 
Simvastatin 
Quinidine 
Ebastine 
Sirolimus 
Sirolimus 
Eletriptan 
Tacrolimus 
Tacrolimus 
Eplerenone 
Ticagrelor 
Terfenadine 
Everolimus 
Tolvaptan 
Ibrutinib 
Tipranavir 
Indinavir 
Triazolam 
Felodipine 
Vardenafil 
Lomitapide 
Sensitive MATE1 Substrates 
Metformin 
Sensitive CYP2B6 Substrates 
CYP2B6 Substrates 
with Narrow Therapeutic Index 
Velpatasvir 
Cyclophosphamide 
P-gp Inhibitors 
P-gp Inducers 
atazanavir 
lopinavir 
Apalutamide 
boceprevir 
lumacaftor 
Atazanavir 
cobicistat 
mifepristone 
Fosamprenavir 
conivaptan 
nelfinavir 
Lopinavir 
cyclosporine 
ombitasvir and paritaprevir 
and ritonavir and dasabuvir 
Rifampicin 
darunavir 
posaconazole 
st. John’s wort (Hypericum perforatum) extract 
diltiazem 
ritonavir 
Tipranavir 
elvitegravir and cobicistat 
and emtricitabine and 
tenofovir DF 
saquinavir 
Verapamil 
erythromycin 
telaprevir 
glecaprevir and pibrentasvir 
tipranavir 
indinavir 
tucatinib 
itraconazole 
verapamil 
ketoconazole 
vonoprazan and amoxicillin 
and clarithromycin 
lonafarnib 
voxilaprevir 
Sensitive OCT Substrates 
imatinib 
h. 
Not an all-inclusive list. 


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10.10. Appendix 10 : Oral Solution or Suspension Palatability Questionnaire 
1. Questionnaire should be administered to adult subjects, preferably by the clinician or 
the nurse. 
2. Use colored copy of the Palatability Questionnaire. 
3. Do not alter (reduce or enlarge) the original size of the Palatability 
Questionnaire. 
4. Please collect the following background information: 
Background Information 
 
Study #/Study Site 
Period and Day 
Subject ID (Rand ID) 
Treatment 
Collect Date 
Collected By 
Entered in PIMS By 
Checked in PIMS By 
Questionnaire Fully Completed (circle one) 
Yes/No 


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Please answer the following questions and provide a mark (X) 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: Mouth feel – Please tell us about the mouth feel (such as grittiness, stickiness, 
waxiness) of the product you tasted. 
Q2: Bitterness – Please tell us about the degree of bitterness of the product you tasted. 
Q3: Sweetness – Please tell us about the degree of sweet taste of the product you tasted. 
Q4: Sourness – Please tell us about the degree of sour taste of the product you tasted. 
Q5: Saltiness – Please tell us about the degree of salty taste of the product you tasted. 
Q6: Tongue/mouth burn – Please tell us about the degree of tongue/mouth burn of the 
product you tasted. 
Q7: Overall liking – Please indicate how much you like or dislike the product you 
tasted. 


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Example: How to provide a mark (X) on the color bar. 
 
 
Good (score = 0) 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Bad (score = 100) 


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Good 
Bad 
Overall 
Liking 
Tongue/ 
Mouth 
Burn 
Saltiness 
Sourness 
Sweetness 
Bitterness 
Mouth 
Feel 
Within 1 minute (immediately) after dosing 
Collection time:  
 
Provide a mark (X) on the color bar. 
 


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Good 
Bad 
Overall 
Liking 
Tongue/ 
Mouth 
Burn 
Saltiness 
Sourness 
Sweetness 
Bitterness 
Mouth 
Feel 
 
5 minutes after dosing 
Collection time:  
 
Provide a mark (X) on the color bar. 
 


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Good 
Bad 
Overall 
Liking 
Tongue/ 
Mouth 
Burn 
Saltiness 
Sourness 
Sweetness 
Bitterness 
Mouth 
Feel 
 
10 minutes after dosing 
Collection time:  
 
Provide a mark (X) on the color bar. 
 


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Good 
Bad 
Overall 
Liking 
Tongue/ 
Mouth 
Burn 
Saltiness 
Sourness 
Sweetness 
Bitterness 
Mouth 
Feel 
 
20 minutes after dosing 
Collection time:  
 
Provide a mark (X) on the color bar. 
 


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Additional Feedback – After completing the “20 minute after dosing” palatability questions, 
please provide any additional descriptive feedback in the box below regarding the taste or 
odor of the drug. 
 


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10.11. Appendix 11: Abbreviations 
The following is a list of abbreviations that may be used in the protocol. 
 
Abbreviation 
Term 
%CV 
percent coefficient of variation 
A1 to A3 
albuminuria (KDIGO albuminuria severity standardization) 
Abs 
absolute 
ADL 
activity/activities of daily living 
AE 
adverse event 
AKI 
acute kidney injury 
ALP 
alkaline phosphatase 
ALT 
alanine aminotransferase 
API 
active pharmaceutical ingredient 
AST 
aspartate aminotransferase 
AUC 
area under the curve 
AUCtau 
area under the concentration-time profile from time zero to time tau 
(the dosing interval), where tau = 12 hours for BID dosing 
AUCtau(dn) 
dose normalized AUCtau 
AV 
atrioventricular 
AxMP 
auxiliary medicinal product 
BBS 
Biospecimen Banking System 
-hCG 
-human chorionic gonadotropin 
BID 
twice-daily dosing 
BMI 
body mass index 
BP 
blood pressure 
bpm 
beats per minute 
BUN 
blood urea nitrogen 
CFR 
Code of Federal Regulations 
CI 
confidence interval 
CIOMS 
Council for International Organizations of Medical Sciences 
CK 
creatine kinase 
CKD-EPI 
chronic kidney disease epidemiology 
CL/F 
apparent clearance 
Cmax 
maximum observed plasma concentration 
Cmax(dn) 
dose normalized maximum plasma concentration 
CO2 
carbon dioxide (bicarbonate) 
COVID-19 
coronavirus disease 2019 
CCI 
CRF 
case report form 
CRO 
contract research organization 
CRU 
clinical research unit 
CSR 
Clinical Study Report 
CT 
clinical trial 


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Abbreviation 
Term 
CTCAE 
Common Terminology Criteria for Adverse Events 
CTIS 
Clinical Trial Information System 
CV 
cardiovascular 
CYP 
cytochrome P450 
D1-4 
day 1 to 4 
D5 
day 5 
DCT 
data collection tool 
DDI 
drug-drug interaction 
DIC 
drug in capsule 
DILI 
drug-induced liver injury 
DPB 
sisunatovir dry powder blend 
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 
EGFR 
epidermal growth factor receptor 
eSAE 
electronic serious adverse event 
ET 
early termination 
EU 
European Union 
EudraCT 
European Union Drug Regulating Authorities Clinical Trials 
(European Clinical Trials Database) 
FDA 
Food and Drug Administration 
FIH 
first in human 
FSH 
follicle-stimulating hormone 
F/U 
follow-up 
G1 to G5 
Grade (KDIGO eGFR category standardization) 
GCP 
Good Clinical Practice 
GFR 
glomerular filtration rate 
GGT 
gamma-glutamyl transferase 
GI 
gastrointestinal 
HBcAb 
hepatitis B core antibody 
HbsAb 
hepatitis B surface antibody 
HbsAg 
hepatitis B surface antigen 
HBP cyclodextrin 
hydroxypropyl-β-cyclodextrin 
HCVAb 
hepatitis C antibody 
HIV 
human immunodeficiency virus 
HR 
heart rate 
HRT 
hormone replacement therapy 


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Abbreviation 
Term 
HRU 
healthcare resource utilization 
Ht 
height 
IB 
Investigator’s Brochure 
CCI 
ICD
informed consent document 
ICH 
International Council for Harmonisation of Technical 
Requirements for Pharmaceuticals for Human Use 
ICU 
intensive care unit 
ID 
identification 
IMP 
investigational medicinal product 
IND 
Investigational New Drug 
INR 
international normalized ratio 
IPAL 
Investigational Product Accountability Log 
IPM 
investigational product manual 
IRB 
Institutional Review Board 
IV 
intravenous(ly) 
K 
Proportionality constant for Bedside and Modified Schwartz 
Equations (kidney function) 
KDIGO 
Kidney Disease Improving Global Outcomes 
LBBB 
left bundle branch block 
LFT 
liver function test 
LRTI 
lower respiratory tract infection 
MAD 
multiple ascending dose 
MATE 
multidrug and toxin extrusion 
MQI 
medically qualified individual 
MTD 
Maximum tolerated dose 
NA 
not applicable 
NIMP 
noninvestigational medicinal product 
CCI 
NOAEL 
no-observed-adverse-effect level 
OAT 
organic anion transporting 
OATP 
organic anion transporting polypeptide 
OCT 
organic cation transporter 
PCR 
polymerase chain reaction 
PD 
pharmacodynamic(s) 
PE 
physical examination 
P-gp 
p-glycoprotein 
PI 
principal investigator 
PIMS 
Phase One Management System 
PK 
pharmacokinetic(s) 
PSSA 
Pfizer's Serious Adverse Event Submission Assistant 
PT 
prothrombin time 


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Abbreviation 
Term 
PVC 
premature ventricular contraction/complex 
Q12 
every 12 
QTc 
corrected QT interval 
QTcF 
QTc corrected using Fridericia’s formula 
QTL 
quality tolerance limit 
qual 
qualitative 
Rac 
observed accumulation ratio for AUC 
Rac,Cmax 
observed accumulation ratio for Cmax 
RBC 
red blood cell 
RNA 
ribonucleic acid 
RSV 
respiratory syncytial virus 
RT-PCR 
reverse transcription polymerase chain reaction 
SAD 
single ascending dose 
SADE 
serious adverse device effect 
SAE 
serious adverse event 
SAP 
Statistical Analysis Plan 
SARS-CoV-2 
severe acute respiratory syndrome coronavirus 2 
SC 
subcutaneous 
Scr 
serum creatinine 
Scys 
serum cystatin C 
SD 
single dose 
SoA 
schedule of activities 
SOC 
system organ class 
SOP 
standard operating procedure 
SRSD 
Single Reference Safety Document 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
t1/2 
terminal elimination half-life 
T3 
total triiodothyronine 
T4 
total thyroxine 
TB 
tuberculosis 
T bili 
total bilirubin 
TEAE 
treatment emergent adverse event 
THC 
tetrahydrocannabinol 
Tmax 
time to reach Cmax 
TOC 
table of contents 
ULN 
upper limit of normal 
US 
United States 
Vz/F 
apparent volume of distribution 
WBC 
white blood cell 
WOCBP 
woman/women of childbearing potential 


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11. REFERENCES 
1. 
Simoes EAF, Bont L, Manzoni P, et al. Past, Present and Future Approaches to the 
Prevention and Treatment of Respiratory Syncytial Virus Infection in Children. Infect 
Dis Ther. 2018;7(1):87-120. 
2. 
Li Y, Wang X, Blau DM, et al. Global, regional, and national disease burden estimates 
of acute lower respiratory infections due to respiratory syncytial virus in children 
younger than 5 years in 2019: a systematic analysis. Lancet. 2022;399(10340):2047- 
2064. 
3. 
Rha B, Curns AT, Lively JY, et al. Respiratory Syncytial Virus-Associated 
Hospitalizations Among Young Children: 2015-2016. Pediatrics. 2020;146(1). 
4. 
Langley JM, Bianco V, Domachowske JB, et al. Incidence of Respiratory Syncytial 
Virus Lower Respiratory Tract Infections During the First 2 Years of Life: A 
Prospective Study Across Diverse Global Settings. J Infect Dis. 2022;226(3):374-385. 
5. 
Jha A, Jarvis H, Fraser C, Openshaw PJM. Respiratory Syncytial Virus. In: Hui DS, 
Rossi GA, Johnston SL, eds. SARS, MERS and other Viral Lung Infections. Sheffield 
(UK)2016. 
6. 
Kim L, Rha B, Abramson JS, et al. Identifying Gaps in Respiratory Syncytial Virus 
Disease Epidemiology in the United States Prior to the Introduction of Vaccines. Clin 
Infect Dis. 2017;65(6):1020-1025. 
7. 
Morgenthien E, Willavize S. Sample size calculation: cross-over trials to demonstrate 
bioequivalence or estimate bioavailability. Clinical biostatistics technical report #5.1 
(Version Date: April 24, 2002). 
8. 
Inker LA et al. N Engl J Med. 2021;385:1737-49. 
9. 
 US FDA, Drug Development and Drug Interactions – Table of Substrates, Inhibitors 
and Inducers (https://www.fda.gov/drugs/drug-interactions-labeling/drug-development- 
and-drug-interactions-table-substrates-inhibitors-and-inducers#table5-1) accessed 
13-January-2022. 
10. Guidance for Industry – Drug Interaction Studies: Study Design, Data Analysis, 
Implications for Dosing, and Labeling Recommendations. US Department of Health 
and Human Services, Food and Drug Administration, Center for Drug Evaluation and 
Research, Feb 2012. 

SAP_001.pdf: 
Protocol C5241006 PF-07923568 Statistical Analysis Plan 
PFIZER CONFIDENTIAL 
Page 1 of 25 
 
 
 
 
 
 
 
 
 
 
 
 
Protocol C5241006 
 
 
 
 
A Phase 1, Randomized, Sponsor Open, Two-Part Crossover Study to Assess Safety, 
Tolerability, Pharmacokinetics and Food Effect of Multiple Doses in Part 1 and 
Palatability of a Single Dose of Sisunatovir in Part 2, in Healthy Adult Participants 
 
 
 
Statistical Analysis Plan 
(SAP) 
 
 
 
 
 
 
 
 
 
 
Version: 
1 
Date: 
14 Feb 2023 


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TABLE OF CONTENTSLIST OF TABLES ............................................................................ 4 
LIST OF FIGURES .................................................................................................................... 4 
APPENDICES ............................................................................................................................ 4 
1. VERSION HISTORY ............................................................................................................ 5 
2. INTRODUCTION .................................................................................................................. 5 
2.1. Modifications to the Analysis Plan Described in the Protocol .................................. 5 
2.2. Study Objectives, Endpoints, and Estimands ............................................................ 5 
2.3. Study Design ............................................................................................................. 6 
3. ENDPOINTS AND BASELINE VARIABLES: DEFINITIONS AND 
CONVENTIONS ................................................................................................................... 8 
3.1. Primary Endpoints ..................................................................................................... 8 
3.2. Secondary Endpoints ................................................................................................. 8 
3.2.1. PK parameters of sisunatovir ........................................................................ 8 
3.2.2. Food effect on the PK of sisunatovir ............................................................. 9 
3.2.3. Palatability of sisunatovir .............................................................................. 9 
CCI 
 
3.4. Baseline Variables ................................................................................................... 10 
3.5. Safety Endpoints ...................................................................................................... 10 
3.5.1. Adverse Events ........................................................................................... 10 
3.5.2. Laboratory Data .......................................................................................... 11 
3.5.3. Vital Signs ................................................................................................... 11 
3.5.4. Electrocardiograms ...................................................................................... 12 
4. ANALYSIS SETS (POPULATIONS FOR ANALYSIS) ................................................... 12 
5. GENERAL METHODOLOGY AND CONVENTIONS .................................................... 13 
5.1. Hypotheses and Decision Rules .............................................................................. 13 
5.2. General Methods ...................................................................................................... 13 
5.2.1. Analyses for Binary/Categorical Endpoints ................................................ 13 
5.2.2. Analyses for Continuous Endpoints ............................................................ 13 
5.3. Methods to Manage Missing Data ........................................................................... 14 
5.3.1. Pharmacokinetic Data ................................................................................. 14 
5.3.2. Safety Data .................................................................................................. 15 
6. ANALYSES AND SUMMARIES ....................................................................................... 15 


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6.1. Primary Endpoints ................................................................................................... 15 
6.2. Secondary Endpoints ............................................................................................... 15 
6.2.1. PK parameters of sisunatovir ...................................................................... 15 
6.2.2. Food effect on the PK of sisunatovir ........................................................... 16 
6.2.3. Palatability of sisunatovir ............................................................................ 17 
CCI 
 
6.4. Subset Analyses ....................................................................................................... 18 
6.5. Baseline and Other Summaries and Analyses ......................................................... 18 
6.5.1. Demographic Summaries ............................................................................ 18 
6.5.2. Study Conduct and Participant Disposition ................................................ 18 
6.5.3. Study Treatment Exposure .......................................................................... 18 
6.5.4. Concomitant Medications and Nondrug Treatments .................................. 18 
6.6. Safety Summaries and Analyses .............................................................................. 19 
6.6.1. Adverse Events ........................................................................................... 19 
6.6.2. Laboratory Data .......................................................................................... 19 
6.6.3. Vital Signs ................................................................................................... 19 
6.6.4. Electrocardiograms ...................................................................................... 19 
7. INTERIM ANALYSES ....................................................................................................... 21 
7.1. Introduction .............................................................................................................. 21 
7.2. Interim Analyses and Summaries ............................................................................ 21 
APPENDICES .......................................................................................................................... 22 


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LIST OF TABLES 
Table 1. 
Summary of Changes .................................................................................. 5 
Table 2. 
Plasma Sisunatovir PK Parameters Definitions ......................................... 9 
CCI 
 
Table 4. 
PK Parameters to be Summarized Descriptively by Treatment and 
Day ............................................................................................................ 15 
 
LIST OF FIGURES 
Figure 1. 
Study Schema.............................................................................................. 8 
 
APPENDICES 
Appendix 1. Categorical Classes for ECG and Vital Signs of Potential Clinical Concern ...... 22 
Appendix 2. Summary of Analyses.......................................................................................... 23 
Appendix 3. List of Abbreviations ........................................................................................... 24 


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NOTE: Italicized text within this document has been taken verbatim from the Protocol. 
1. VERSION HISTORY 
Table 1. 
Summary of Changes 
 
Version/ 
Date 
Associated 
Protocol 
Amendment 
Rationale 
Specific Changes 
1 
14 Feb 2023 
Amendment 1 
23 Dec 2022 
N/A 
N/A 
 
2. INTRODUCTION 
Sisunatovir (PF-07923568) is an orally administered RSV F-protein inhibitor being 
developed to target viral-host cell fusion for the treatment of adult and pediatric patients 
with RSV. This study is designed to assess safety and tolerability, pharmacokinetics, and food 
effect of multiple oral doses of sisunatovir. Additionally, the study is also designed to 
generate preliminary palatability data that will inform further development of formulations 
appropriate for pediatric Phase 2 and 3 studies. 
This SAP provides the detailed methodology for summary and statistical analyses of the data 
collected in Study C5241006. 
2.1. Modifications to the Analysis Plan Described in the Protocol 
None. 
2.2. Study Objectives, Endpoints, and Estimands 
The following are the objectives and endpoints in this study. Estimand framework will not 
be applied to this Phase 1 study in healthy participants. 


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Objectives 
Endpoints 
Primary: 
Primary: 
• To characterize the safety and tolerability 
of multiple oral doses of sisunatovir in 
healthy adult participants 
• Assessment of TEAEs, clinical laboratory 
abnormalities, vital signs, and 12-lead 
ECGs 
Secondary: 
Secondary: 
• To characterize the PK of multiple oral 
doses of sisunatovir 
• PK Parameters AUCtau, Cmax, Tmax, 
AUCtau(dn), Cmax(dn) for Day 1 and 
AUCtau, Cmax, Tmax, AUCtau(dn), Cmax(dn), 
CL/F Rac, Rac,Cmax; and t1/2 and Vz/F (if 
data permits) post last dose on Day 5 
• To evaluate the effect of food on the PK of 
multiple oral doses of sisunatovir 
• The ratio of AUCtau and Cmax, on Day 5; 
Tmax on Day 5 
• To characterize the impact of liquid 
vehicles on the palatability of sisunatovir 
• Palatability Assessment Questionnaire 
Scoring Metrics: mouth feel, bitterness, 
sweetness, sourness, saltiness, 
tongue/mouth burn, overall liking 
CCI 
 
 
 
 
 
 
2.3. Study Design 
This is a Phase 1 study that will be conducted in up to two cohorts. 
Cohort 1 is a randomized, 2-part, crossover design. Part 1 has 3 periods, Periods 1and 2 are 
double blind, sponsor open, placebo controlled crossover design to evaluate the safety and 
tolerability and PK of the planned 400 mg and 200 mg of sisunatovir given Q12 hours x 4 
days plus 1 dose as 50 mg capsules in a fed state. Period 3, is an open label period to 
evaluate the food effect of the planned 400 mg of sisunatovir given Q12 hours x 4 days plus 1 
dose in a fasted state. Part 2, Periods 4 7, is open label to assess the palatability of 50 mg of 
sisunatovir in 4 different vehicles (water, infant formula, apple juice, and saline) in a 
randomized crossover design. 
Cohort 1 will include approximately 12 participants that will be randomized into 4 sequences 
with 3 participants in each sequence. Each sequence will receive treatment in a pre-specified 
manner (see Figure 1). 
Over the first 2 periods, all participants are planned to receive (A) 400 mg and either (B) 
200 mg plus matching placebo or (C) placebo dosed Q12 hours for 4 days plus 1 dose in the 
fed state. All participants in Period 3 will receive (D) 400 mg dosed Q12 hours for 4 days 


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plus 1 dose in the fasted state. A minimum 7-day washout period will occur between the last 
dose of Periods 1 and 2 and the first dose of Periods 2 and 3. 
Prior to proceeding to Period 2 of Cohort 1, the Period 1 Day 5 PK up to 12 hours post-dose 
will be assessed. If the mean exposures (AUC or Cmax) at 400 mg in Period 1 exceeds the 
rat (most sensitive species) NOAEL, the doses for the subsequent period(s) will be capped to 
a dose that is not expected to exceed the rat NOAEL. Similarly, prior to proceeding to 
Period 3 of Cohort 1, the Periods 1 and 2 Day 5 PK up to 12 hours post-dose will be 
assessed, and if the mean exposures (AUC or Cmax) at 400 mg exceeds the rat (most 
sensitive species) NOAEL, the doses for the subsequent period(s) will be capped to a dose 
that is not expected to exceed the rat NOAEL. Furthermore, safety will also be assessed 
following each period and doses for subsequent periods may be reduced if the safety and 
tolerability of the previous dose was not deemed sufficiently tolerated. 
During Periods 4-7 participants will taste sisunatovir 50 mg capsule content in different 
dosing vehicles ((E) water, (F) infant formula, (G) apple juice, and (H) saline) in a cross 
over manner and then spit out the drug with the intention of assessing the palatability of 
sisunatovir in different dosing vehicles. The palatability questionnaire will be completed for 
each vehicle, the questionnaire asks participants to assess each vehicle at 4 different time 
increments after tasting. At least 60 minutes will pass between tasting each vehicle. Period 4 
may start after the last PK draw of Period 3. 
Cohort 2 is an optional randomized, crossover cohort with 3 periods. Periods 1-2 are double 
blind, sponsor open, placebo controlled crossover design evaluating the safety, tolerability, 
and PK of sisunatovir administered Q12 hours for 4 days plus 1 dose in a fed state. Period 3, 
is an open label period to evaluate the food effect of sisunatovir given Q12 hours x 4 days 
plus 1 dose in a fasted state. Doses will not exceed 400 mg Q12 hours x 4 days plus 1 dose. 
Note that if the mean Day 5 exposure exceeds the rat NOAEL in Cohort 1, the dose in Cohort 
2 will be capped at a dose that is not anticipated to exceed the rat NOAEL. Cohort 2 will be 
conducted at the discretion of the Sponsor after review of Cohort 1 data (including PK for at 
least periods 1 and 2), and there will be 2 sequences of 6 participants for Cohort 2. 


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Figure 1. Study Schema 
 
 
3. ENDPOINTS AND BASELINE VARIABLES: DEFINITIONS AND 
CONVENTIONS 
3.1. Primary Endpoints 
As listed in Section 2.2, the primary endpoint is related to safety/tolerability of multiple oral 
doses of sisunatovir and is described in Section 3.5. 
3.2. Secondary Endpoints 
3.2.1. PK parameters of sisunatovir 
Blood samples for the PK analysis of susinatovir will be collected according to the Schedule 
of Activity given in the protocol. 
 
Plasma PK parameters of sisunatovir will be derived (if data permit) from the concentration- 
time data using standard noncompartmental methods of analysis as outlined in Table 2. 
Actual PK sampling times will be used in the derivation of sisunatovir PK parameters when 
available. 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 2. 
Plasma Sisunatovir PK Parameters Definitions 
 
Parameter 
Definition 
Method of Determination 
AUCtau 
Area under the concentration- 
time profile from time zero to 
time tau (the dosing interval), 
where tau = 12 hours for BID 
dosing. 
Linear/Log trapezoidal method. 
AUCtau(dn) 
Dose normalized AUCtau 
AUCtau/Dose 
Cmax 
Maximum observed plasma 
concentration 
Observed directly from data 
Cmax(dn) 
Dose normalized maximum 
plasma concentration 
Cmax/Dose 
Tmax 
Time to reach Cmax 
Observed directly from data as time of 
first occurrence 
* 
t½ 
Terminal elimination half-life 
Loge(2)/kel, where kel is the terminal 
phase rate constant calculated by a 
linear regression of the loglinear 
concentration-time curve. Only those 
data points judged to describe the 
terminal loglinear decline will be used in 
the regression. 
CL/F 
Apparent clearance 
Dose/AUCtau 
Vz/F* 
Apparent volume of distribution 
Dose/(AUCtau • kel) 
Rac 
Observed accumulation ratio for 
AUC 
AUCtau Day5/AUCtau Day1 
Rac,Cmax 
Observed accumulation ratio for 
Cmax 
Cmax Day5/Cmax Day1 
* If data permit. 
 
3.2.2. Food effect on the PK of sisunatovir 
The test/reference ratios for AUCtau and Cmax will be derived, with Treatment A (sisunatovir 
the highest tolerated dose Q12 hours administered under fed condition) as the test treatment 
and Treatment D (sisunatovir the highest tolerated dose Q12 hours administered under fasted 
condition) as the reference treatment. In addition, an estimate of the difference in Tmax 
between Treatments A and D will be obtained from a non-parametric method (Hodges- 
Lehmann estimator). 
3.2.3. Palatability of sisunatovir 
The data collected for palatability assessment using the sponsor-provided palatability 
questionnaire will be numerically derived by measuring length (using a scale with gradations 
of at least 0.1 cm) of the “x” marked by the participant relative to the “good trait”. For 
palatability 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. 


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CCI 
 
 
 
CCI 
 
 
 
3.4. Baseline Variables 
Baseline characteristics will be collected according to the schedule of activities (SoA) as 
specified in the protocol. 
3.5. Safety Endpoints 
The following data will be considered in standard safety summaries (see protocol for 
collection days, baseline assessment, and list of parameters): 
• Adverse events (AE) 
• Laboratory data 
• Vital signs data 
• ECG results 
3.5.1. Adverse Events 
Any adverse events occurring following start of treatment will be considered as treatment 
emergent adverse event (TEAE). If an AE starts on the same day as the first dose date, it will 
be considered treatment emergent unless the CRF data indicates otherwise via explicitly 
recording time for AE onset which was occurred before the first treatment dosing. Events 
that occur during follow-up within the lag time of up to 28-35 days after the last dose of 
study intervention will be counted as treatment emergent and attributed to the last treatment 
taken. Events that occur during the washout period between study periods will be counted as 


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treatment emergent and attributed to the previous treatment taken. The time period for 
collecting AEs (“active collection period”) for each participant begins from the time the 
participant provides informed consent. The algorithm will not consider any events that 
started prior to the first dose date. 
3.5.2. Laboratory Data 
Safety laboratory tests will be performed as described in the protocol. 
To determine if there are any clinically significant laboratory abnormalities, the 
haematological, clinical chemistry (serum) and urinalysis safety tests will be assessed against 
the criteria specified in the sponsor reporting standards. The assessment will not take into 
account whether each participants’s baseline test result is within or outside the laboratory 
reference range for the particular laboratory parameter. 
For Periods 1 to 3, the baseline measurement is the predose measurement on Day -1 in each 
period. Changes from baseline will be defined as the change between the postdose and 
baseline measurements in each period. 
3.5.3. Vital Signs 
Supine blood pressure (BP) and pulse rate (PR) will be measured at times specified in the 
SoA given in the protocol. 
For Periods 1 to 3, the baseline measurement is the predose measurement on Day 1 in each 
period. Changes from baseline will be defined as the change between the postdose and 
baseline measurements in each period. 
• The maximum decrease from baseline over all measurements taken post-dose for supine blood 
pressure. 
• The maximum increase from baseline over all measurements taken post-dose for supine pulse 
rate. 
 
The maximum increase from baseline will be calculated by first subtracting the baseline value 
from each post-dose measurement to give the change from baseline. The maximum of these 
values over the respective period will then be selected, except in the case where a participant 
does not show an increase. In such an instance, the minimum decrease should be taken. 
 
Similarly, the maximum decrease from baseline will be determined by selecting the minimum 
value of the changes from baseline. In cases where a participant does not show a decrease, the 
minimum increase should be taken. 
If 3 of more participants have an unplanned measurements at the same timepoint these may be 
summarized in addition to the planned timepoints. 


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3.5.4. Electrocardiograms 
A 12-lead ECG will be obtained on all participants at screening. 12-lead ECGs will be recorded 
on all participants at times detailed in the SoA given in the protocol. Triplicate measurements 
will be performed. 
The QT, QTcF, PR, QRS and heart rate (HR) will be recorded at each assessment time. The 
average of the triplicate readings collected (where applicable) at each assessment time will be 
calculated for each ECG parameter. If not supplied, QTcF will be derived using Fridericia’s 
heart rate correction formula: 
QTcF = QT / (RR)^(1/3) where RR = 60/HR (if not provided) 
For Periods 1 to 3, the baseline value is the average of the triplicate ECG measurements 
collected before dose administration on Day 1 in each period. Changes from baseline will be 
defined as the change between the average of the postdose triplicate ECG measurements and 
the baseline ECG. 
The following ECG endpoints will be determined: 
• Change from baseline in QT interval, heart rate, QTcF interval, PR interval, and QRS complex. 
 
• The maximum absolute value (post-dose) will be calculated for QTcF, PR and QRS. 
• The maximum increase from baseline over all measurements taken post-dose will be calculated 
for QTcF. 
 
The maximum increase from baseline will be calculated by first subtracting the baseline 
value from each postdose measurement to give the change from baseline. The maximum of 
these values over the respective period will then be selected, except in the case where a 
participant does not show an increase. In such an instance, the minimum decrease should be 
taken. 
4. ANALYSIS SETS (POPULATIONS FOR ANALYSIS) 
Data for all participants will be assessed to determine if participants meet the criteria for 
inclusion in each analysis population prior to unblinding and releasing the database and 
classifications will be documented per standard operating procedures. 
 
Participant Analysis Set Description 
Enrolled 
“Enrolled” means a participant, or their legally authorized 
representative’s, agreement to participate in a clinical study 
following completion of the informed consent process and 
randomization to study intervention. A participant will be 
considered enrolled if the informed consent is not withdrawn 
prior to participating in any study activity after screening. 
Potential participants who are screened for the purpose of 
determining eligibility for the study, but do not participate in 


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Participant Analysis Set Description 
the study, are not considered enrolled, unless otherwise 
specified by the protocol. 
Safety Analysis Set 
All participants randomly assigned to study intervention and 
who take at least 1 dose of study intervention. Participants 
will be analyzed according to the product they actually 
received. 
PK Concentration 
Population 
All participants randomly assigned to study intervention and 
who take at least 1 dose of study intervention and in whom at 
least 1 concentration value can be reported. 
PK Parameter Analysis 
Population 
All participants randomly assigned to study intervention and 
who take at least 1 dose of study intervention and in whom at 
least 1 of the PK parameters of interest can be reported. 
5. GENERAL METHODOLOGY AND CONVENTIONS 
Final analysis will be performed after study participant data set release following the last 
participant last visit. 
5.1. Hypotheses and Decision Rules 
No statistical hypothesis will be tested in this study. 
5.2. General Methods 
Descriptive analyses will be performed. Some measures will be summarized using graphical 
representations. 
Summaries by treatment will include summaries by administrated dose and fed/fasted 
condition, when applicable. 
5.2.1. Analyses for Binary/Categorical Endpoints 
For binary or categorical variables, number of participants, numbers and percentages of 
participants meeting the categorical criteria will be presented in accordance with the sponsor 
reporting standards. 
5.2.2. Analyses for Continuous Endpoints 
For continuous variables, the data will be summarized using the number of participants, 
mean, median, standard deviation (SD), minimum, and maximum in accordance with the 
sponsor reporting standards. For appropriate PK parameters, geometric mean and geometric 
coefficient of variation (%CV) will also be summarized. 
Log transformed continuous variables will be presented using summary statistics: number of 
observations, arithmetic mean, median, cv%, standard deviation, minimum, maximum, geometric 
mean and geometric cv%. 


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5.3. Methods to Manage Missing Data 
5.3.1. Pharmacokinetic Data 
Methods to handle missing PK data are described below. 
Concentrations Below the Limit of Quantification: 
In all data presentations (except listings), concentrations below the limit of quantification 
(BLQ) will be set to zero. In listings BLQ values will be reported as “<LLQ”, where LLQ 
will be replaced with the value for the lower limit of quantification. 
Deviations, Missing Concentrations and Anomalous Values: 
In summary tables and plots of mean/median profiles, statistics will be calculated having set 
concentrations to missing if one of the following cases is true: 
1. A concentration has been collected as ND (ie, not done) or NS (ie, no sample). 
2. A deviation in sampling time is of sufficient concern or a concentration has been 
flagged as anomalous by the pharmacokineticist. 
Note that summary statistics will not be presented at a particular time point if more than 50% 
of the data are missing. 
An anomalous concentration value is one that, after verification of bioanalytical validity, is 
grossly inconsistent with other concentration data from the same individual or from other 
participants. For example, a BLQ concentration that is between quantifiable values from the 
same dose is considered as anomalous. Anomalous concentration values may be excluded 
from PK analysis at the discretion of the PK analyst or pharmacokineticist. 
PK Parameters: 
Actual PK sampling times will be used in the derivation of PK parameters. If a PK parameter 
cannot be derived from a participant’s concentration data, the parameter will be coded as NC 
(ie, not calculated). (Note that NC values will not be generated beyond the day that a 
participant discontinues). In summary tables, statistics will be calculated by setting NC 
values to missing; and statistics will be presented for a particular treatment with ≥3 evaluable 
measurements. PK parameter analyses will not be performed for a particular parameter if 
more than 50% of the data are NC. 
If an individual participant has a known biased estimate of a PK parameter (due for example 
to an unexpected event such as vomiting before all the compound is adequately absorbed 
from the gastrointestinal tract), this will be footnoted in summary tables and will not be 
included in the calculation of summary statistics or statistical analyses. 


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5.3.2. Safety Data 
For the analysis of safety endpoints, the sponsor data standard rules for imputation will be 
applied. 
 
6. ANALYSES AND SUMMARIES 
6.1. Primary Endpoints 
The primary endpoints are related to safety/tolerability and their analyses are described 
Section 6.6. 
6.2. Secondary Endpoints 
6.2.1. PK parameters of sisunatovir 
The secondary endpoints are related to PK and are described herein. 
PK parameter summaries: 
The plasma sisunatovir PK parameters detailed in Section 3.2.1 will be listed and 
summarized descriptively by treatment in accordance with Pfizer data standards for the PK 
Parameter Analysis Population, as data permit. Missing values will be handled as detailed in 
Section 5.3.1. Each PK parameter will be summarized by treatment and will include the set 
of summary statistics as specified in Table 4. 
 
Table 4. 
PK Parameters to be Summarized Descriptively by Treatment and Day 
 
Parameter 
Summary Statistics 
AUCtau, AUCtau(dn), Cmax, 
Cmax(dn), CL/Fa, Vz/Fa, 
R a, R a 
 
ac 
ac, Cmax 
N, arithmetic mean, median, SD, %CV, minimum, maximum, 
geometric mean and geometric %CV 
Tmax 
N, median, minimum, maximum 
a 
t½ 
N, arithmetic mean, median, SD, %CV, minimum, maximum 
a. Applicable for Day 5 only 
 
 
To assess the relationship between the PK parameters and dose, dose normalized Cmax, AUCtau 
of sisunatovir will be plotted against dose (using a logarithmic scale), and will include individual 
participant values and the geometric means for each dose. Geometric means will have a different 
symbol than the individual values. The values will be dose normalized (to a 1 mg dose) by 
dividing the individual values and raw geometric means by dose. A footnote will be added to the 
plots to indicate that geometric means are presented. 
All dose normalized parameters will be listed along with other individual PK parameters. 


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Box and whisker plots for individual participant parameters (AUCtau and Cmax) will be presented 
by treatment and overlaid with geometric means. These plots may be presented for both the dose- 
normalized and non dose-normalized versions of these parameters, as data permit. 
PK concentration summaries: 
The plasma concentrations of sisunatovir will be listed and descriptively summarized by 
nominal PK sampling time and treatment for the PK Concentration Population. Individual 
participant and summary profiles (mean and median plots) of the plasma concentration-time 
data will be plotted by treatment using actual and nominal times, respectively. Mean and 
median sisunatovir plasma concentration profiles will be presented on both linear and semi- 
log scales. 
Presentations for sisunatovir plasma concentrations will include: 
• A listing of all concentrations sorted by participant ID, treatment, and nominal time 
postdose. The concentration listing will also include the actual times. Deviations from the 
nominal time will be provided in a separate listing. 
• A summary of concentrations by treatment and nominal time postdose, where the set of 
statistics will include n, mean, median, SD, %CV, minimum, maximum and the number 
of concentrations above the LLQ. 
• Median concentrations time plots (on both linear and semi-log scales) against nominal 
time postdose by treatment (all treatments on the same plot per scale, based on the 
summary of concentrations by treatment and time postdose). 
• Mean concentrations time plots (on both linear and semi-log scales) against nominal time 
postdose by treatment (all treatments on the same plot per scale, based on the summary of 
concentrations by treatment and time postdose). 
• Individual concentration time plots by treatment (on both linear and semi-log scales) 
against actual time postdose (there will be separate spaghetti plots for each treatment per 
scale). 
• Individual concentration time plots by participant (on both linear and semi-log scales) 
against actual time postdose [there will be separate plots for each participant (containing 
all treatments) per scale]. 
6.2.2. Food effect on the PK of sisunatovir 
For the food effect evaluation, natural log transformed AUCtau, and Cmax of sisunatovir will 
be analyzed using a mixed effect model with sequence, and treatment as fixed effects and 
participant within sequence as a random effect. The Kenward-Roger adjustment for the 
degrees of freedom will be used. Estimates of the adjusted mean differences (Test Reference) 
and corresponding 90% CIs will be obtained from the model. The adjusted mean differences 
and 90% CIs for the differences will be exponentiated to provide estimates of the ratio of 


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adjusted geometric means (Test/Reference) and 90% CI for the ratios. Treatment D 
(sisunatovir the highest tolerated dose Q12 hours administered under fasted condition) is the 
Reference treatment and Treatment A (sisunatovir the highest tolerated dose Q12 hours 
administered under fed condition) is the Test treatment. For the food effect comparison only 
the data from treatment A and D will be included in the model. 
For AUCtau and Cmax a listing of the individual participant ratios (Treatment A (fed)/Treatment D 
(fasted)) will be provided. Box and whisker plots for individual participant parameters (AUCtau 
and Cmax) will be presented by treatment and overlaid with geometric means. 
Residuals from the model will be examined for normality and the presence of outliers via 
visual inspection of plots of residuals vs predicted values and normal probability plots of 
residuals but these will not be included in the CSR. If there are major deviations from 
normality or outliers then the effect of these on the conclusions will be investigated through 
alternative transformations and/or analyses excluding outliers. Justification for any 
alternative to the planned analysis will be provided in the clinical study report. 
6.2.3. Palatability of sisunatovir 
The sensory attributes (mouth feel, bitterness, sweetness, sourness, saltiness, tongue/mouth 
burn, overall liking) from the taste questionnaires (for questionnaire tool please see protocol) 
will be listed and descriptively summarized by treatment sequence, and question across 
participants. Summary statistics (mean and 90% CI) will be calculated for the various 
questions. Radar plots for each of 4 time points, summarizing all attributes will be generated. 
Boxplots of each attribute will be plotted against the time points. 
Palatability of sisunatovir may be analyzed using a mixed effect model with treatment and 
period as fixed effects and participant as a random effect(data permitting). Estimates and 
corresponding 90% CIs will be obtained from the model. 
 
CCI 
 
 
 
Parameter 
Summary Statistics 
AUCtau 
Tmax 
Cmax 
N, arithmetic mean, median, cv%, standard 
deviation, minimum, 
maximum, geometric mean and geometric 
cv%. 
 
CCI 
 
 
 
CCI 
 
 


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• a listing of all concentrations sorted by participant ID, treatment, matrix and nominal 
time post-dose. The concentration listing will also include the actual times. 
Deviations from the nominal time will be given in a separate listing. 
• a summary of concentrations by treatment and nominal time post-dose, where the set 
of statistics will include n, mean, median, standard deviation, coefficient of variation 
(cv), minimum, maximum and the number of concentrations above the lower limit of 
quantification. 
• individual concentration-time plots by treatment (on both linear and semi-log scales) 
against actual time post-dose (there will be separate spaghetti plots for each dose per 
scale). 
• median concentrations-time plots (on both linear and semi-log scales) against nominal 
time post-dose by treatment (all treatment on the same plot per scale, based on the 
summary of concentrations by dose and time post-dose). 
• mean concentrations-time plots (on both linear and semi-log scales) against nominal 
time post-dose by treatment (all treatment on the same plot per scale, based on the 
summary of concentrations by dose and time post-dose). 
 
CCI 
 
 
For summary statistics, median and mean plots 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. 
 
6.4. Subset Analyses 
There are no planned subset analyses. 
6.5. Baseline and Other Summaries and Analyses 
6.5.1. Demographic Summaries 
Demographic characteristics will be summarized for enrolled population in accordance with 
with the sponsor reporting standards. 
6.5.2. Study Conduct and Participant Disposition 
Participants evaluation groups will show end of study participant disposition. Frequency 
counts will be supplied for participant discontinuation(s) by treatment. Data will be reported 
in accordance with the sponsor reporting standards. 
6.5.3. Study Treatment Exposure 
Study treatment exposure will be listed. 
6.5.4. Concomitant Medications and Nondrug Treatments 
All concomitant medication(s) as well as non-drug treatment(s) will be reported in the 
listings according to current sponsor reporting standards. 


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6.6. Safety Summaries and Analyses 
All safety analyses will be performed on the Safety Analysis Set. 
Safety data will be presented in tabular and/or graphical format and summarized 
descriptively, where appropriate. 
6.6.1. Adverse Events 
Adverse events will be reported in accordance with the sponsor reporting standards. 
Participant discontinuations due to adverse events will be detailed by treatment. Data will be 
reported in accordance with the sponsor reporting standards. 
6.6.2. Laboratory Data 
Laboratory data will be listed and summarized by treatment in accordance with the sponsor 
reporting standards. Baseline is as defined in Section 3.5.2. 
6.6.3. Vital Signs 
Vital signs data will be listed and summarized by treatment in accordance with the sponsor 
reporting standards. 
Absolute values and changes from baseline in supine systolic blood pressure and 
pulse rate will be summarized by treatment and time postdose, according to sponsor reporting 
standards. Tables will be paged by parameter. Baseline is as defined in Section 3.5.3. 
 
Mean changes from baseline for supine systolic blood pressure and pulse rate will be plotted 
against time post-dose. Each part will have its own output with 1 line for each treatment. 
Corresponding individual plots of changes from baseline will also be produced for each 
treatment. 
Maximum decrease from baseline for supine systolic blood pressures and maximum increase 
from baseline for supine pulse rate will be summarized by treatment, according to sponsor 
reporting standards. 
 
Minimum and/or maximum absolute values and changes from baseline for supine vital signs 
will also be summarized descriptively by treatment using categories as defined in 
Appendix 1. Numbers and percentages of participants meeting the categorical criteria will be 
provided. All planned and unplanned post-dose time points will be counted in these 
categorical summaries. 
6.6.4. Electrocardiograms 
Changes from baseline for the ECG parameters HR, QTcF , PR interval, and QRS complex 
will be summarized by treatment and time. The frequency of uncorrected QT values above 
500 ms will be tabulated. 


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The number (%) of participants with maximum postdose QTcF values and maximum 
increases from baseline in the following categories will be tabulated by treatment: 
 
Safety QTcF Assessment 
 
Degree of 
Prolongation 
Mild (ms) 
Moderate (ms) 
Severe (ms) 
Absolute value 
>450-480 
>480-500 
>500 
Increase from 
baseline 
>30 and ≤ 60 
>60 
If more than 1 ECG is collected at a nominal time after dose administration (for example, 
triplicate ECGs), the mean of the replicate measurements will be used to represent a single 
observation at that time point. If any of the 3 individual ECG tracings has a QTcF value 
>500 ms, but the mean of the triplicates is not >500 ms, the data from the participant’s 
individual tracing will be described in a safety section of the CSR in order to place the >500 
ms value in appropriate clinical context. However, values from individual tracings within 
triplicate measurements that are >500 ms will not be included in the categorical analysis 
unless the average from the triplicate measurements is also >500 ms. 
Absolute values and changes from baseline in QT, heart rate, QTcF, PR and QRS will be 
summarized by treatment and time post-dose using sponsor reporting standards. Tables will 
be paged by parameter. Baseline is as defined in Section 3.5.4. 
Mean changes from baseline in QT, heart rate and QTcF will be plotted against time 
postdose. Each period will have its own output with 1 line for each treatment. Corresponding 
individual plots of changes from baseline will also be produced for each treatment. 
Changes from baseline in QTcF will also be plotted separately against drug concentrations of 
sisunatovir and fed condition. This will be a scatter plot for all observations where QTcF and 
drug concentration are recorded. Placebo data will also be included (with drug concentration 
set to zero). Different symbols will be used for each treatment. 
Maximum increase from baseline for QTcF will be summarized by treatment, according to 
sponsor reporting standards. 
ECG endpoints and changes from baseline (QTcF, PR and QRS) will also be summarized 
descriptively by treatment using categories as defined in Appendix 1 (for QTcF these 
correspond to the Pfizer Guidance in Section 8). Numbers and percentages of participants 
meeting the categorical criteria will be provided. All planned and unplanned postdose time 
points will be counted in these categorical summaries. 
Listings of participants with any single post-dose value >500 msec will also be produced for 
QTcF. 


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CCI 
7. INTERIM ANALYSES 
No interim analysis will be conducted for this study. As this is a sponsor open study, the 
sponsor may conduct unblinded reviews of the data during the course of the study for the 
purpose of safety assessment, facilitating PK/PD modeling, and/or supporting clinical 
development. 
 
 
 
7.1. Introduction 
Not applicable. 
7.2. Interim Analyses and Summaries 
Available safety and PK data will be reviewed after Period 1 and Period 2. 
8. REFERENCES 
Pfizer Guidance for Evaluation of QT / QTc Interval Prolongation and Proarrhythmic Potential 
for Non-antiarrhythmic Drugs; Members of the Cardiovascular Safety & Advisory Council 
(CVSAC); January 26, 2018 


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APPENDICES 
Appendix 1. Categorical Classes for ECG and Vital Signs of Potential Clinical Concern 
Categories for QTcF 
 
Absolute value of QTcF 
(msec) 
>450 and ≤480 
>480 and ≤500 
>500 
Increase from baseline in 
QTcF (msec) 
>30 and ≤60 
>60 
 
Categories for PR and QRS 
 
PR (ms) 
max. ≥300 
PR (ms) increase from baseline 
Baseline >200 and max. ≥25% 
increase 
Baseline ≤200 and max. ≥50% 
increase 
QRS (ms) 
max. ≥140 
QRS (ms) increase from baseline 
≥50% increase 
 
Categories for Vital Signs 
 
Systolic BP (mm Hg) 
min. <90 
Systolic BP (mm Hg) change 
from baseline 
max. decrease ≥30 
max. increase ≥30 
Diastolic BP (mm Hg) 
min. <50 
Diastolic BP (mm Hg) change 
from baseline 
max. decrease ≥20 
max. increase ≥20 
Supine pulse rate (bpm) 
min. <40 
max. >120 


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Appendix 2. Summary of Analyses 
 
Endpoint 
Population 
Data Inclusion and 
Rules for Handling 
Intercurrent Events 
and Missing Data 
Analysis Method 
Ratio of AUCtau, Cmax 
PK Parameter 
Analysis Population 
Observed data 
Mixed effect 
ANOVA model 
PK parameters 
PK Parameter 
Analysis Population 
Observed data 
Descriptive statistics 
PK concentrations 
PK Concentration 
Population 
Observed and 
imputed (Section 
5.3.1) data 
Descriptive statistics 
Safety Data 
Safety analysis set 
Observed and 
imputed (Section 
5.3.2) data 
Descriptive statistics 
CCI 
 
 


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Appendix 3. List of Abbreviations 
 
Abbreviation 
Term 
%CV 
coefficient of variation 
AE 
adverse event 
Ae(0-12) 
Amount of endogenous CCI 
 recovered unchanged in urine 
from 0 to 12 hours post-dose 
AUCtau 
area under the concentration-time profile from time zero to time tau 
(the dosing interval), where tau = 12 hours for BID dosing 
AUCtau(dn) 
dose normalized AUCtau 
BID 
twice-daily dosing 
BLQ 
below the limit of quantitation 
BP 
blood pressure 
CI 
confidence interval 
CL/F 
apparent clearance 
CLr 
Renal clearance 
Cmax 
maximum observed plasma concentration 
Cmax(dn) 
dose normalized maximum plasma concentration 
CCI  
CRF 
case report form 
CSR 
clinical study report 
ECG 
electrocardiogram 
HR 
heart rate 
CCI  
kel 
elimination rate constant estimated from the log-linear regression 
analysis 
LLQ 
lower limit of quantitation 
mg 
milligram 
ms 
milliseconds 
N/A 
not applicable 
NC 
not calculated 
ND 
not done 
CCI 
 
NS 
no sample 
OATP 
organic anion transporting polypeptide 
PK 
pharmacokinetic(s) 
PR 
pulse rate 
Q12 
every 12 
QRS 
Combination of Q-, R- and S- wave on an electrocardiogram 
representing ventricular depolarization 
QTc 
corrected QT interval 
QTcF 
corrected QT (Fridericia method) 
Rac 
observed accumulation ratio for AUC 
Rac, Cmax 
observed accumulation ratio for Cmax 


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Abbreviation 
Term 
RR 
respiratory rate 
RSV 
respiratory syncytial virus 
SAP 
statistical analysis plan 
SD 
standard deviation 
SoA 
schedule of activities 
t1/2 
terminal plasma elimination half-life 
TBD 
to be determined 
TEAE 
treatment emergent adverse event 
Tmax 
time to reach Cmax 
Vz/F 
apparent volume of distribution