Clinical trial NCT05047601
Conditions: COVID-19
Keywords: Severe acute respiratory syndrome coronavirus 2 (SARS-Cov-2)
Sponsor: Pfizer
Start date: 2021-09-09; Completion date: 2022-04-12
Enrollment: 2954 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this clinical trial is to learn whether the study medicine prevent symptoms of COVID-19 in adults who have been exposed to household member(s) with a confirmed symptomatic COVID-19 infection.

All participants in the study will receive treatment for COVID-19 as needed, based on their regular doctor's recommendation. Two-thirds of participants will also receive two study medicines (PF-07321332 and ritonavir) by mouth twice a day for either five or ten days. We will compare the experiences of people receiving the study medicines to those of the people who do not. This will help us determine if the study medicines are safe and effective

Detailed description:

Arms: arm 1: Participants will receive PF-07321332/ritonavir every 12 hours from Day 1 through Day 5 followed by Placebo every 12 hours from Day 6 through Day 10 arm 2: Participants will receive PF-07321332/ritonavir every 12 hours from Day 1 through Day 10. arm 3: Participants will receive placebo every 12 hours from Day 1 through Day 10.
Interventions: intervention 1: PF-07321332 intervention 2: Placebo for PF-07321332 intervention 3: Placebo for Ritonavir intervention 4: Ritonavir
Intervention descriptions: intervention 1: PF-07321332 intervention 2: Placebo intervention 3: Placebo intervention 4: Ritonavir

Protocol documents:
Prot_000.pdf: 
PF-07321332
Protocol C4671006
Final Protocol Amendment 2, 25 January 2022
PFIZER CONFIDENTIAL
Page 1
A PHASE 2/3, RANDOMIZED, DOUBLE-BLIND, DOUBLE-DUMMY, 
PLACEBO-CONTROLLED STUDY TO EVALUATE THE SAFETY AND 
EFFICACY OF 2 REGIMENS OF ORALLY ADMINISTERED 
PF-07321332/RITONAVIR IN PREVENTING SYMPTOMATIC SARS-COV-2 
INFECTION IN ADULT HOUSEHOLD CONTACTS OF AN INDIVIDUAL WITH 
SYMPTOMATIC COVID-19
Study Intervention Number:
PF-07321332
Study Intervention Name:
NA
US IND Number:
153517
EudraCT Number:
2021-002894-24
ClinicalTrials.gov ID:  
NCT05047601
Protocol Number:
C4671006
Phase:
2/3
Brief Title: A Phase 2/3 Postexposure Prophylaxis Study of PF-07321332/Ritonavir 
in Adult Household Contacts of an Individual With Symptomatic COVID-19
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.


PF-07321332
Protocol C4671006
Final Protocol Amendment 2, 25 January 2022
PFIZER CONFIDENTIAL
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Document History
Document 
Version Date
Amendment 2
25 January 2022
Amendment 1
20 August 2021
Original protocol
02 July 2021
This amendment incorporates all revisions to date, including amendments made at the 
request of country health authorities and IRBs/ECs and any protocol administrative 
clarification letter.
Amendment 2 (25-January-2022)
Overall Rationale for the Amendment: 
Considering the high anti-SARS-CoV-2 antibody seropositivity rate observed in 
Study C4671006 participants recruited to date, the lower-than-expected event rate 
(symptomatic SARS-CoV-2 infection confirmed by RT-PCR), efficacy data from 
Study C4671005, and emerging data on the Omicron variant of the SARS-CoV-2 virus, this 
amendment includes updates to the definition for the primary endpoint events, the timing of 
the interim analysis and associated statistical considerations, assumptions for sample size 
estimation, and a provision to permit enrollment of previously vaccinated participants.  
Section # and Name
Description of Change
Brief Rationale
Section 1.1 Synopsis
Section 3. 
OBJECTIVES, 
ENDPOINTS, and 
ESTIMANDS
Section 9.1.
Section 9.1.1. Estimands
Section 9.1.1.2
Section 9.1.2. 
Multiplicity Adjustment
Section 9.3.1. General 
Considerations
Primary objective, endpoint, and 
estimand updated to include rapid 
antigen test-confirmed SARS-CoV-
2 infection.
Updated the secondary objective 
and secondary endpoint to assess 
viral titers in participants with a 
positive RT-PCR result at baseline.
Updated to reduce the possibility 
of missing a laboratory 
confirmed SARS-CoV-2 
infection (and therefore a 
potential primary endpoint 
event) possibly related to 
participant swab collection 
methodology.  


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Protocol C4671006
Final Protocol Amendment 2, 25 January 2022
PFIZER CONFIDENTIAL
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Section # and Name
Description of Change
Brief Rationale
Section 9.3.2. Primary 
Endpoint(s)/Estimand(s) 
Analysis
Section 9.3.3. Key 
Secondary Efficacy 
Endpoint(s)/Estimand(s) 
Analysis
Section 9.3.4. Secondary 
Endpoint(s)/Estimand(s) 
Analysis
Section 1.1. Synopsis
Section 4.1. Overall 
Design
Section 9.4. Interim 
Analyses
Section 10.1.5.1. Data 
Monitoring Committee
Updated the timing of the 
planned interim analysis from 
45% to 70% of enrollment (ie, 
when approximately 70% of 
overall participants have 
completed the Day 14 
assessments with the minimum 
number of 24 symptomatic 
infection events).
Updated the O’Brien-Fleming 
boundary accordingly based on 
the timing of the planned interim 
analysis. 
To maximize the amount of 
data for the Omicron variant in 
the interim dataset.
Section 1.1. Synopsis
Section 4.1. Overall 
Design
Section 9.5. Sample Size 
Determination
Increased the sample size to reflect 
the adjustment of the relative risk 
reduction and the placebo event 
rate. 
Updated based on results in 
Study C4671005 and the relative 
risk reduction and the incidence 
of primary endpoints events 
observed in the REGEN-COV 
postexposure prophylaxis study 
and baseline seropositivity rate 
observed in the study.
Section 1.3. Schedule of 
Activities
Section 6.2.1. 
Preparation and 
Dispensing
Added text to specify when study 
intervention is to be dispensed. 
For clarification.


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Final Protocol Amendment 2, 25 January 2022
PFIZER CONFIDENTIAL
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Section # and Name
Description of Change
Brief Rationale
Section 1.3. Schedule of 
Assessments
Section 8.2.5. 
Electrocardiograms
Section 10.7. Appendix 
7: ECG Findings of 
Potential Clinical 
Concern
Section removed as ECGs are no 
longer required per Dear 
Investigator Letter dated 31 August 
2021.
Updated to reflect changes from 
the Dear Investigator Letter.
Section 1.3. Schedule of 
Activities
Section 8.2.1. Medical 
History
Added note regarding prior 
documented infection and details of 
vaccination.
For clarification.
Section 1.3. Schedule of 
Activities
Section 8.6.4.2
Specified that nasal swabs will be 
collected by the HCP on Days 5, 
10, and 14, or during any 
COVID-19 Signs and Symptoms 
Onset visit or unplanned visit. 
Also specified for in-person visits 
that occur on the same day as self 
collection of the nasal swab that 
the HCP should collect the nasal 
swab.
Nasal swab collection was to be 
done under observation by site 
staff during specified in-person 
visits as per PACL dated 
14 December 2021.
To ensure accurate collection 
of nasal swab data.
Updated to reflect changes 
from PACL.
Section 2.2. Background
Updated the number of 
COVID-19 cases and deaths 
worldwide.
Added text about SARS-CoV-2 
variants of concern in relation to 
vaccine efficacy.
To provide recent data.
To provide background on 
emerging variants of concern 
with respect to vaccine 
efficacy and risk for 
reinfection.
Section 2.2.2. Clinical 
Overview
Added results from 
Study C4671005 and the 
45% interim analysis results from 
Study C4671002.
To provide a brief summary of 
available clinical efficacy and 
safety data.


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Final Protocol Amendment 2, 25 January 2022
PFIZER CONFIDENTIAL
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Section # and Name
Description of Change
Brief Rationale
Section 2.3.2. Benefit 
Assessment
Described 2 orally administered 
antivirals that have received EUA 
in the US and EU.
Updated benefit assessment. 
To describe treatment options 
for COVID-19 in patients at 
high risk of progression to 
severe COVID-19.
To support the potential 
benefit of treatment and 
postexposure prophylaxis. 
Section 5.2. Exclusion 
Criteria
Updated Exclusion Criteria #1 to 
exclude participants with a prior 
documented infection within 
6 months of the screening visit. 
Also updated Exclusion Criterion 
# 14 to exclude participants who 
received any SARS-CoV-2 
vaccine within 6 months prior to 
screening or were expected to 
receive a SARS-CoV-2 vaccine, 
or other approved, authorized, or 
investigational postexposure 
prophylaxis treatment through 
Day 38.
For Exclusion Criterion #13, 
specified that participants who 
have received approved, 
authorized, or investigational 
anti-SARS-CoV-2 mAb, 
convalescent plasma, other drugs 
for treatment of COVID-19, or 
other anti-SARS-CoV-2 biologic 
products within 6 months of 
screening would be excluded.
Added clarification to Exclusion 
Criterion #7 to align with the 
exclusion criterion in Appendix 
11. 
Updated Exclusion 
Criterion #1 because emerging 
data related to the omicron 
variant suggest a higher risk 
for reinfection with 
SARS-COV-2 and that 
protection afforded by current 
vaccines against symptomatic 
infection due to the omicron 
variant wanes after several 
months. Exclusion Criterion 
#14 has been updated to allow 
participants who have been 
previously vaccinated to be 
enrolled because they may 
benefit from postexposure 
prophylaxis.
To facilitate inclusion of 
previously infected 
participants who may have 
been treated with a product 
that could confound efficacy 
assessments.
Updated Exclusion Criterion 
#7 to reflect changes from the 
PACL dated 13 October 2021.
Section 6.1.1. 
Administration
Co-administration of PF-07321332 
and ritonavir should be at the same 
time, but no more than 10 minutes 
apart is acceptable.
Added language to specify what 
is considered to be an acceptable 
time for co-administration of 
PF-07321332 and ritonavir.


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Protocol C4671006
Final Protocol Amendment 2, 25 January 2022
PFIZER CONFIDENTIAL
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Section # and Name
Description of Change
Brief Rationale
Section 6.3.2. Blinding 
of the Sponsor
Language was added to provide 
additional information about the 
study unblinding plan.
To provide additional 
information so that an unblinded 
submission team could be 
formed at the time of an interim 
analysis for preparing unblinded 
analyses and documents to 
support regulatory activities.
Section 6.8. 
Concomitant Therapy
For medications permitted during 
the study, clarified that any 
authorized or approved COVID-19
therapy would result in study 
intervention discontinuation.
Added antiviral treatment for 
COVID-19 to the prohibited 
medications during the study.
Based on the availability of EUA 
oral antiviral and mAb 
treatments.
Section 9.3.1 General 
Considerations
Summarized possible combinations 
of RT-PCR and rapid antigen test
results that may be available for a 
participant and how these results 
would be considered toward 
confirming SARS-CoV-2 infection 
in the analyses of the primary and 
relevant secondary endpoints.
Based on the updates to the 
primary and relevant secondary 
endpoints where, in addition to 
RT-PCR, rapid antigen test 
results may also confirm 
SARS-CoV-2 infection.
Section 9.2. Analysis 
Sets
Removed reference to postbaseline 
measurement in the analysis set 
definitions.
Updated based on FDA 
feedback.
Appendix 12. Country 
Specific Requirements
Removed France country-specific 
guidance.
Was previously included in 
error.
Appendix 12:
Section 10.12.3. 
Bulgaria
Added Bulgaria country-specific 
guidance regarding Exclusion 
Criteria #3 and #5.
To incorporate country-specific 
changes into the global protocol
and to align with the 
26 October 2021 PACL.
Appendix 12: Section 
10.12.4. Ukraine
Added Ukraine country-specific 
guidance regarding nasal swab 
collection.
To incorporate country-specific 
changes into the global protocol
and to align with the 
22 December 2021 PACL.
Section 10.8. Appendix 
8: Prohibited 
Concomitant 
Medications That May 
Result in DDI
Updated table.
Corrections and updates to the 
list of precautionary and 
To align with the Emergency 
Use Authorization Fact Sheet 
for PaxlovidTM.1


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PFIZER CONFIDENTIAL
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Section # and Name
Description of Change
Brief Rationale
prohibited medications as per 
PACL dated 29 September 2021.
Updated to reflect changes 
from the PACL.
Section 10.9. Appendix 
9. Signs and Symptoms 
Consistent with COVID-
19
Added fatigue (low energy or 
tiredness) to targeted symptoms for 
analysis.
Was inadvertently omitted in 
the previous version.
10.13 Appendix 13. 
Protocol Amendment 
History
Modified with Amendment 1 
changes.
Per Pfizer protocol template.
Throughout
Other administrative edits.
Updated to provide clarity.


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Protocol C4671006
Final Protocol Amendment 2, 25 January 2022
PFIZER CONFIDENTIAL
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TABLE OF CONTENTS
LIST OF TABLES...................................................................................................................13
1. PROTOCOL SUMMARY...................................................................................................14
1.1. Synopsis ..................................................................................................................14
1.2. Schema ....................................................................................................................19
1.3. Schedule of Activities .............................................................................................20
2. INTRODUCTION ...............................................................................................................30
2.1. Study Rationale .......................................................................................................30
2.2. Background .............................................................................................................30
2.2.1. Nonclinical Studies of PF-07321332..........................................................32
2.2.2. Clinical Overview.......................................................................................32
2.3. Benefit/Risk Assessment.........................................................................................34
2.3.1. Risk Assessment.........................................................................................35
2.3.2. Benefit Assessment.....................................................................................37
2.3.3. Overall Benefit/Risk Conclusion................................................................37
3. OBJECTIVES, ENDPOINTS, AND ESTIMANDS ...........................................................37
4. STUDY DESIGN.................................................................................................................39
4.1. Overall Design.........................................................................................................39
4.2. Scientific Rationale for Study Design.....................................................................40
4.2.1. Diversity of Study Population ....................................................................41
4.2.2. Choice of Contraception/Barrier Requirements .........................................41
4.2.3. Collection of Retained Research Samples..................................................41
4.3. Justification for Dose ..............................................................................................41
4.4. End of Study Definition ..........................................................................................42
5. STUDY POPULATION......................................................................................................43
5.1. Inclusion Criteria.....................................................................................................43
5.2. Exclusion Criteria....................................................................................................44
5.3. Lifestyle Considerations..........................................................................................46
5.3.1. Contraception..............................................................................................46
5.4. Screen Failures ........................................................................................................46
5.5. Criteria for Temporarily Delaying 
Enrollment/Randomization/Administration of Study Intervention...........................47


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6. STUDY INTERVENTION(S) AND CONCOMITANT THERAPY.................................47
6.1. Study Intervention(s) Administered........................................................................47
6.1.1. Administration............................................................................................48
6.2. Preparation, Handling, Storage, and Accountability...............................................49
6.2.1. Preparation and Dispensing........................................................................50
6.3. Measures to Minimize Bias: Randomization and Blinding.....................................50
6.3.1. Allocation to Study Intervention ................................................................50
6.3.2. Blinding of the Sponsor..............................................................................51
6.3.3. Breaking the Blind......................................................................................51
6.4. Study Intervention Compliance...............................................................................51
6.5. Dose Modification...................................................................................................52
6.6. Continued Access to Study Intervention After the End of the Study......................52
6.7. Treatment of Overdose............................................................................................52
6.8. Concomitant Therapy..............................................................................................53
6.8.1. Rescue Medicine.........................................................................................54
7. DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL...........................................................................54
7.1. Discontinuation of Study Intervention ....................................................................54
7.1.1. Potential Cases of Decreased eGFR ...........................................................55
7.2. Participant Discontinuation/Withdrawal From the Study.......................................55
7.2.1. Withdrawal of Consent...............................................................................56
7.3. Lost to Follow-Up ...................................................................................................56
8. STUDY ASSESSMENTS AND PROCEDURES...............................................................56
8.1. Efficacy Assessments..............................................................................................57
8.1.1. Participant Diary.........................................................................................57
8.1.2. Daily Signs and Symptoms of COVID-19 .................................................58
8.1.3. COVID-19 Related Medical Visit Details..................................................58
8.1.4. Oxygen Support Details..............................................................................59
8.1.5. Index Case Characteristics..........................................................................59
8.1.6. Household Characteristics ..........................................................................60
8.1.7. PRO Assessments.......................................................................................60
8.1.7.1. WPAI.........................................................................................60


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8.1.7.2. EQ-5D-5L Scale........................................................................60
8.1.7.3. Global Impression Questions ....................................................61
8.2. Safety Assessments .................................................................................................61
8.2.1. Medical History ..........................................................................................61
8.2.2. Height and Weight......................................................................................61
8.2.3. Targeted Physical Examinations.................................................................61
8.2.4. Vital Signs ..................................................................................................61
8.2.5. Clinical Safety Laboratory Assessments ....................................................62
8.2.6. Pregnancy Testing ......................................................................................63
8.3. Adverse Events, Serious Adverse Events, and Other Safety Reporting .................63
8.3.1. Time Period and Frequency for Collecting AE and SAE Information.......64
8.3.1.1. Reporting SAEs to Pfizer Safety...............................................64
8.3.1.2. Recording Nonserious AEs and SAEs on the CRF...................64
8.3.2. Method of Detecting AEs and SAEs ..........................................................65
8.3.3. Follow-Up of AEs and SAEs......................................................................65
8.3.4. Regulatory Reporting Requirements for SAEs...........................................65
8.3.5. Environmental Exposure, Exposure During Pregnancy or 
Breastfeeding, and Occupational Exposure.....................................................65
8.3.5.1. Exposure During Pregnancy......................................................66
8.3.5.2. Exposure During Breastfeeding ................................................67
8.3.5.3. Occupational Exposure .............................................................68
8.3.6. Cardiovascular and Death Events...............................................................68
8.3.7. Disease-Related Events and/or Disease-Related Outcomes Not 
Qualifying as AEs or SAEs..............................................................................68
8.3.8. Adverse Events of Special Interest.............................................................68
8.3.8.1. Lack of Efficacy........................................................................68
8.3.9. Medical Device Deficiencies......................................................................69
8.3.10. Medication Errors.....................................................................................69
8.4. Pharmacokinetics ....................................................................................................70
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8.6. Biomarkers ..............................................................................................................71
8.6.1. Specified Gene Expression (RNA) Research .............................................71
8.6.2. Specified Protein Research.........................................................................71
8.6.3. Specified Metabolomic Research ...............................................................72
8.6.4. SARS-CoV-2 Assessments.........................................................................72
8.6.4.1. Rapid Antigen Assessments......................................................72
8.6.4.2. Viral Load Assessments............................................................72
8.6.5. Assessments for Other Respiratory Pathogens...........................................72
8.6.6. Retained Research Samples for Biomarkers...............................................73
8.7. Immunogenicity Assessments.................................................................................73
8.8. Health Economics ...................................................................................................73
9. STATISTICAL CONSIDERATIONS ................................................................................73
9.1. Statistical Hypotheses .............................................................................................73
9.1.1. Estimands....................................................................................................74
9.1.1.1. Primary Estimand/Co-Primary Estimands ................................74
9.1.1.2. Secondary Estimand..................................................................74
9.1.2. Multiplicity Adjustment..............................................................................74
9.2. Analysis Sets ...........................................................................................................75
9.3. Statistical Analyses .................................................................................................76
9.3.1. General Considerations...............................................................................76
9.3.2. Primary Endpoint(s)/Estimand(s) Analysis ................................................77
9.3.3. Key Secondary Efficacy Endpoint(s)/Estimand(s) Analysis......................78
9.3.4. Secondary Endpoint(s)/Estimand(s) Analysis............................................78
9.3.6. Other Safety Analyses ................................................................................79
9.3.6.1. Laboratory.................................................................................79
9.3.6.2. Physical Examination and Vital Signs ......................................79
9.3.7. Other Analyses............................................................................................79
9.3.7.1. PK Analyses ..............................................................................79
9.4. Interim Analyses .....................................................................................................80
9.5. Sample Size Determination.....................................................................................80
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10. SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS..........................................................................................................82
10.1. Appendix 1: Regulatory, Ethical, and Study Oversight Considerations...............82
10.1.1. Regulatory and Ethical Considerations ....................................................82
10.1.1.1. Reporting of Safety Issues and Serious Breaches of the 
Protocol or ICH GCP.........................................................................82
10.1.2. Financial Disclosure .................................................................................83
10.1.3. Informed Consent Process ........................................................................83
10.1.4. Data Protection .........................................................................................84
10.1.5. Committees Structure ...............................................................................84
10.1.5.1. Data Monitoring Committee ...................................................84
10.1.6. Dissemination of Clinical Study Data ......................................................85
10.1.7. Data Quality Assurance ............................................................................86
10.1.8. Source Documents....................................................................................87
10.1.9. Study and Site Start and Closure ..............................................................88
10.1.10. Publication Policy...................................................................................89
10.1.11. Sponsor’s Qualified Medical Personnel .................................................89
10.2. Appendix 2: Clinical Laboratory Tests .................................................................91
10.3. Appendix 3: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-Up, and Reporting .....................................................................92
10.3.1. Definition of AE .......................................................................................92
10.3.2. Definition of an SAE ................................................................................93
10.3.3. Recording/Reporting and Follow-Up of AEs and/or SAEs During 
the Active Collection Period............................................................................94
10.3.4. Reporting of SAEs....................................................................................98
10.4. Appendix 4: Contraceptive and Barrier Guidance ................................................99
10.4.1. Male Participant Reproductive Inclusion Criteria....................................99
10.4.2. Female Participant Reproductive Inclusion Criteria.................................99
10.4.3. Woman of Childbearing Potential ..........................................................100
10.4.4. Contraception Methods...........................................................................101
10.6. Appendix 6: Liver Safety: Suggested Actions and Follow-Up Assessments 
and Study Intervention Rechallenge Guidelines .....................................................104
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10.7. Appendix 7: ECG Findings of Potential Clinical Concern (No Longer 
Applicable) ..............................................................................................................106
10.8. Appendix 8: Prohibited Concomitant Medications That May Result in DDI.....107
10.9. Appendix 9: Signs and Symptoms Consistent With COVID-19 ........................116
10.10. Appendix 10: High-Risk Close Contact Behaviors...........................................117
10.11. Appendix 11: Risk Factors Associated With Severe COVID-19 Illness67 .......118
10.12. Appendix 12: Country Specific Requirements..................................................119
10.12.1. Japan .....................................................................................................119
10.12.2. Bulgaria.................................................................................................119
10.12.3. Ukraine .................................................................................................120
10.13. Appendix 13: Glossary of Terms ......................................................................121
10.14. Appendix 14: Abbreviations .............................................................................123
10.15. Appendix 14: Protocol Amendment History.....................................................127
11. REFERENCES ................................................................................................................131
LIST OF TABLES
Table 1.
Protocol-Required Safety Laboratory Assessments .................................91
Table 2.
Signs and Symptoms Consistent With COVID-19.................................116


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1. PROTOCOL SUMMARY
1.1. Synopsis 
A Phase 2/3, Randomized, Double-Blind, Double-Dummy, Placebo-Controlled Study To 
Evaluate The Safety And Efficacy Of 2 Regimens Of Orally Administered 
PF-07321332/Ritonavir In Preventing Symptomatic SARS-CoV-2 Infection In Adult 
Household Contacts Of An Individual With Symptomatic COVID-19.
Brief Title: A Phase 2/3 Postexposure Prophylaxis Study of PF-07321332/Ritonavir in Adult 
Household Contacts of an Individual with Symptomatic COVID-19
Rationale
The purpose of this study is to evaluate the efficacy and safety of PF-07321332/ritonavir as 
postexposure prophylaxis for adult household contacts of an individual with symptomatic 
COVID-19.
Objectives, Endpoints, and Estimands
Objectives
Endpoints
Estimands
Primary: 
Primary:
Primary: 

To compare the efficacy of 5-day 
and 10-day regimens of 
PF-07321332/ritonavir versus 
placebo in preventing 
symptomatic RT-PCR or rapid 
antigen test- confirmed 
SARS-CoV-2 infection in adult 
participants who have a negative 
RT-PCR result at baseline and 
who are household contacts of an 
individual with symptomatic 
COVID-19. 
Of the participants who have a negative 
RT-PCR result at baseline:
Proportion of participants who 
develop a symptomatic, RT-PCR or 
rapid antigen test-confirmed 
SARS-CoV-2 infection through 
Day 14.

The risk reduction between 5-day 
and 10-day regimens of 
PF-07321332/ritonavir versus 
placebo in the proportion of 
individuals who develop 
symptomatic RT-PCR or rapid 
antigen test-confirmed 
SARS-CoV-2 infection through 
Day 14 in adults who have a 
negative RT-PCR result at 
baseline and are household 
contacts of an individual with 
symptomatic COVID-19. This 
will be estimated without regard 
to adherence to randomized 
treatment.
Secondary: 
Secondary:
Secondary: 

To describe the safety and 
tolerability of 5-day and 10-day 
regimens of 
PF-07321332/ritonavir relative to 
placebo in adult participants who 
have a negative or positive 
RT-PCR result at baseline and 
who are household contacts of an 
individual with symptomatic 
COVID-19.
Incidence of TEAEs
Incidence of SAEs and AEs leading 
to discontinuation.

Not applicable.

To compare the efficacy of 5-day 
and 10-day regimens of 
Of the participants who have a negative 
RT-PCR result at baseline and who are 

The risk reduction between 5-day 
and 10-day regimens of 


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Objectives
Endpoints
Estimands
PF-07321332/ritonavir versus 
placebo in preventing 
symptomatic RT-PCR or rapid 
antigen test-confirmed 
SARS-CoV-2 infection in adult 
participants who have a negative 
RT-PCR result at baseline, who 
are at increased risk of severe 
COVID-19 illness, and who are 
household contacts of an 
individual with symptomatic 
COVID-19.
at increased risk of severe COVID-19 
illness:

Proportion of participants with 
symptomatic, RT-PCR or rapid 
antigen test-confirmed 
SARS-CoV-2 infection through 
Day 14.

Proportion of participants with 
COVID-19 related 
hospitalization or death from any 
cause by Day 28.
PF-07321332/ritonavir versus 
placebo in the proportion of 
individuals who develop 
symptomatic RT-PCR or rapid 
antigen test-confirmed 
SARS-CoV-2 infection through 
Day 14 in adults who have a 
negative RT-PCR result at 
baseline, who are at increased 
risk of severe COVID-19 illness, 
and who are household contacts 
of an individual with 
symptomatic COVID-19. This 
will be estimated without regard 
to adherence to randomized 
treatment.

To compare the efficacy of 5-day 
and 10-day regimens of 
PF-07321332/ritonavir versus 
placebo in preventing 
SARS-CoV-2 infection in adult 
participants who have a negative 
or positive RT-PCR result at 
baseline and who are household 
contacts of an individual with 
symptomatic COVID-19.
Of the participants who have a negative 
RT-PCR result at baseline:

Proportion of participants with 
asymptomatic RT-PCR or rapid 
antigen test-confirmed 
SARS-CoV-2 infection through 
Day 14.

Time to RT-PCR or rapid 
antigen test-confirmed 
SARS-CoV-2 infection through 
Day 14.
Of the participants who have a positive 
RT-PCR result at baseline:

Proportion of participants with 
symptomatic RT-PCR or rapid 
antigen test-confirmed 
SARS-CoV-2 infection through 
Day 14.
Of the participants who have a negative 
or positive RT-PCR result at baseline:

Proportion of participants with 
symptomatic RT-PCR or rapid 
antigen test-confirmed 
SARS-CoV-2 infection through 
Day 14.

Not applicable.

To compare the efficacy of 5-day 
and 10-day regimens of 
PF-07321332/ritonavir versus 
placebo in the duration and 
severity of COVID-19 related 
signs and symptoms in adult 
participants who have a negative 
RT-PCR result at baseline and 
who are household contacts of an 
individual with symptomatic 
COVID-19.
Of the participants who have a negative 
RT-PCR result at baseline:

Proportion of participants with 
no, mild, moderate, or severe 
signs and symptoms attributed to 
COVID-19 through Day 28.

Number of days of symptomatic 
SARS-CoV-2 infection through 
Day 28.

Not applicable.

To determine the PK of 
PF-07321332 in adult 
participants who have a negative 
PF-07321332 PK in plasma and 
whole blood (if feasible).

Not applicable.


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Objectives
Endpoints
Estimands
or positive RT-PCR result at 
baseline and who are household 
contacts of an individual with 
symptomatic COVID-19.

To describe all-cause mortality in 
adult participants who have a 
negative RT-PCR result at 
baseline and who are household 
contacts of an individual with 
symptomatic COVID-19.
Of the participants who have a negative 
RT-PCR result at baseline:
Proportion of participants with 
death (all-cause) through Day 38.

Not applicable.

To describe the viral load in 
nasal samples over time in adult 
participants who have a negative 
or positive RT-PCR result at 
baseline and who are household 
contacts of an individual with 
symptomatic COVID-19.
Of the participants who have a negative 
RT-PCR result at baseline:
Viral titers measured via RT-PCR 
in nasal swabs over time.
Of the participants who have a positive 
RT-PCR result at baseline:
Viral titers measured via RT-PCR 
in nasal swabs over time.

Not applicable.

To describe hospitalizations in 
adult participants who have a 
negative RT-PCR result at 
baseline and who are household 
contacts of an individual with 
symptomatic COVID-19.
Of the participants who have a negative 
RT-PCR result at baseline:
Number of days of hospital and ICU 
stay in participants with 
COVID-19-related hospitalization 
through Day 28.

Not applicable.

To describe COVID-19 related 
medical visits in adult 
participants who have a negative 
RT-PCR result at baseline and 
who are household contacts of an 
individual with symptomatic 
COVID-19.
Of the participants who have a negative 
RT-PCR result at baseline:
Number of COVID-19 related 
medical visits through Day 28.

Not applicable.
Overall Design
Brief Summary
This Phase 2/3, randomized, double-blind, double-dummy, placebo-controlled study in 
approximately 2880 participants who have a negative screening SARS-CoV-2 rapid antigen 
test result and who are asymptomatic household contacts of individuals who are symptomatic 
and recently tested positive for SARS-CoV-2 (index case: defined as patient with 
symptomatic COVID-19) will compare the efficacy of 2 regimens of PF-07321332/ritonavir 
versus placebo. Index cases may be participants in Phase 2/3 safety and efficacy studies of 
PF-07321332/ritonavir (C4671002 and C4671005), but this is not required. Eligible 
participants for this study will be randomly assigned (1:1:1) within 96 hours after collection 
of the index case’s first positive SARS-CoV-2 test to treatment in 1 of 3 intervention groups. 
Randomization will be stratified based on the presence of risk factors associated with severe 
COVID-19 illness and geographic region at screening.


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Number of Participants
Assuming approximately 5% of participants will have a positive RT-PCR result at baseline, 
and assuming an approximately 10% dropout rate, the total sample size for this study will be 
approximately 2880 participants. 
Note: "Enrolled" means a participant's, or his or her legally authorized representative’s, 
agreement to participate in a clinical study following completion of the informed consent 
process and screening. 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. 
Intervention Groups and Duration
Eligible participants for this study (C4671006) will be randomly assigned (1:1:1) within 
96 hours after collection of the index case’s first positive SARS-CoV-2 test to receive: 

PF-07321332/ritonavir q12h for 5 days followed by matching placebo q12h for 
5 days; or

PF-07321332/ritonavir q12h for 10 days; or 

Matching placebo for PF-07321332/ritonavir q12h for 10 days.
Participants will be screened within 24 hours before randomization. The total duration of the 
study is up to 42 days and includes screening, study intervention through Day 10, efficacy 
assessments through Day 14, and a safety follow-up period through Day 38 [±3 days].
Data Monitoring Committee or Other Independent Oversight Committee: Yes
An independent E-DMC will review unblinded data to ensure the safety of participants on an 
ongoing basis throughout the duration of the study. In addition to up to weekly reviews of 
safety data, the E-DMC will review the following:

Sentinel cohort safety review: The E-DMC will review unblinded safety data after 
approximately the first 150 participants have completed Day 10 of the study, at which 
point enrollment will be paused pending E-DMC review of the safety data. After 
review of the sentinel cohort, the frequency of safety reviews may be reduced 
subsequently based on E-DMC recommendations.

Interim analysis: An interim analysis will be conducted for efficacy, futility, and 
sample size re-estimation and reviewed by the E-DMC after a prespecified accrual of 
participants (ie, before or at approximately 70% overall participants have completed 


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Final Protocol Amendment 2, 25 January 2022
PFIZER CONFIDENTIAL
Page 18
the Day 14 assessments with a minimum number of 24 participants having 
symptomatic infection [mITT analysis set]).
Statistical Methods
For the primary efficacy analysis, GEE will be used to analyze the proportion of participants 
with a negative RT-PCR result at baseline who develop a symptomatic RT-PCR or rapid 
antigen test-confirmed SARS-CoV-2 infection through Day 14 for each treatment group. 
Comparisons between 5-day regimen of PF-07321332/ritonavir versus placebo group and 10-
day regimen of PF-07321332/ritonavir versus placebo group will be presented as risk 
reduction with 95% CIs based on GEE analysis.
Based on the results from Study C4671005, which showed PF-07321332/ritonavir treatment 
significantly reduced the risk of hospitalization or death from any cause by 89% compared 
with placebo in nonhospitalized symptomatic adult participants with COVID-19 who were at 
increased risk of progression to severe disease when they were treated within 3 days of 
symptom onset, and the high relative risk reduction (approximately 80%) observed in 
Regeneron REGEN-COV post-exposure prophylaxis study, the risk reduction between 
PF-07321332/ritonavir group versus placebo group is assumed to be 70%. The symptomatic 
infection rate assumption in the placebo group is adjusted to 4% based on the observed 
seropositivity rate in this study and the impact of seropositivity on the incidence of primary 
endpoint events in the REGEN-COV post-exposure prophylaxis study where the incidence of 
symptomatic infection was 2% in participants who were seropositive and 8% in those who 
were seronegative.2
Among baseline RT-PCR negative participants, assuming an 4% symptomatic infection rate 
in the placebo group, a 70% reduction in symptomatic infection (1.2% symptomatic infection 
rate) in the PF-07321332/ritonavir group (5-day and 10-day regimen), a sample size of 
821 participants per group (2463 participants total) will provide approximately 90% power 
for each comparison between 5-day and 10-day regimens of PF-07321332/ritonavir group 
versus placebo group under a 2-sided type-1 error rate of 5%. Assuming approximately 5% 
of participants with negative rapid antigen test at screening will have a positive RT-PCR 
result at baseline, and assuming an approximately 10% dropout rate, the total sample size for 
this study will be approximately 2880 participants.
An interim analysis will be conducted for efficacy, futility, and sample size re-estimation and 
reviewed by an independent E-DMC after a prespecified accrual of participants (ie, before or 
at approximately 70% overall participants have completed the Day 14 assessments with a 
minimum number of 24 participants having symptomatic infection [mITT analysis set]).


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1.2. Schema


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Protocol C4671006
Final Protocol Amendment 2, 25 January 2022
PFIZER CONFIDENTIAL
Page 20
1.3. Schedule of Activities
The SoA table provides an overview of the protocol visits and procedures. Refer to the STUDY ASSESSMENTS AND 
PROCEDURES section of the protocol for detailed information on each procedure and assessment required for compliance with the 
protocol. 
The investigator may schedule visits (unplanned visits) in addition to those listed in the SoA table, in order to conduct evaluations or 
assessments required to protect the well-being of the participant. 
Visit Identifier
Abbreviations used in this 
table may be found in 
Appendix 14.
Screening Baseline
(Day 1)
Day 3
Day 5
Day 10
Day 14
Day 28
Day 38 
EOS
COVID-19 
Signs/ 
Symptoms 
Onset
ET
NOTES
Visit Window
Day -1 to 
Day 1
0 days
± 1 day
± 1 day
±1 day
±2 days
±2 days ±3 days
+2 days 
ELIGIBILITY
Informed consent
X
See Section 10.1.3.
Verify 
inclusion/exclusion 
criteria
X
See Section 5.1 and Section 5.2.
Demographics & medical 
history
X
Will include assessment of prior 
documented infection and details of 
vaccination.
See Section 8.2.1.
COVID-19 risk factor 
assessment
X
See Appendix 11.
Index Case 
Characteristics
X

As permitted by local laws and 
regulations, index case 
characteristics will be collected 
through interview with the study 
participant to aid in characterization 
of the exposure period.

See Section 8.1.5


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Protocol C4671006
Final Protocol Amendment 2, 25 January 2022
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Visit Identifier
Abbreviations used in this 
table may be found in 
Appendix 14.
Screening Baseline
(Day 1)
Day 3
Day 5
Day 10
Day 14
Day 28
Day 38 
EOS
COVID-19 
Signs/ 
Symptoms 
Onset
ET
NOTES
Visit Window
Day -1 to 
Day 1
0 days
± 1 day
± 1 day
±1 day
±2 days
±2 days ±3 days
+2 days 
PHYSICAL EXAM AND VITAL SIGNS
Targeted physical 
examination
X
X
X
X
X
X
X
[X]

Will be completed at all in-person 
visits. In the event that an in-person 
visit is not feasible at the 
investigational site, targeted physical 
examinations and vital signs 
assessment may be performed by a 
licensed HCP at an alternate site 
approved by the investigator (eg, the 
participant's home) when feasible.

AEs should be assessed by means of 
a telemedicine visit if not feasible 
during an in person visit.

Previously identified AEs (either by 
interview, physical exam, or other 
assessment) should be monitored to 
the extent possible if telemedicine is 
used.

Vital signs assessment at the 
COVID-19 Signs/Symptoms Onset 
visit will include oxygen saturation.

See Section 8.2.4.
Vital signs
X
X
X
X
X
X
X
[X]
Weight, height
X
See Section 8.2.2.
CLINICAL LABORATORY TESTS
Hematology
X
X
X
X*
X*
[X]

Screening visit: Laboratory 
assessments are not required at 
screening unless deemed necessary 
by the investigator to confirm 
eligibility. If deemed necessary, 
laboratory assessments at screening 
will be performed at the local 
laboratory. The medical laboratory 


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Protocol C4671006
Final Protocol Amendment 2, 25 January 2022
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Page 22
Visit Identifier
Abbreviations used in this 
table may be found in 
Appendix 14.
Screening Baseline
(Day 1)
Day 3
Day 5
Day 10
Day 14
Day 28
Day 38 
EOS
COVID-19 
Signs/ 
Symptoms 
Onset
ET
NOTES
Visit Window
Day -1 to 
Day 1
0 days
± 1 day
± 1 day
±1 day
±2 days
±2 days ±3 days
+2 days 
Blood chemistry
X
X
X
X*
X*
[X]
test abnormalities within 6 months 
prior to screening must be closely 
assessed. If abnormalities cannot be 
verified, consider conducting local 
laboratory testing at screening to 
confirm eligibility for the study.

Baseline laboratory assessments 
should be collected prior to first dose 
of study intervention. If 
post-screening eGFR is 
<45 mL/min/1.73m2, the participant 
will be instructed to discontinue any 
remaining study intervention doses 
as soon as study staff become aware 
of the eGFR results. If another 
baseline laboratory result meets 
protocol Section 5.2 exclusionary 
values and the participant is still 
receiving study treatment, contact 
the Medical Monitor.

If a baseline laboratory result meets 
Section 5.2 exclusionary laboratory 
values and the participant is still 
receiving study treatment, the 
investigator should contact the 
Medical Monitor.

Abnormal laboratory values related 
to AEs should be followed until 
resolution. See Section 8.2.5 and
Appendix 2.

*Safety laboratory tests at Days 14 
and 38 are required only if clinically 
significant abnormal laboratory 
values were present from a sample 
drawn at the previous study visit 
Other laboratory 
assessments
X
X
X
X
X
[X]


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Protocol C4671006
Final Protocol Amendment 2, 25 January 2022
PFIZER CONFIDENTIAL
Page 23
Visit Identifier
Abbreviations used in this 
table may be found in 
Appendix 14.
Screening Baseline
(Day 1)
Day 3
Day 5
Day 10
Day 14
Day 28
Day 38 
EOS
COVID-19 
Signs/ 
Symptoms 
Onset
ET
NOTES
Visit Window
Day -1 to 
Day 1
0 days
± 1 day
± 1 day
±1 day
±2 days
±2 days ±3 days
+2 days 
when laboratory assessments were 
performed.

At Day 14 and Day 38, serology is 
collected for all participants. 
Pregnancy test 
X
X
[X]

A negative urine or serum (β-hCG) 
pregnancy test must be confirmed at 
Screening for WOCBP only.

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 Day 
38 or ET.

See Section 8.2.6 and Appendix 2.
FSH
X

FSH is to be performed locally in 
female participants <60 years of age 
at Screening who are not using 
hormonal contraception or hormonal 
replacement therapy, to confirm 
postmenopausal status. Female 
participants aged 50 to 60 years with 
no menses for 12 months do not 
need FSH confirmation.

When FSH testing is required to 
confirm postmenopausal status, a 
participant may be enrolled in the 
study prior to the test result being 
available as long as the FSH test 
result confirms postmenopausal 
status prior to dosing.

See Section 10.4.3 and Appendix 2.


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Protocol C4671006
Final Protocol Amendment 2, 25 January 2022
PFIZER CONFIDENTIAL
Page 24
Visit Identifier
Abbreviations used in this 
table may be found in 
Appendix 14.
Screening Baseline
(Day 1)
Day 3
Day 5
Day 10
Day 14
Day 28
Day 38 
EOS
COVID-19 
Signs/ 
Symptoms 
Onset
ET
NOTES
Visit Window
Day -1 to 
Day 1
0 days
± 1 day
± 1 day
±1 day
±2 days
±2 days ±3 days
+2 days 
Rapid antigen test
X
X
See Section 8.6.4.1.
Collected as a separate swab from nasal 
swab, specifically for local testing.
Nasal swab
Daily from Day 1 through Day 14
X
X
•
At baseline, a nasal swab will be self 
collected by the participant to 
determine RT-PCR status (+ or -); 
this test will not be used to 
determine study eligibility. The 
baseline sample will be collected 
under observation by site staff to 
ensure correct collection method. 
Thereafter, nasal swabs will be self 
collected by the participant at about 
the same time each day, preferably 
in the morning, except on Day 5, 
Day 10, Day 14, or during any 
COVID-19 Signs and Symptoms 
Onset visit or unplanned visit, in 
which case, the nasal swab should be 
collected by the HCP.
•
On the days where there is an 
in-person visit, the nasal swab 
should be collected by the HCP and 
the participants instructed to not 
collect the nasal swab before the 
visit
•
See Section 8.6.4.2. and
Section 8.6.5.
Specified protein research 
(plasma biomarkers)
X
X
X
See Section 8.6.2.
CCI


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Protocol C4671006
Final Protocol Amendment 2, 25 January 2022
PFIZER CONFIDENTIAL
Page 25
Visit Identifier
Abbreviations used in this 
table may be found in 
Appendix 14.
Screening Baseline
(Day 1)
Day 3
Day 5
Day 10
Day 14
Day 28
Day 38 
EOS
COVID-19 
Signs/ 
Symptoms 
Onset
ET
NOTES
Visit Window
Day -1 to 
Day 1
0 days
± 1 day
± 1 day
±1 day
±2 days
±2 days ±3 days
+2 days 
Retained research 
samples for biomarkers 
(Prep B2)
X
X
X
X
•
See Section 8.6.5.
PHARMACOKINETIC
S
PK Sample 
(PF-07321332)
X
X
•
On Day 1, one blood sample for PK 
will be collected 30 to 90 minutes 
postdose for those participants who 
receive their first dose onsite and are 
able to remain onsite following dose 
administration. 
•
On Day 5, one blood sample for PK 
will be collected predose (up to 
2 hours before study intervention 
administration) if feasible; 
otherwise, collect anytime during the 
visit.
•
See Section 8.4.
Optional PK samples 
(self collected by 
participant)
X
•
Whole blood self-collected PK 
samples using the Tasso 
microsampling device (selected sites, 
if feasible) at the following times:
•
Day 3: after the morning dose 
at the following times: 
o
1 sample between 30 to 
90 minutes, 
o
1 sample between 2 to 6 
hours, and 
o
1 sample 8 to 12 hours 
after the dose (the last 
sample should be collected 
before the evening dose).
CCI


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Protocol C4671006
Final Protocol Amendment 2, 25 January 2022
PFIZER CONFIDENTIAL
Page 26
Visit Identifier
Abbreviations used in this 
table may be found in 
Appendix 14.
Screening Baseline
(Day 1)
Day 3
Day 5
Day 10
Day 14
Day 28
Day 38 
EOS
COVID-19 
Signs/ 
Symptoms 
Onset
ET
NOTES
Visit Window
Day -1 to 
Day 1
0 days
± 1 day
± 1 day
±1 day
±2 days
±2 days ±3 days
+2 days 

See Section 8.4.
RANDOMIZATION
X
STUDY INTERVENTION
Study intervention 
dispensation
X
X

Study intervention will be dispensed 
on Day 1 and Day 5 (see
Section 6.1.1).

Day 5 visit has to be scheduled on 
time to dispense study intervention 
prior to the 11th dose which should 
be on the morning of study Day 6 if 
2 doses were taken on Day 1 or on 
the evening of study Day 6, if a 
single dose was taken on Day 1.  
Study intervention 
administration
Daily from Day 1 through Day 10

For Treatment Days: Participants 
will receive 20 doses of study 
intervention over 10 days. The first 
dose will be administered on Day 1. 
The second dose will be 
administered at least 4 hours later so 
that the dosing schedule is 
convenient for the participant. All 
subsequent doses will be q12h [±30 
minutes]. 

The last day of treatment will be Day 
11 if only 1 dose was administered 
on Day 1.
STUDY PROCEDURES AND ASSESSMENTS
Collect/update secondary 
contacts
X
X
X
X
X
X
On Day 1, the investigator will collect 
contact information for at least 
2 individuals who can be contacted if 
the participant cannot be reached after 
multiple attempts (repeat/update as 
needed). 
Record/update household 
characteristics
X
X
X
X
X
X
X
X
See Section 8.1.6.


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Protocol C4671006
Final Protocol Amendment 2, 25 January 2022
PFIZER CONFIDENTIAL
Page 27
Visit Identifier
Abbreviations used in this 
table may be found in 
Appendix 14.
Screening Baseline
(Day 1)
Day 3
Day 5
Day 10
Day 14
Day 28
Day 38 
EOS
COVID-19 
Signs/ 
Symptoms 
Onset
ET
NOTES
Visit Window
Day -1 to 
Day 1
0 days
± 1 day
± 1 day
±1 day
±2 days
±2 days ±3 days
+2 days 
Record supplemental 
oxygen requirements
X
X
X
X
X
X
X
X
See Section 8.1.4.
Study kit dispensed and 
participant instructed on 
its use
X
The study kit includes documents and 
materials that will facilitate participant 
completion of at-home study 
procedures.
Participant-completed 
study diary (COVID-19 
signs and symptoms and 
global impression 
questions)
Daily from Day 1 through Day 28

Global impression questions will be 
answered every day from the first 
day a symptom is reported in the 
diary through Day 28.

These assessments will be answered 
on the day of the COVID-19 Signs/ 
Symptoms Onset visit or the ET visit 
if the visit occurs from Day 1 
through Day 28. 

For participants who are using an 
eDiary provided through the study, 
the eDiary will be collected on Day 
38 or ET visit, after completion of 
all logs and questionnaires executed 
on the device.
See Section 8.1.1 and Section 8.1.7.3.
EQ-5D-5L
X
X
X
X
X

If supported by technology, PRO 
assessments will be reported by 
participants in the study diary 
(Section 8.1.1). 

See Section 8.1.7.
WPAI
X
X
X
Staff review of study 
diary
X
X
X
X
X
X
X
X
Participant completes 
study intervention log
Daily from Day 1 through Day 10

The last day of treatment will be 
Day 10 or Day 11, depending on 
how many doses were administered 
on Day 1.

Study intervention log will be 
completed on the day of the 


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Protocol C4671006
Final Protocol Amendment 2, 25 January 2022
PFIZER CONFIDENTIAL
Page 28
Visit Identifier
Abbreviations used in this 
table may be found in 
Appendix 14.
Screening Baseline
(Day 1)
Day 3
Day 5
Day 10
Day 14
Day 28
Day 38 
EOS
COVID-19 
Signs/ 
Symptoms 
Onset
ET
NOTES
Visit Window
Day -1 to 
Day 1
0 days
± 1 day
± 1 day
±1 day
±2 days
±2 days ±3 days
+2 days 
COVID-19 Signs/ Symptoms Onset 
or ET visits if the visit occurs from 
Day 1 through Day 10.
Record COVID-19 
related medical visits 
since last visit
X
X
X
X
X
X

Day 10: Record visits since 
randomization.

All subsequent visits: Record 
COVID-19 related medical visits 
since the prior assessment/visit.

See Section 8.1.3
Retrieval of unused 
study intervention and 
empty study intervention 
containers
X
X
X
X
[X]

Empty study intervention containers 
and unused study intervention 
should be returned at the next in-
person visit.

See Section 6.4.
Study intervention 
accountability
X
X
[X] if 
needed
Contraception check
X
X
X
X
X
X
X
X
X
See Appendix 4.
Vital status
X
X
Record 
prior/concomitant 
medication(s)
X
X
X
X
X
X
X
X
X

All prescription and over-the-counter 
medications being taken by the 
participant and any vaccine for 
14 days before study entry 
(considered prior treatment) will be 
recorded. 

Refer to Section 6.8.
Record adjunctive 
therapeutic procedures
X
X
X
X
X
X
X
X
X

Nondrug treatments.

Collected only if the participant 
becomes symptomatic.
SERIOUS AND 
NONSERIOUS AE 
MONITORING
X
X
X
X
X
X
X
X
X

AEs should be assessed by means of 
a telemedicine visit if not feasible 
via an in-person visit. 

Refer to Section 8.3.

Site staff should, in discussion with participants, determine the most appropriate location to conduct study visits, whether in-person or remotely by telemedicine. In person 
visits should take place at the investigational site. If investigational site in-person visit is not feasible, then alternate venues may include the participant's home or an alternate, 
noninvestigational site location approved by the investigator. If an in-person visit is held at a location other than the investigational site, in certain situations the assigned HCP 


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Visit Identifier
Abbreviations used in this 
table may be found in 
Appendix 14.
Screening Baseline
(Day 1)
Day 3
Day 5
Day 10
Day 14
Day 28
Day 38 
EOS
COVID-19 
Signs/ 
Symptoms 
Onset
ET
NOTES
Visit Window
Day -1 to 
Day 1
0 days
± 1 day
± 1 day
±1 day
±2 days
±2 days ±3 days
+2 days 
performing the visit may be unable to complete all assessments. In these cases, a telemedicine visit should also occur to perform the remaining assessments. Remote visits can 
be conducted using a telemedicine system approved for use at the site. 

Assessments indicated in brackets [X] will be performed only for in-person visits.

Screening procedures may be done from Day -1 to Day 1. In many cases, all screening procedures can be completed in <24 hours. For these participants, screening procedures 
may be completed on the same calendar day as randomization and Baseline/Day 1 procedures, including first dose of study intervention.

Baseline assessments should be performed before the administration of the first dose of study intervention.

Day 1 is the start of dosing.

Study Intervention Dispensation: Participants will receive their first set of study intervention containers at the Day 1 visit and the second set of study intervention containers 
at the Day 5 visit. Each set contains 10 doses of study intervention. Day 5 visit should be scheduled so that there is no interruption in dosing and so the participant does not use 
any overage from the set dispensed at the Day 1 visit (see Section 6.2.1). 

For Study Intervention Administration: Participants will receive study intervention for 10 days (20 doses total). The first dose will be administered at the Baseline/Day 1 
visit during the in-person visit, if possible. All subsequent doses (ie, 19) will be self administered outside the study clinic (eg, at home).

Screening, Baseline, Day 5, Day 10, Day 14 and Day 38 visits will be conducted in person (at the investigational site or another location, including a participant’s home) 
provided the planned assessments can be performed at the location selected.

Day 3 visit involves self-collected PK samples (using Tasso) only for participants who consent to the optional PK sampling. There is no planned in-person or telemedicine visit 
on this study day.

Day 3 and Day 5 visits should be conducted on separate calendar days.

Day 28 visit will be conducted by telemedicine system.

COVID-19 Signs/Symptoms Onset visit will occur as soon as possible after the participant experiences signs or symptoms of COVID-19 and will be conducted in-person any 
time up to Day 38. When the COVID-19 Signs/Symptoms Onset visit occurs within the visit window prior to a scheduled visit, the 2 visits can be combined.

Early Termination visit will be conducted in person or by telemedicine system.

Telemedicine Visits, while planned to be virtual (ie, over the phone or other approved system), they may also be conducted in-person at the investigator’s discretion.


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2. INTRODUCTION
PF-07321332, a potent and selective SARS-CoV-2 3CL protease inhibitor, is being 
investigated as oral antiviral postexposure prophylaxis for adult household contacts of an 
individual with symptomatic COVID-19.
2.1. Study Rationale 
The purpose of this study is to evaluate the efficacy and safety of PF-07321332/ritonavir as 
postexposure prophylaxis for adult household contacts of an individual with symptomatic 
COVID-19.
2.2. Background 
In December 2019, COVID-19 was identified as a new, potentially fatal, respiratory infection 
caused by the novel coronavirus, SARS-CoV-2. The WHO declared COVID-19 a Public 
Health Emergency of International Concern3 on 30 January 2020 and further characterized 
the disease outbreak as a pandemic on 11 March 2020.4 As of 12 January 2022, at least, 
315 million cases have been confirmed worldwide, and at least 5.5 million deaths have 
occurred.5
COVID-19 manifests as a wide range of illness, from asymptomatic infection to severe 
pneumonia, ARDS, and death. Although most (approximately 80%) cases are asymptomatic 
or mild,6 patients who are hospitalized with COVID-19 may have significant morbidity and 
mortality, 7,8 COVID-19 manifests as a wide range of illness, from asymptomatic infection to 
severe pneumonia, ARDS, and death. Although most (approximately 80%) cases are 
asymptomatic or mild,6 patients who are hospitalized with COVID-19 may have significant 
morbidity and mortality,7,8 and are at increased risk of developing complications such as 
severe inflammation associated with elevations in proinflammatory cytokines, ARDS, acute 
cardiac injury, thromboembolic events, hypercoagulability, and/or kidney injury.9-12
Moreover, other comorbidities, such as hypertension, obesity, and diabetes, as well as older 
age and male sex increase the risk for worse outcomes.7
Although there are symptomatic and/or supportive treatments for COVID-19, few antiviral 
drugs are available or in late-stage development to help treat COVID-19 in patients with mild 
to moderate COVID-19. Existing compounds, such as hydroxychloroquine and 
lopinavir/ritonavir, have been evaluated as potential treatment options for COVID-19, but
have not demonstrated benefit or efficacy beyond the SoC.13-15 The FDA has approved IV 
remdesivir,16 an antiviral drug with activity against SARS-CoV-2, for hospitalized patients 
with COVID-19. However, remdesivir monotherapy may not be sufficient in all subsets of 
patients17 across the COVID-19 spectrum or has shown modest effects.18,19 Favipiravir is 
currently under investigation for its activity against SARS-CoV-2 due to its broad-spectrum 
activity against various RNA viruses20,21 and has been approved in India and Russia to treat 
mild to moderate COVID-19.22 Although favipiravir has been generally well tolerated in 
clinical studies primarily for the treatment of the influenza virus, teratogenic findings in 
multiple animal species at exposures comparable to those achieved with the dosage regimen 
to treat influenza have limited its clinical use.20


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Among contacts of persons with COVID-19, the percentage in whom new cases develop 
(secondary attack rate) has been estimated at 10 to 15%.23-26 The primary infection-control 
strategy currently employed relies on basic hygiene measures such as hand washing, use of 
personal protective equipment such face masks, social distancing, and isolation of case 
patients and their contacts.27 The effectiveness of isolation depends on the promptness of the 
intervention, the level of contact tracing, and the level of isolation adherence28. 
Implementation of these measures however, has not been fully effective and spread of 
SARS-CoV-2 in many countries continues to occur. Furthermore, modeling of SARS-CoV-2 
viral shedding dynamics suggests that up to 44% of transmission occurs prior to symptom 
onset of the index case (presymptomatic transmission) and that start and peak infectiousness 
can be up to 2 days before symptom onset.29
There are large efforts in progress to develop vaccines30 with several now authorized for 
emergency use or conditionally approved by Health Authorities for those aged 12 years and 
older.31 These vaccines will take time to deploy and may not be taken by everyone. Also, the 
duration of potential protection is not known leading to continued efforts to identify effective 
antiviral treatments. Moreover, currently authorized/approved vaccines may not be as 
effective against potential outbreaks from new coronavirus variants.32,33 Emergence of the 
Omicron variant in late 2021 provides an example of the potential impact emerging variants 
of SARS-CoV-2 may have on vaccine efficacy. More specifically, gene mutations in the 
Omicron variant appear to result in vaccine efficacy against symptomatic disease that is 
significantly lower than against the Delta variant.34 Regarding protection afforded by prior 
infection with SARS-CoV-2, the Omicron variant appears to be associated with a 3- to 8-fold 
increased risk of reinfection relative to other variants that have been observed.35
Postexposure prophylaxis for healthy contacts is among the measures used for outbreak 
control of several infectious diseases (eg, pandemic influenza).36 No oral agents are known to 
be effective in preventing SARS-CoV-2 infection or COVID-19, but aminoquinolines 
(hydroxychloroquine and chloroquine) and antiretrovirals (eg, lopinavir/ritonavir) have been 
or are in the process of being assessed for potential utility in the postexposure, preemptive 
treatment/prophylaxis outpatient settings.37 The direct reduction of viral replication, through 
inhibition of other critical viral enzymes, offers an important mechanism to achieve greater 
patient benefit and perhaps aid in control of the COVID-19 pandemic. The US FDA has 
granted EUA for an IV- or SC-administered mAb regimen as postexposure prophylaxis for 
COVID-19 in adults and adolescents who are at high risk for progressing to severe COVID-
19.38 As of January 2022, no orally administered therapeutic intervention has been approved 
or authorized for use in postexposure/preemptive treatment/prophylaxis.
The coronavirus 3CL protease is a virally encoded enzyme that is critical to the 
SARS-CoV-2 replication cycle, analogous to other obligatory virally encoded proteases 
(eg, HIV Protease, HCV Protease).39 Mutagenesis experiments with other coronaviruses and 
picornaviruses that are related to SARS-CoV-2 (picornavirus-like supercluster) have 
demonstrated that the activity of the 3CL protease (or the corresponding picornaviral 
3C enzyme) is essential for viral replication. No close human analogs of coronavirus 3CL 


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enzymes are known, suggesting that appropriate 3CL inhibitors may function as selective 
inhibitors of SARS-CoV-2 and other coronaviruses as therapeutic agents.
PF-07321332, a potent and selective inhibitor of the SARS-CoV-2 3CL protease, is being 
developed as an oral treatment and/or postexposure prophylaxis in patients with COVID-19.
In this study, PF-07321332 will be coadministered with ritonavir. Ritonavir is a strong 
CYP3A4 inhibitor and is being used as a PK enhancer in this study to inhibit the metabolism 
of PF-07321332 in order to increase plasma concentrations of PF-07321332 to values that are 
anticipated to be efficacious. Ritonavir, at the dose administered in this study, is not expected 
to have any antiviral activity on the SARS-CoV-2 virus and is being used only as a PK 
enhancing agent .
2.2.1. Nonclinical Studies of PF-07321332
Data from nonclinical studies support the planned clinical trials with PF-07321332; these 
studies are described in the IB.40
PF-07321332 exhibits a broad-spectrum activity across the Coronaviridae family of 3CL 
proteases demonstrating its potential for antiviral efficacy.
In vitro, PF-07321332 inhibited SARS-CoV-2 viral-induced cytopathic effect in monkey 
kidney Vero cell assays. PF-07321332 exhibited antiviral activity against SARS-CoV-2 in 
dNHBE cells. Furthermore, PF-07321332 inhibited HCoV229E viral-induced cytopathic 
effect in human MRC-5 cells with no detectable cytotoxicity at the highest compound 
concentration tested.
Test article-related findings identified in the safety pharmacology studies included changes in 
locomotor activity and transient higher respiratory rate and minute volume in rats at the high 
dose, as well as minor and transient hemodynamic changes (increased blood pressure and 
decreased heart rate) at the high dose in cynomolgus monkeys. The potential effects on safety 
pharmacology parameters are monitorable in the clinic, and no correlated clinical signs or 
histopathological findings in the relevant organs were observed in the 14-day or 15-day 
repeat dose GLP toxicity studies in rats or monkeys. ECG data were also collected in the 
15-day GLP monkey study and there were no test article-related changes in ECG parameters 
(HR, RR-, PR-, QRS-, QT-, QTc-intervals) or ECG morphology in that study.
2.2.2. Clinical Overview
C4671001 (NCT04756531) is an ongoing FIH single and multiple dose escalation study to 
evaluate the safety, tolerability, and PK of PF-07321332 in healthy adult participants. 
Preliminary data from this study collected as of 07 April 2021 (SAD) and 14 April 2021 
(MAD) in a total of 31 participants who were randomized and treated with PF-07321332 or 
placebo, the clinical safety profile of PF 07321332 appears to be acceptable at single doses 
up to 1500 mg alone and up to 750 mg administered with ritonavir (100 mg at -12h, 0h, 12h), 
and at repeated daily doses administered orally for 10 days of up to 500 mg PF-07321332 
BID with 100 mg ritonavir BID.


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Preliminary PK data on Day 1, Day 5 and Day 10 following multiple oral administration of 
PF-07321332/ritonavir 75/100 mg, 250/100 mg, and 500/100 mg BID suggest less than 
proportional increase in exposures at steady state. Multiple dosing over 10 days achieved 
steady state on Day 2 with approximately 2-fold accumulation. Day 5 and Day 10 exposure 
was similar at all doses.
Following single doses of PF-07321332 with and without ritonavir, all AEs were mild and 
none were considered treatment related. There were no obvious trends in, or association of, 
TEAEs with dose level of PF-07321332. Following multiple doses, the most commonly 
observed AEs by SOC were Gastrointestinal disorders and Nervous system disorders. 
Diarrhea was the most common reported AE, occurring in 4 participants across treatment 
groups. A total of 5 treatment related TEAEs were observed in Part-2:MAD.
Across treatment groups, blood TSH increased in 3 participants, and 2 participants reported 
dysgeusia. The 3 participants with elevated TSH results did not experience related clinical 
symptoms and the free T4 results remained within reference range. No SAEs or deaths were 
reported based on these preliminary safety data as of 07 April 2021 and 14 April 2021.
Current evidence indicates the clinical safety profile of PF 07321332 is acceptable at single 
doses up to 1500 mg alone and up to 750 mg administered with ritonavir (100 mg at -12h, 0h, 
12h), and at repeated daily doses administered orally for 10 days of up to 500 mg 
PF-07321332 BID with 100 mg ritonavir BID.
C4671005 (NCT04960202), a Phase 2/3, randomized, double-blind, placebo-controlled study 
in nonhospitalized symptomatic adult participants with a laboratory-confirmed diagnosis of 
SARS-CoV-2 infection, included participants 18 years of age and older with at least 1 risk 
factor for progression to severe disease and with a COVID-19 symptom onset of 
≤5 days. The study excluded individuals with a history of prior COVID-19 infection or 
SARS-CoV-2 vaccination before the Day 34 visit. The primary efficacy endpoint was the 
proportion of participants with COVID-19 related hospitalization or death from any cause 
through Day 28. 
In the analysis of the primary endpoint from all participants enrolled in Study C4671005, an 
89% reduction in COVID-19-related hospitalization or death from any cause compared with 
placebo in participants treated within 3 days of symptom onset was observed. 0.7% of 
participants who received PF-07321332/ritonavir were hospitalized through Day 28 
following randomization (5 of 697 hospitalized with no deaths), compared to 6.5% of 
participants who received placebo and were hospitalized or died (44 of 682 hospitalized with 
9 subsequent deaths) (p<0.0001). In a secondary endpoint, PF-07321332/ritonavir reduced 
the risk of hospitalization or death for any cause by 88% compared with placebo in 
participants treated within 5 days of symptom onset; 0.8% of patients who received 
PF-07321332/ritonavir were hospitalized or died through Day 28 following randomization 
(8 of 1039 hospitalized with no deaths) compared with 6.3% of patients who received 
placebo (66 of 1046 hospitalized with 12 subsequent deaths) (p<0.0001). Treatment with 
PF-07321332/ritonavir was safe and well tolerated.


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Results from a protocol-specified interim analysis of Study C4671002 (NCT05011513), 
which included 45% of the study’s planned enrollment, showed that the novel primary 
endpoint of self-reported, sustained alleviation of all symptoms for 4 consecutive days, as 
compared with placebo, was not met. However, the key secondary endpoint of 
COVID-19-related hospitalization or death from any cause through Day 28 was also 
examined at the interim analysis, showing 0.6% of those who received 
PF-07321332/ritonavir were hospitalized following randomization (2 of 333 hospitalized 
with no deaths), compared to 2.4% of participants who received placebo and were 
hospitalized (8 of 329 hospitalized with no deaths). 
2.3. Benefit/Risk Assessment
More detailed information about the known and expected benefits and risks and reasonably 
expected AEs of PF-07321332 may be found in the investigator’s brochure, which is the 
SRSD for this study. The SRSD for the ritonavir is the USPI41 for NORVIR.


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2.3.1. Risk Assessment
Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
Study Intervention(s) PF-07321332
Emesis
Sporadic emesis was observed at ≥100 mg/kg/day of 
PF-07321332 in the 15-day NHP toxicology study.
AEs will be monitored and participants may 
receive antiemetics.
Hemodynamic and inflammatory effects
Low level inflammation (increase in fibrinogen) in 
15-day NHP toxicology study and changes in 
platelets, globulin and albumin/globulin ratio and 
coagulation system (increase in PT and aPTT) in 
14-day rat toxicology study.
In addition to vital signs and close observation for 
AEs, fibrinogen, platelets, D-dimer, PT and aPTT, 
albumin, and total protein will also be monitored.
Refer to Section 8.3.8.
TSH elevations
TSH changes observed with the administration of 
PF-07321332 during study C4671001
TSH and T4 (free) will be monitored.
Refer to Section 8.3.8.
Study Intervention(s): Ritonavir
Gastrointestinal disturbances (including 
diarrhea, nausea, vomiting and abdominal pain)
Frequently reported adverse reaction in patients who 
are HIV-positive at 600 mg BID.
Lower dose of 100 mg twice daily is used in this 
study. There will be close observation of AEs. 
In addition to ongoing review of AEs by the 
sponsor, an E-DMC will review safety data as 
described in Section 10.1.5.1.
Taking study intervention with food may improve 
tolerability.
Neurological disturbances (eg, paresthesia, 
including oral paresthesia, dysgeusia and 
dizziness)
Frequently reported adverse reaction in patients who 
are HIV-positive at 600 mg BID.
Lower dose used in this study. There will be close 
observation of AEs.  
In addition to ongoing review of AEs by the 
sponsor, an E-DMC will review safety data as 
described in Section 10.1.5.1.
Rash (most commonly reported as erythematous 
and maculopapular, followed by pruritic)
Frequently reported adverse reaction in patients who 
are HIV-positive at 600 mg BID.
Lower dose used in this study. There will be close 
observation of AEs and monitoring through 


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Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
targeted physical exams. If needed therapeutic 
interventions per SoC may be provided.
Fatigue/Asthenia
Frequently reported adverse reaction in patients who 
are HIV-positive at 600 mg BID.
Lower dose used in this study. There will be close 
observation of AEs. Fatigue (low energy or 
tiredness) will be assessed through collection of 
daily signs and symptoms and will also be 
assessed through targeted physical examinations 
when performed during the study visits.


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2.3.2. Benefit Assessment
As of January 2022, no orally administered therapeutic intervention has been approved or 
received an EUA in the US for use in postexposure/preemptive treatment/prophylaxis, but 2 
orally administered antivirals for the treatment of COVID-19 in patients at high risk of 
progression to severe COVID-19 (eg, Paxlovid42 and molnupiravir43) have begun receiving 
EUAs (or equivalent) in various regions. Additionally, the emergence of variants such as the 
omicron variant that may be associated with reduced protection afforded by vaccine and 
monoclonal antibodies further emphasizes the need for additional treatment and postexposure 
prophylaxis options.34,35 On this basis, the potential benefit to individual study participants 
who receive the study intervention may include preventing development of symptomatic 
SARS-CoV-2 infection following exposure to a household contact (an index patient) with 
symptomatic COVID-19. By virtue of participating in the study and ongoing evaluation and 
assessment for SARS-CoV-2 infection, there is the potential benefit of early detection and 
subsequent medical management should infection with SARS-CoV-2 be detected.
2.3.3. Overall Benefit/Risk Conclusion
Taking into account the seriousness of COVID-19, the lack of readily available postexposure 
prophylactic treatment options and the measures taken to minimize risk to participants in this 
study, the potential risks identified in association with PF-07321332 are justified by the 
anticipated benefits that may be afforded to study participants by preventing development of 
symptomatic SARS-CoV-2 infection. An independent E-DMC will be responsible for 
monitoring the safety of participants at regularly scheduled intervals throughout the duration 
of the study and for assessing efficacy, futility, and sample size re-estimation at the time of 
the interim analysis according to the E-DMC charter.
3. OBJECTIVES, ENDPOINTS, AND ESTIMANDS
Objectives
Endpoints
Estimands
Primary: 
Primary:
Primary: 

To compare the efficacy of 5-day 
and 10-day regimens of 
PF-07321332/ritonavir versus 
placebo in preventing 
symptomatic RT-PCR or rapid 
antigen test-confirmed 
SARS-CoV-2 infection in adult 
participants who have a negative 
RT-PCR result at baseline and 
who are household contacts of an 
individual with symptomatic 
COVID-19.
Of the participants who have a negative 
RT-PCR result at baseline:

Proportion of participants who 
develop a symptomatic, RT-PCR 
or rapid antigen test--confirmed 
SARS-CoV-2 infection through 
Day 14.

The risk reduction between 5-day 
and 10-day regimens of 
PF-07321332/ritonavir versus 
placebo in the proportion of 
individuals who develop 
symptomatic RT-PCR or rapid 
antigen test--confirmed 
SARS-CoV-2 infection through 
Day 14 in adults who have a 
negative RT-PCR result at 
baseline and are household 
contacts of an individual with 
symptomatic COVID-19. This 
will be estimated without regard 
to adherence to randomized 
treatment. 


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Objectives
Endpoints
Estimands
Secondary: 
Secondary:
Secondary: 

To describe the safety and 
tolerability of 5-day and 10-day 
regimens of 
PF-07321332/ritonavir relative to 
placebo in adult participants who 
have a negative or positive 
RT-PCR result at baseline and 
who are household contacts of an 
individual with symptomatic 
COVID-19.
Incidence of TEAEs
Incidence of SAEs and AEs leading 
to discontinuation.

Not applicable.

To compare the efficacy of 5-day 
and 10-day regimens of 
PF-07321332/ritonavir versus 
placebo in preventing 
symptomatic RT-PCR or rapid 
antigen test-confirmed 
SARS-CoV-2 infection in adult 
participants who have a negative 
RT-PCR result at baseline, who 
are at increased risk of severe 
COVID-19 illness, and who are 
household contacts of an 
individual with symptomatic 
COVID-19.
Of the participants who have a 
negative RT-PCR result at baseline 
and who are at increased risk of 
severe COVID-19 illness:

Proportion of participants with 
symptomatic, RT-PCR or rapid 
antigen test-confirmed 
SARS-CoV-2 infection through 
Day 14.

Proportion of participants with 
COVID-19 related 
hospitalization or death from any 
cause by Day 28.

The risk reduction between 5-day 
and 10-day regimens of 
PF-07321332/ritonavir versus 
placebo in the proportion of 
individuals who develop 
symptomatic RT-PCR or rapid 
antigen test--confirmed 
SARS-CoV-2 infection through 
Day 14 in adults who have a 
negative RT-PCR result at 
baseline, who are at increased 
risk of severe COVID-19 illness, 
and who are household contacts 
of an individual with 
symptomatic COVID-19. This 
will be estimated without regard 
to adherence to randomized 
treatment.

To compare the efficacy of 5-day
and 10-day regimens of 
PF-07321332/ritonavir versus 
placebo in preventing 
SARS-CoV-2 infection in adult 
participants who have a negative 
or positive RT-PCR result at 
baseline and who are household 
contacts of an individual with 
symptomatic COVID-19.
Of the participants who have a negative 
RT-PCR result at baseline:

Proportion of participants with 
asymptomatic RT-PCR or rapid 
antigen test--confirmed SARS-
CoV-2 infection through Day 14.

Time to RT-PCR or rapid 
antigen test--confirmed SARS-
CoV-2 infection through Day 14.
Of the participants who have a positive 
RT-PCR result at baseline:

Proportion of participants with 
symptomatic RT-PCR or rapid 
antigen test--confirmed SARS-
CoV-2 infection through Day 14.
Of the participants who have a negative 
or positive RT-PCR result at baseline:

Proportion of participants with 
symptomatic RT-PCR or rapid 
antigen test--confirmed SARS-
CoV-2 infection through Day 14.

Not applicable.

To compare the efficacy of 5-day 
and 10-day regimens of 
PF-07321332/ritonavir versus 
placebo in the duration and 
Of the participants who have a negative 
RT-PCR result at baseline:

Proportion of participants with 
no, mild, moderate, or severe 

Not applicable.


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Objectives
Endpoints
Estimands
severity of COVID-19 related 
signs and symptoms in adult 
participants who have a negative 
RT-PCR result at baseline and 
who are household contacts of an 
individual with symptomatic 
COVID-19.
signs and symptoms attributed to 
COVID-19 through Day 28.

Number of days of symptomatic 
SARS-CoV-2 infection through 
Day 28.

To determine the PK of 
PF-07321332 in adult 
participants who have a negative 
or positive RT-PCR result at 
baseline and who are household 
contacts of an individual with 
symptomatic COVID-19.
PF-07321332 PK in plasma and 
whole blood (if feasible).

Not applicable.

To describe all-cause mortality in 
adult participants who have a 
negative RT-PCR result at 
baseline and who are household 
contacts of an individual with 
symptomatic COVID-19.
Of the participants who have a negative 
RT-PCR result at baseline:
Proportion of participants with 
death (all-cause) through Day 38.

Not applicable.

To describe the viral load in 
nasal samples over time in adult 
participants who have a negative 
or positive RT-PCR result at 
baseline and who are household 
contacts of an individual with 
symptomatic COVID-19.
Of the participants who have a negative 
RT-PCR result at baseline:
Viral titers measured via RT-PCR 
in nasal swabs over time.
Of the participants who have a positive 
RT-PCR result at baseline:
Viral titers measured via RT-PCR 
in nasal swabs over time.

Not applicable.

To describe hospitalizations in 
adult participants who have a 
negative RT-PCR result at 
baseline and who are household 
contacts of an individual with 
symptomatic COVID-19.
Of the participants who have a negative 
RT-PCR result at baseline:
Number of days of hospital and ICU 
stay in participants with 
COVID-19-related hospitalization 
through Day 28.

Not applicable.

To describe COVID-19 related 
medical visits in adult 
participants who have a negative 
RT-PCR result at baseline and 
who are household contacts of an 
individual with symptomatic 
COVID-19.
Of the participants who have a negative 
RT-PCR result at baseline:
Number of COVID-19 related 
medical visits through Day 28.

Not applicable.
4. STUDY DESIGN
4.1. Overall Design
This Phase 2/3, randomized, double-blind, double-dummy, placebo-controlled study will 
compare the efficacy of 2 regimens of PF-07321332/ritonavir versus placebo in 
approximately 2880 participants who have a negative screening SARS-CoV-2 rapid antigen 
test result and are asymptomatic household contacts of individuals who are symptomatic and 
recently tested positive for SARS-CoV-2 (index case: defined as patient with symptomatic 


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COVID-19). Index cases may be participants in Phase 2/3 safety and efficacy studies of 
PF-07321332/ritonavir (C4671002 and C4671005), but this is not required. Eligible 
participants for this study will be randomly assigned (1:1:1) within 96 hours after collection 
of the index case’s first positive SARS-CoV-2 test to receive: 

PF-07321332/ritonavir q12h for 5 days followed by matching placebo q12h for 
5 days; or

PF-07321332/ritonavir q12h for 10 days; or 

Matching placebo for PF-07321332/ritonavir q12h for 10 days.
Randomization will be stratified based on the presence of risk factors associated with severe 
COVID-19 illness (see Appendix 11) and geographic region at screening. Throughout the 
study period, provision will be made to allow study visits to be conducted at a participant’s 
home or at another nonclinic location approved by the investigator where possible when 
participants are unwilling or unable to attend a clinic visit at the investigational site. 
Participants will be screened within 24h before randomization. The total duration of the study 
is up to 42 days and includes screening, study intervention through Day 10, efficacy 
assessments through Day 14, and a safety follow-up period through Day 38 [±3 days]. 
An independent E-DMC will review unblinded data to ensure the safety of participants on an 
ongoing basis throughout the duration of the study. In addition to up to weekly reviews of 
safety data, the E-DMC will review the following:

Sentinel cohort safety review: The E-DMC will review unblinded safety data after 
approximately the first 150 participants have completed Day 10 of the study, at which 
point enrollment will be paused pending E-DMC review of the safety data. After 
review of the sentinel cohort, the frequency of safety reviews may be reduced 
subsequently based on E-DMC recommendations.

Interim analysis: An interim analysis will be conducted for efficacy, futility, and 
sample size re-estimation and reviewed by an E-DMC after a prespecified accrual of 
participants (ie, before or at approximately 70% participants have completed the 
Day 14 assessments with a minimum number of 24 participants having symptomatic 
infection [mITT analysis set]).
Subsequent to the planned interim analysis, there will be a single analysis for reporting the 
results of this study after all participants have had their last study visit. 
4.2. Scientific Rationale for Study Design
This study evaluates safety and the potential efficacy of an investigational agent on 
preventing symptomatic SARS-CoV-2 infection (postexposure prophylaxis) in household 
contacts of individuals who recently tested positive for SARS-CoV-2 and are symptomatic 


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(ie, index case: patient with symptomatic COVID-19). Prior studies of antiviral, mAb, and 
antimalarial agents have evaluated the efficacy of these agents as postexposure prophylaxis 
and/or preemptive treatment for symptomatic SARS-CoV-2 infection. Studies with mAb 
suggest that post-exposure treatment of asymptomatic patients may reduce symptomatic 
SARS-CoV-2 infection.37,44-49
Efficacy assessments (including collection of nasal swabs and participant-reported 
COVID-19 symptoms) will be collected through Day 14 and 28, respectively. The symptom 
endpoint includes those recommended by FDA and relies on symptoms that have been 
associated with COVID-19, and which are expected to be dynamic and improve with 
effective anti-SARS-CoV-2 therapy. Nasal swabs will be collected daily through Day 14 to 
determine if and when participants become RT-PCR positive. Participants who develop signs 
or symptoms consistent with COVID-19 during the study will undergo an in-person medical 
assessment including a rapid antigen test to confirm SARS-CoV-2 infection so that the 
participants may receive SoC therapy as described in Section 6.8. Additional testing may be 
performed in accordance with local medical practice. 
This study uses a randomized, double-blind, double-dummy, placebo-controlled design, 
which is a well-accepted approach for evaluating efficacy in a clinical research setting.
4.2.1. Diversity of Study Population
Reasonable attempts will be made to enroll participants to ensure the study population is 
representative of the patient population that will be treated with PF-07321332/ritonavir in 
clinical practice.
4.2.2. Choice of Contraception/Barrier Requirements
Studies to evaluate the developmental toxicity of PF-07321332 have not been conducted. 
Therefore, the use of a highly effective method of contraception is required (see Appendix 4).
4.2.3. Collection of Retained Research Samples
Retained Research Samples will be collected and stored for further analyses which may, for 
example, provide greater understanding of the study intervention.
4.3. Justification for Dose
Dosing regimens of 300 mg PF-07321332 coadministered with 100 mg ritonavir q12h 
administered orally for 5 days or 10 days will be evaluated in this study. Dose selection for 
this study included consideration of all relevant available preclinical and clinical data, 
including repeat-dose toxicology studies, clinical safety, and PK data from the Phase 1 study 
(C4671001), and in vitro pharmacology studies with PF-07321332.
A preliminary population PK model was developed from the Phase 1 (C4671001) PK data. 
Following a first dose of 300 mg PF-07321332 coadministered with 100 mg ritonavir q12h, 
median Ctrough of unbound (free) PF-07321332 is predicted to be approximately 289 ng/mL 
(equivalent to 933 ng/mL total), ie, approximately 3-fold higher than the in vitro EC90 of 


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90.4 ng/mL determined in dNHBE cells (equivalent to 181 nM, fu, human=0.310). At this 
dose, for a hypothetical intersubject variability of 60%, more than 95% of the participants are 
predicted to maintain free PF-07321332 concentrations above the in vitro EC90 over the 
12- hour dosing interval.
Based upon epidemiological characteristics of SARS-CoV-229 and assuming a range of 
different scenarios related to the timing of initiation of treatment for the household contact 
relative to the timing of exposure to the index case or relative to the onset of symptoms for 
the index case, simulations using a previously published QSP model50 were performed to 
advise on the potential impact of different treatment durations on the viral load for household 
contacts.   
Based upon these simulations, initiation of treatment for household contact nearer to the 
timing of exposure or onset of symptoms for the index case suggest some possibility for 
shorter treatment durations to be associated with an increase of the viral load of household 
contacts after completion of the treatment regimen. Although modeling simulations suggest 
some potential for an increase of the viral load of household contacts after completion of the 
treatment regimen, there is supportive evidence that a shorter treatment may be effective in 
the setting of post-exposure prophylaxis. More specifically, the viral epidemiology 
characteristics of SARS-CoV-2 are considered to be similar to the characteristics of influenza 
and recently, a 5-day treatment regimen of oseltamivir was shown to be non-inferior to a 
10-day treatment regimen in post-exposure prophylactic treatment of hospitalized patients 
exposed to influenza and not immediately isolated from the index case.51
Considering the uncertainty of the potential impact of treatment duration on providing 
effective post-exposure prophylaxis in household contacts exposed to persons with 
COVID-19, the efficacy and safety of 5- and 10-day treatment durations will be assessed in 
this study.
Preliminary safety data from study C4671001, collected up to 07 April 2021 for PART-1 and 
14 April 2021 for PART-2, showed an acceptable safety profile for single doses of 
PF-07321332 ranging from 150 mg to 1500 mg dosed alone and of 250 mg and 750 mg 
dosed with ritonavir (100 mg administered at -12h, 0h, 12h) and for 10 day repeated doses 
ranging from 75 mg BID to 500 mg BID with 100 mg ritonavir BID.
The proposed dosing regimens of 300 mg PF-07321332 coadministered with 
100 mg ritonavir q12h administered orally for 5 or 10 days is thus expected to be safe and 
efficacious.
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 
shown in the SoA for the last participant in the trial globally.
A participant is considered to have completed the study if he/she has completed all periods of 
the study, including the last visit shown in the SoA.


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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 pre-
screener for study recruitment purposes will include collection of information that reflects the 
enrollment of a diverse participant population including, where permitted under local 
regulations, age, sex, race, and ethnicity. The following eligibility 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 ≥18 years of age (or the minimum country-specific age of consent if >18) 
at the screening visit.

WOCBP may be enrolled.

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.
Type of Participant and Disease Characteristics:
2. Participants who are willing and able to comply with all scheduled visits, treatment 
plan, laboratory tests, lifestyle considerations, and other study procedures.
3. Participants who have a negative screening SARS-CoV-2 rapid antigen test result and 
who are asymptomatic household contacts (ie, living in the same residence, see 
Appendix 13) of an individual who is symptomatic and recently tested positive for 
SARS-CoV-2 (ie, index case: patient with symptomatic COVID-19). To be included 
in the study, participants must be randomized within 24 hours of their negative 
SARS-CoV-2 rapid antigen test and within 96 hours of collection of the index case’s 
first positive SARS-CoV-2 test.  
Note: The index case will have confirmation of SARS-CoV-2 infection by RT-PCR 
or other molecular or antigen tests that detect viral RNA or protein (see 
Section 8.1.5). 


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Note: Participants with a negative screening SARS-CoV-2 local rapid antigen test 
result and whose baseline RT-PCR result is returned as positive would be allowed to 
remain on treatment in the study.
Note: Asymptomatic is defined as having no signs/symptoms consistent with 
COVID-19 and symptomatic is defined as having at least 1 of the specified signs or 
symptoms consistent with COVID-19 (see Appendix 9).
Informed Consent: 
4. Capable of giving signed informed consent as described in Appendix 1, which 
includes compliance with the 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. History of SARS-CoV-2 infection as determined by a molecular test (antibody, antigen, 
or nucleic acid) from any specimen collected within 6 months before or during the 
screening visit.
2. Experiencing measured fever (documented temperature >38˚C or 100.4˚F) or other signs 
or symptoms consistent with COVID-19 (see Appendix 9).
3. Known medical history of active liver disease (other than nonalcoholic hepatic steatosis), 
including chronic or active hepatitis B or C infection, or primary biliary cirrhosis, 
ChildPugh Class B or C, or acute liver failure.
4. CKD or have known moderate to severe renal impairment.
5. Known HIV infection with viral load >400 copies/mL within the last 6 months or taking 
prohibited medications for HIV treatment (from known medical history within past 
6 months of the screening visit) (see Appendix 8).
6. Suspected or confirmed concurrent active systemic infection that may interfere with the 
evaluation of response to the study intervention.
7. Active cancer requiring treatment, with prohibited medication (Appendix 8) that must be 
administered/continued during the trial period.
8. Any comorbidity requiring hospitalization and/or surgery within 7 days prior to study 
entry, or that is considered life-threatening within 30 days prior to study entry, as 
determined by the investigator.


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9. Has hypersensitivity or other contraindication to any of the components of the study 
intervention, as determined by the investigator. 
10. Other medical or psychiatric condition including recent (within the past year) or active 
suicidal ideation/behavior or laboratory abnormality that may increase the risk of study 
participation or, in the investigator’s judgment, make the participant inappropriate for the 
study.
Prior/Concomitant Therapy:
11. Current or expected use of any medications or substances that are highly dependent on 
CYP3A4 for clearance and for which elevated plasma concentrations may be associated 
with serious and/or life-threatening events during treatment and for 4 days after the last 
dose of PF-07321332/ritonavir (see Appendix 8).
12. Concomitant use of any medications or substances that are strong inducers of CYP3A4 
are prohibited within 28 days prior to first dose of PF-07321332/ritonavir and during 
study treatment (see Appendix 8).
13. Has received approved, authorized, or investigational anti-SARS-CoV-2 mAb, 
convalescent plasma, other drugs for treatment of COVID-19, or other anti-SARS-CoV-2 
biologic products within 6 months of screening. 
14. Has received any SARS-CoV-2 vaccine (includes any level of vaccination) within 
6 months prior to screening or is expected to receive a SARS-CoV-2 vaccine or other 
approved, authorized, or investigational postexposure prophylaxis treatments through 
Day 38.
15. Is unwilling to abstain from participating in another interventional clinical study with an 
investigational compound or device, including those for COVID-19 therapeutics, through 
the End of Study visit.
Prior/Concurrent Clinical Study Experience:
16. Previous administration with an investigational drug within 30 days (or as determined by 
local requirement) or 5 half-lives preceding the first dose of study intervention used in 
this study (whichever is longer).
17. Known or prior participation in this trial or another trial involving PF-07321332.
Diagnostic Assessments:
18. Participants with known history of any of the following abnormalities in clinical 
laboratory tests (within 6 months of the screening visit):

AST or ALT level ≥2.5 X ULN;


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
Total bilirubin level ≥2 X ULN (≥ 3X ULN for Gilbert’s syndrome);

eGFR <45 mL/min/1.73 m2 within 6 months of the screening visit, using the serum 
creatinine-based CKD-EPI formula52

Absolute neutrophil count <1,000/mm3.

Note: If the investigator suspects the participant may have any of the above 
laboratory values, confirmatory tests should be performed at screening to confirm 
eligibility before the first dose of study intervention. See Appendix 2 for more details.
Other Exclusions:
19. Females who are pregnant or breastfeeding.
20. Investigator site staff or Pfizer employees directly involved in the conduct of the study, 
site staff otherwise supervised by the investigator, and their respective family members. 
5.3. Lifestyle Considerations
5.3.1. Contraception
The investigator or his or her designee, in consultation with the participant, will confirm that 
the participant has selected an appropriate method of contraception for the individual 
participant and his or her partner(s) from the permitted list of contraception methods 
(see Appendix 4 Section 10.4.4) and will confirm that the participant has been instructed in 
its consistent and correct use. At time points indicated in the 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 or if 
pregnancy is known or suspected in the participant or partner.
5.4. Screen Failures
Screen failures are defined as participants who consent to participate in the clinical study but 
are not subsequently randomly assigned to study intervention. A minimal set of screen failure 
information is required to ensure transparent reporting of screen failure participants to meet
the CONSORT publishing requirements and to respond to queries from regulatory 
authorities. Minimal information includes demography, screen failure details, eligibility 
criteria, and any SAE.
Individuals who do not meet the criteria for participation in this study (screen failure) may 
not be rescreened.  


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5.5. Criteria for Temporarily Delaying Enrollment/Randomization/Administration of 
Study Intervention
Not applicable.
6. STUDY INTERVENTION(S) AND CONCOMITANT THERAPY
Study intervention is defined as any investigational intervention(s), marketed product(s), 
placebo, medical device(s), or study procedure(s) intended to be administered to a study 
participant according to the study protocol.
For the purposes of this protocol, study intervention refers to PF-07321332 150 mg tablets 
and matching placebo and ritonavir 100 mg capsules and matching placebo.
6.1. Study Intervention(s) Administered
Study Interventions(s)
Intervention Name
PF-07321332
Placebo for 
PF-07321332
Ritonavir 
Placebo for 
Ritonavir
ARM Name
(group of patients 
receiving a specific 
treatment (or no 
treatment)
PF-07321332/ritonavir
Placebo
PF-07321332/ 
ritonavir
Placebo
Type
drug
placebo
drug
placebo
Dose Formulation
tablet
tablet
capsule
capsule
Unit Dose Strength(s)
150 mg 
0 mg
100 mg
0 mg
Dosage Level(s)
300 mg 
0 mg 
100 mg 
0 mg 
Route of 
Administration
oral
oral
oral
oral
Use
experimental
placebo
experimental
placebo
IMP or NIMP
IMP
IMP
IMP
IMP
Sourcing
Provided centrally by 
the sponsor.
Refer to the IP manual.
Provided 
centrally by 
the sponsor.
Refer to the IP 
manual.
Provided centrally by 
the sponsor.
Refer to the IP 
manual.
Provided 
centrally by 
the sponsor.
Refer to the IP 
manual.
Packaging and 
Labeling
Study intervention will 
be provided in blister 
wallets. Each wallet 
will be labeled as 
Study 
intervention 
will be 
provided in 
Study intervention 
will be provided in 
HDPE bottles. Each 
bottle will be labeled 
Study 
intervention 
will be 
provided in 


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Study Interventions(s)
required per country 
requirement. Products 
will be provided with 
blinded labels.
blister wallets. 
Each wallet 
will be labeled 
as required per 
country 
requirement.
as required per 
country requirement.
HDPE bottles. 
Each bottle 
will be labeled 
as required 
per country 
requirement.
Current/Former 
Name(s) or Alias(es)
PF-07321332
NA
ritonavir
NA
Study Arm(s)
Arm Title
PF-07321332/ritonavir 
(5-Day)
Placebo 
PF-07321332/ritonavir 
(10-Day)
Arm Type
experimental 
placebo
experimental 
Arm Description
Participants will receive 
PF-07321332/ritonavir 
300 mg/100 mg q12h from 
Day 1 through Day 5 
followed by 0 mg/0 mg 
q12h from Day 6 through 
Day 10.
Participants will receive 
0 mg/0 mg q12h for 
10 days from Day 1 
through Day 10.
Participants will receive 
PF-07321332/ritonavir
300 mg/100 mg q12h for 
10 days from Day 1 
through Day 10.
Associated 
Intervention 
Labels
PF-07321332/ritonavir and 
Placebo for PF-07321332 
/Placebo for Ritonavir
Placebo for PF-07321332 
and Placebo for Ritonavir
PF-07321332/ritonavir
6.1.1. Administration
PF-07321332 150 mg tablet or placebo for PF-07321332 will be administered with ritonavir 
100 mg or placebo for ritonavir capsule for 10 days. Participants will be dispensed:

2 tablets of PF-07321332 150 mg or placebo for PF-07321332 (single tablet from 
each blister cell, one at a time) q12h

1 capsule of ritonavir 100 mg or placebo for ritonavir q12h.
Participants should take the first dose of study intervention on Day 1, preferably during the 
in-person visit; that is, participants should take 2 tablets of PF-07321332 150 mg or placebo 
and 1 capsule of ritonavir 100 mg or placebo at the same time and no more than 10 minutes 
apart. To allow the participant to select a convenient 12-hour dosing schedule, timing of 
dosing for the second dose may be adjusted slightly, but should be taken at least 4 hours but 
no later than 12 hours after the first dose. The remaining doses should be taken every 12 
hours [±30 minutes]. Participants will swallow the study intervention whole and will not 


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manipulate or chew the study intervention prior to swallowing. Participants may take the 
study intervention with or without food. Taking study intervention with food may improve 
tolerability. Refer to the IP Manual for additional dosing and administration instructions.
If a dose is delayed, it should be taken as soon as possible, but no later than 4 hours before 
the next scheduled dose. Participants should not double up the next dose of study 
intervention in order to “make up” what had been missed. Dosing should be stopped at the 
end of the treatment period. Any remaining tablets and/or capsules at the end of 10 days (or 
11 days if only one dose was administered on Day 1) should be returned.
6.2. Preparation, Handling, Storage, and Accountability
1. The investigator or designee must confirm appropriate temperature conditions 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 or administer study intervention. 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 for 
all site storage locations upon return to business. Study intervention may be shipped 
by courier to study participants if permitted by local regulations and in accordance 
with storage and transportation requirements for study intervention. Pfizer does not 
permit the shipment of study intervention by mail. The tracking record of shipments 
and the chain of custody of study intervention must be kept in the participant’s source 
documents/medical records. For investigational sites using ground transportation to 
deliver study intervention to participants, stability data reveal that if the total duration 
of transit is less than 24 hours, temperature monitoring is not required.
3. Any excursions from the study intervention label storage conditions should be 
reported to Pfizer upon discovery along with any actions taken. The site should 
actively pursue options for returning the study intervention to the storage conditions 
described in the labeling, 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 definition of an excursion 
and information the site should report for each excursion will be provided to the site 
in the IP manual.
4. Any storage conditions stated in the SRSD will be superseded by the storage 
conditions stated on the label.
5. Study interventions should be stored in their original containers.


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6. Site staff will instruct participants on the proper storage requirements for take-home 
study intervention.
7. The investigator, institution, or the head of the medical institution (where applicable) 
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. All study intervention that is 
taken home by the participant, both used and unused, must be returned to the 
investigator by the participant. Returned study intervention must not be redispensed 
to the participants.
8. Further guidance and information for the final disposition of unused study 
interventions are provided in the IP manual. 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 IP manual.
6.2.1. Preparation and Dispensing
A qualified staff member will dispense the study intervention using the IRT system via 
unique container numbers in the bottles and blister cards provided, in quantities appropriate 
according to the SoA. A second staff member will verify the dispensing. The participant 
should be instructed to maintain the product in the bottle and blister cards, as appropriate 
provided throughout the course of dosing and return the bottle and blister cards, as 
appropriate to the site at the next study visit.
Study intervention and placebo will be dispensed by qualified blinded site personnel 
according to the IP manual. The study intervention will be administered in a blinded fashion 
to the participants.
Study intervention will be dispensed as noted in the SoA.
6.3. Measures to Minimize Bias: Randomization and Blinding
6.3.1. Allocation to Study Intervention
Allocation of participants to treatment groups will proceed through the use of an IRT system 
(IWR). The site personnel (study coordinator or specified designee) will be required to enter 
or select information including but not limited to the user’s ID and password, the protocol 
number, and the participant number. The site personnel will then be provided with a 
treatment assignment, randomization number, and DU or container number when study 
intervention is being supplied via the IRT system. The IRT system will provide a 


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confirmation report containing the participant number, randomization number, and DU or 
container number assigned. The confirmation report must be stored in the site’s files. 
Study intervention will be dispensed at the study visit summarized in the SoA. 
Returned study intervention must not be redispensed to the participants.
The study-specific IRT reference manual and IP manual will provide the contact information 
and further details on the use of the IRT system.
6.3.2. Blinding of the Sponsor
The majority of sponsor staff will be blinded to study intervention allocation. There will be 
an unblinded team supporting the interactions with, and the analyses for, the E-DMC while 
the study is ongoing. The team will consist of clinicians, statistician(s), and programmer(s) 
and will be separate from the blinded members of the study team.
The study will be unblinded at the group and participant level after all participants complete 
the Day 38 visit (or ET prior to Day 38 visit). However, if efficacy is demonstrated at the 
interim analysis, an unblinded submissions team may be assembled to prepare unblinded 
analyses and documents to support regulatory activities that may be required while the study 
is ongoing.
Details of the unblinded sponsor staff supporting the E-DMC and the timing of unblinding 
will be outlined in the Unblinding Plan.
6.3.3. Breaking the Blind 
The IRT will be programmed with blind-breaking instructions. In case of an emergency, the 
investigator has the sole responsibility for determining if unblinding of a participant’s 
treatment assignment is warranted. Participant safety must always be the first consideration 
in making such a determination. If the investigator decides that unblinding is warranted, the 
investigator should make every effort to contact the sponsor prior to unblinding a 
participant’s treatment assignment unless this could delay further management of the 
participant. If a participant’s treatment assignment is unblinded, the sponsor must be notified 
within 24 hours after breaking the blind. The date and reason that the blind was broken must 
be recorded in the source documentation and CRF.
The study-specific IRT reference manual and IP manual will provide the contact information 
and further details on the use of the IRT system.
6.4. Study Intervention Compliance
Participants will be issued an electronic study intervention diary (ie, participant-completed 
study intervention log) or may use an application installed on their device and will be 
educated to record the date and time of their study intervention dosing preferably at the time 
of first dose.


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Compliance with study intervention will be assessed by delegated site personnel through the 
accounting of unused study intervention returned by the participant at the study visits, review 
of the electronic study intervention diary, and discussion with the participant.
Study intervention administration, including any deviation(s) from the prescribed dosage 
regimen, should be recorded in the CRF.
A record of the number of study intervention tablets/capsules dispensed to and taken by each 
participant must be maintained and reconciled with study intervention and compliance 
records. Intervention start and stop dates, including dates for intervention delays and/or dose 
reductions, will also be recorded in the CRF.
The following noncompliance cases will be considered medication errors 
(See Section 8.3.10):

Participants interrupting study intervention for 2 consecutive doses;

Participants taking either PF-07321332 or ritonavir alone for 2 consecutive doses.

Participants who have an overall study intervention compliance of <80% or >115%. 
In addition to the above-listed medication errors, any deviation from protocol-specified 
dosing (eg, missed single dose or partial dose) should be recorded as a protocol deviation and 
the investigator or designee is to counsel the participant and ensure steps are taken to 
improve compliance.
6.5. Dose Modification 
Dose modification for PF-07321332/ritonavir is not allowed.
6.6. Continued Access to Study Intervention After the End of the Study
No intervention will be provided to study participants at the end of their study participation.
6.7. Treatment of Overdose
For this study, any dose of PF-07321332 greater than 900 mg or ritonavir greater than 
300 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 medical monitor within 24 hours.
2. Closely monitor the participant for any AEs/SAEs and laboratory abnormalities for at 
least 5 half-lives or 28 calendar days after the overdose of study intervention 
(whichever is longer).


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3. Document the quantity of the excess dose as well as the duration of the overdose in 
the CRF.
4. Overdose is reportable to Pfizer Safety only when associated with an SAE.
5. Obtain a blood sample for PK analysis within 1 day from the date of the last dose of 
study intervention if requested by the 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 medical monitor based on the clinical evaluation of the participant.  
6.8. Concomitant Therapy
Hormonal contraceptives that meet the requirements of this study are allowed to be used in 
participants who are WOCBP (see Appendix 4).
Permitted During the Study
All participants who develop confirmed COVID-19 may continue study intervention and 
may receive SoC therapy including products authorized under an Emergency Use 
Authorization (or equivalent in countries where the study is being conducted) where 
appropriate, in addition to study intervention, unless listed as prohibited medication (see 
below and Appendix 8). Discontinuation of study intervention is at the investigator’s 
discretion. However, if the investigator decides to administer SoC therapy for COVID-19 
that is prohibited for DDI reasons, the participant must discontinue study intervention but 
should continue in the study. SoC therapy is defined as any therapy that is approved and used 
as indicated by the local regulatory authorities (including approvals for emergency use, 
compassionate use, or through similar regulatory guidance), or any therapy as recommended 
by a relevant national (or a reputable international) scientific body (eg, WHO, ECDC, CDC, 
NIH). Sites should consult with the sponsor if a new SoC option becomes available after 
study initiation. The investigator should ensure that any recommended SoC therapy is not a 
strong inducer of CYP3A4 or highly dependent on CYP3A4 for clearance if it is planned to
be administered concomitantly with study intervention.
In countries in which therapiesare are authorized or approved for the treatment of 
COVID-19, all participants who develop confirmed COVID-19 disease will be referred 
locally for treatment as deemed appropriate by the investigator (see above) and local 
guidelines. This referral should be documented. Notwithstanding, this treatment is not 
mandatory for participation in this study.
Prohibited During the Study
Participants may not receive therapeutics, drugs, or vaccines described in the exclusion 
criteria (see Section 5.2), antiviral treatment for COVID-19 (eg, molnupiravir, Paxlovid) or 
listed as prohibited medications (see Appendix 8) during the study period with the exceptions
described above for participants who develop confirmed COVID-19.


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PF-07321332 and ritonavir are both primarily metabolized by cytochrome P450 (CYP) 3A4. 
Therefore, concomitant use of any medications or substances that are strong inducers of 
CYP3A4 are prohibited within 28 days prior to dosing of study intervention and during study 
treatment.
Additionally, PF-07321332 and ritonavir are inhibitors of CYP3A4. Therefore, medications 
highly dependent on CYP3A4 for clearance and for which elevated plasma concentrations 
may be associated with serious and/or life-threatening events are not permitted during dosing 
of PF-07321332/ritonavir and for 4 days after the last dose of PF-07321332/ritonavir. 
Because ritonavir 100 mg every 12 hours is being used to boost the exposure of 
PF-07321332, no additional DDIs are expected other than those associated with ritonavir 
100 mg q12h based on in vitro assessments.
A nonexhaustive list of prohibited and precautionary medications is provided in Appendix 8. 
If a medication is not listed, it should not automatically be assumed it is safe to coadminister. 
Appropriately qualified site staff will review all concomitant medications to determine if they 
are strong inducers of CYP3A4 or highly dependent on CYP3A4 for clearance, and thus 
prohibited.
6.8.1. Rescue Medicine
Standard medical supportive care may be provided to manage AEs.
7. DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL
7.1. Discontinuation of Study Intervention
It may be necessary for a participant to permanently discontinue study intervention. Reasons 
for permanent discontinuation of study intervention include the following:

AE (including Grade 3 severity or greater and considered by the investigator to be 
related to study intervention);

SAE considered by the investigator to be related to the study intervention;

Requirement for prohibited concomitant medication;

Death;

Pregnancy; 

Study terminated by sponsor;

Withdrawal by participant;

Hospitalization during the active treatment period;


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
Miss more than 2 consecutive doses of study intervention.
Note that discontinuation of study intervention does not represent withdrawal from the study.
If study intervention is permanently discontinued, the participant will remain in the study to 
be evaluated for all subsequent scheduled assessments. See the SoA for data to be collected 
at the time of discontinuation of study intervention and follow-up for any further evaluations 
that need to be completed.
In the event of discontinuation of study intervention, it must be documented on the 
appropriate CRF/in the medical records whether the participant is discontinuing further 
receipt of study intervention or also from study procedures, posttreatment study follow-up, 
and/or future collection of additional information.
7.1.1. Potential Cases of Decreased eGFR
If postcreening eGFR is <45 mL/min/1.73m2, the participant will be instructed to discontinue 
any remaining study intervention doses as soon as study staff become aware of laboratory 
results.
7.2. Participant Discontinuation/Withdrawal From the Study 
A participant may withdraw from the study at any time at his/her own request. Reasons for 
discontinuation from the study include the following:

Refused further study procedures;

Lost to follow-up;

Death;

Study terminated by sponsor;
At the time of discontinuing from the study, if possible, an early discontinuation visit should 
be conducted. See the SoA for assessments to be collected at the time of study 
discontinuation and follow up and for any further evaluations that need to be completed. 
The early discontinuation visit applies only to participants who are enrolled/randomized and 
then are prematurely withdrawn from the study. Participants should be questioned regarding 
their reason for withdrawal.  
If a participant withdraws from the study, he/she 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 should be performed and no 


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additional data should 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 him or her or persons previously authorized by the participant to provide this 
information. Participants should notify the investigator in writing of the decision to withdraw 
consent from future follow up, whenever possible. The withdrawal of consent should be 
explained in detail in the medical records by the investigator, as to whether the withdrawal is 
only from further receipt of study intervention or also from study procedures and/or 
posttreatment study follow up, and entered on the appropriate CRF page. In the event that 
vital status (whether the participant is alive or dead) is being measured, publicly available 
information should be used to determine vital status only as appropriately directed in 
accordance with local law.
7.3. Lost to Follow-Up 
A participant will be considered lost to follow-up if he or she repeatedly fails to return for 
scheduled visits and is unable to be contacted by the study site.
The following actions must be taken if a participant fails to be available 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, he/she will be considered to have 
withdrawn from the study. 
8. STUDY ASSESSMENTS AND 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.


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Safety issues should be discussed with the sponsor immediately upon occurrence or 
awareness to determine whether the participant should continue or discontinue study 
intervention.
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.
Procedures conducted as part of the participant’s routine clinical management (eg, blood 
count) and obtained before signing of the ICD may be utilized for screening or baseline 
purposes provided the procedures met the protocol-specified criteria and were performed 
within the time frame defined in the SoA.
In the event a participant is hospitalized, study assessments should be performed as feasible. 
Procedures not performed due to hospitalizations would not be considered protocol 
deviations.
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 may 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 he or she has 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.
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 
183 mL. There will be an additional optional 1 mL of blood collected for a subset of 
participants who agree to self collect an optional PK sample (Tasso device). 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.
8.1. Efficacy Assessments
8.1.1. Participant Diary
Participants will be provided an electronic handheld device or application to use on their own 
device to record daily COVID-19 signs and symptoms, study intervention administration, 
and PRO assessments in the study diary. 


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Participants will receive daily reminders to complete entries on their own as specified in the 
SoA. The diary should be completed at approximately the same time every day. Staff will 
review the participant’s study diary online as specified in the SoA.
The diary allows recording of these assessments only within a fixed time window (eg, 24h), 
thus providing an accurate representation of the participant’s experience at that time. The 
participant is able to make revisions to incorrect entries before pressing the save or submit 
button. In the event that a participant becomes aware of an error in data after the entry is 
saved, a change to the diary data may only be made by the investigator submitting a data 
clarification form. Data reported in the participant diary will be transferred electronically to a 
third-party vendor, where they will be available for review by investigators and the sponsor 
or delegate at all times via an internet-based portal.
8.1.2. Daily Signs and Symptoms of COVID-19
On Day 1, participants will complete the study diary before receiving study intervention. 
Participant assessment of COVID-19-related symptoms should be recorded at approximately 
the same time each day as specified in the SoA and as described in Section 8.1.1.
COVID-19-related symptoms will be evaluated in accordance with FDA guidelines 
(Appendix 9).53 Participants will record a daily severity rating of their symptoms  over the 
past 24 hours based on a 4-point scale in which 0 is reported if no symptoms were present; 1 
if mild; 2 if moderate; and 3 if severe. 
Vomiting and diarrhea will each be rated on a 4-point frequency scale where 0 is reported for 
no occurrence, 1 for 1 to 2 times, 2 for 3 to 4 times, and 3 for 5 or greater. 
Sense of smell and sense of taste will each be rated on a 3-point Likert scale where 0 is 
reported if the sense of smell/taste was the same as usual, 1 if the sense of smell/taste was 
less than usual, and 2 for no sense of smell/taste. Investigators will instruct participants to 
contact them if they develop signs/symptoms of COVID-19 – to inform them of their 
symptoms and to schedule a COVID-19 Signs/Symptoms Onset visit as soon as possible, but 
no later than 2 days after symptom onset, as specified in the SoA. Investigators will instruct 
symptomatic participants to follow local public health measures to reduce the spread of 
COVID-19.
8.1.3. COVID-19 Related Medical Visit Details
Details of participants’ COVID-19-related medical visits (ie, hospitalization, practitioner’s
office, home healthcare services, telemedicine, urgent care, emergency room ≤24h, 
extended care facility stay) will be collected during study visits, including level of care 
(ICU status) and dates of utilization, including admission and discharge, as applicable. 
If the participant has a COVID-19 Signs/Symptoms Onset visit, this must be reported as a 
COVID-19 related medical visit.


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Hospitalization is defined as >24h of acute care, in a hospital or similar acute care facility, 
including Emergency Rooms or temporary facilities instituted to address medical needs of 
those with severe COVID-19 during the COVID-19 pandemic. This includes specialized 
acute medical care unit within an assisted living facility or nursing home. This does not 
include hospitalization for the purpose of public health or clinical trial execution.
8.1.4. Oxygen Support Details
Type of oxygen support (eg, oxygen supplementation received at home, mechanical 
ventilation received in hospital) will be collected.
8.1.5. Index Case Characteristics
Index cases will be determined through interview with the C4671006 study participant. The 
index case may be a participant in the C4671002 or C4671005 studies, but this is not 
required. However, minimum data as outlined below must be collected for confirmation of 
the C4671006 study participant’s status as a household contact and the exposure period.
The following information about the index case will be collected through interview with the 
study participant: 

Date of index case SARS-CoV-2 infection diagnosis (sample collection date of first 
positive test);

Date of onset of COVID-19 symptoms.
The following information about the index case will be collected through interview with the 
study participant to characterize the exposure period. For index cases who are participants in 
the C4671002 or C4671005 study, this information will be collected in those studies. If the 
index case is not a participant in the C4671002 or C4671005 study, this information will only 
be collected if available and permitted by local laws and regulations:

Age; 

Whether the index case received vaccination or treatment for COVID-19 prior to or 
during the exposure period;

Whether the index case was isolated from the study participant after the initial 
exposure;

Relationship of the index case to the study participant (spouse, parent, son/daughter, 
etc);

Does the index case sleep in the same room as the study participant.


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8.1.6. Household Characteristics 
Household characteristics will be determined through interview with the C4671006 study 
participant and may be updated during the study. This assessment will support the 
characterization of the exposure period and may be relevant for interpretation of efficacy 
data. The household characteristics include:
•
Number of people living in household;
•
Number of additional confirmed SARS-CoV positive or suspected (ie, symptomatic) 
household members;
•
Number of other household contacts in this residence who are participants in this 
study or receiving another COVID-19 treatment.
8.1.7. PRO Assessments
8.1.7.1. WPAI
COVID-19 impacts manual and office-based work, and results in missed work due to illness 
or quarantine and loss in productivity.54 The WPAI-GH is being implemented for COVID-19 
(ie, WPAI-COVID-19) in order to evaluate change from baseline in work burdens. The 
WPAI-GH has demonstrated validity, reliability and sufficient predictive value to measure 
the impact of disease on absenteeism, presenteeism, and overall productivity in a manner that 
can also be monetized.55
 
 
 
 
 
 
 
8.1.7.2. EQ-5D-5L Scale
The EQ-5D is a validated, standardized, generic instrument that is a preference-based health 
related quality of life questionnaire in cost effectiveness and HTA.56-58 Recently, a version 
was developed called EQ-5D-5L with 5 response levels on each dimension.56-62
Measurement properties of the EQ-5D-5L demonstrated to be a valid version of the 3 level 
questionnaire that improved measurements by adding discriminatory power, reducing the 
ceiling, and establishing convergent and known groups validity.56,58,60,61 Both the EuroQol 
EQ-5D-3L and EQ-5D-5L versions are well established instruments used to measure health 
CCI


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states and utilities in various diseases areas and assess mobility, self care, usual activities, 
pain/discomfort, anxiety/depression and health status using a VAS.59,63 The EQ-5D-5L 
should be completed as described in the SoA.
8.1.7.3. Global Impression Questions
For participants who report COVID-19 symptoms in the diary, 3 additional questions will be 
included in the ePRO to assess patient-reported global impression items: a) return to usual 
health; b) return to usual activities; and c) overall COVID-19-related symptoms.53
8.2. Safety Assessments
Planned time points for all safety assessments are provided in the SoA. Unscheduled clinical 
laboratory measurements may be obtained at any time during the study to assess any 
perceived safety issues.
8.2.1. Medical History
Medical history (including prior documented infection) and demographics will be collected 
at screening. Smoking status will be collected. Complete medication history of all 
prescription or nonprescription drugs (including vaccinations), and dietary and herbal 
supplements taken within 30 days prior to the planned first dose will be collected.
Risk factors for the study participant developing severe COVID-19 illness will be recorded 
(Appendix 11).
8.2.2. Height and Weight
Height and weight will also be measured and recorded at screening. Height may be self-
reported.
8.2.3. Targeted Physical Examinations
A targeted physical examination will include, at a minimum, cardiopulmonary assessments. 
Investigators should pay special attention to any previously identified or new AE/targeted 
condition that the participant has experienced.
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 8.3.1 to 8.3.3.
8.2.4. Vital Signs
Temperature, pulse rate, respiratory rate, and blood pressure will be assessed as specified in 
the SoA. In addition to this, participants attending a COVID-19 Signs/Symptoms Onset visit 
will also have oxygen saturation measured.


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Blood pressure and pulse rate measurements will be assessed with the participant in the 
supine or seated position with their feet on the floor when possible with a completely 
automated device. It is recommended that the same position should be used for a participant 
throughout the study duration. Manual techniques will be used only if an automated device is 
not available.
Blood pressure and pulse rate measurements should be preceded by at least 5 minutes of rest 
for the participant in a quiet setting without distractions (eg, television, cell phones).
Investigators will supply each participant with a thermometer and will instruct them to 
measure their temperature if they are feeling feverish. Investigators will instruct participants 
to contact them if they develop a fever (>100.4°F or >38°C), to inform them of their fever and 
to schedule a COVID-19 Signs/Symptoms Onset visit as soon as possible but no later than 
2 days after symptom onset, as specified in the SoA. Investigators will instruct participants 
with fever to follow local public health measures to reduce the spread of COVID-19.
Each participant will also be supplied with a pulse oximeter to be used at home as directed by 
the investigator. This may include monitoring of oxygen saturation for participants who 
develop COVID-19 symptoms and will be implemented at the discretion of the investigator. 
The investigator will instruct the participant regarding use of the pulse oximeter and what 
value should trigger a call to the investigator.
Vital signs are to be taken before blood collection for laboratory tests.
8.2.5. Clinical Safety Laboratory Assessments
See Appendix 2 for the list of clinical safety laboratory tests to be performed and the SoA for 
the timing and frequency. All protocol-required laboratory assessments, as defined in 
Appendix 2, must be conducted in accordance with the laboratory manual and the SoA. 
Unscheduled clinical laboratory measurements may be obtained at any time during the study 
to assess any perceived safety issues.  
Laboratory safety parameters will be graded according to the Division of AIDS (DAIDS) 
Table for Grading the Severity of Adult and Pediatric Adverse Events,64 version 2.1. The 
investigator must review the laboratory report, document this review, and record any 
clinically relevant changes occurring during the study in the AE section of the CRF. 
Clinically significant abnormal laboratory findings are those which are not associated with 
the underlying disease, unless judged by the investigator to be more severe than expected for 
the participant's condition.
If a baseline laboratory result meets Section 5.2 exclusionary laboratory values and the 
participant is still receiving study treatment, the investigator should contact the Medical 
Monitor. All laboratory tests with values considered clinically significantly abnormal during 
participation in the study or within 28 days after the last dose of study intervention should be 
repeated until the values return to normal or baseline or are no longer considered clinically 
significant by the investigator or medical monitor.


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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 
drug-induced liver injury.
8.2.6. Pregnancy Testing
Pregnancy tests may be urine or serum tests, but 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. 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.
If a participant requiring pregnancy testing cannot visit a local laboratory, a home urine 
pregnancy testing kit with a sensitivity of at least 25 mIU/mL may be used by the participant 
to perform the test at home, if compliant with local regulatory requirements. The pregnancy 
test outcome should be documented in the participant’s source documents/medical records. If 
the pregnancy test is positive, the EDP should be reported (Section 8.3.5.1). Confirm that the 
participant is adhering to the contraception method(s) required in the protocol.
8.3. 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 8.3.1, 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.


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8.3.1. 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 the participant’s participation in the study (ie, before undergoing 
any study-related procedure and/or receiving study intervention), through and including a 
minimum of 28 calendar days, except as indicated below, after the last administration of the 
study intervention. 
Follow-up by the investigator continues throughout and after the active collection period and 
until the AE or SAE or its sequelae resolve or stabilize at a level acceptable to the 
investigator.
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 he/she 
considers 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.
8.3.1.1. Reporting SAEs to Pfizer Safety
All SAEs occurring in a participant during the active collection period as described in 
Section 8.3.1 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 it being available.
8.3.1.2. 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 8.3.1, 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.


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8.3.2. 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.
8.3.3. 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 given in Appendix 3.
8.3.4. Regulatory Reporting Requirements for SAEs
Prompt notification by the investigator to the sponsor of an SAE is essential so that legal 
obligations and ethical responsibilities toward the safety of participants and the safety of a 
study intervention under clinical investigation are met.
The sponsor has a legal responsibility to notify both the local regulatory authority and other 
regulatory agencies about the safety of a study intervention under clinical investigation. The 
sponsor will comply with country-specific regulatory requirements relating to safety 
reporting to the regulatory authority, IRBs/ECs, and investigators.
Investigator safety reports must be prepared for SUSARs according to local regulatory 
requirements and sponsor policy and forwarded to investigators as necessary.
An investigator who receives SUSARs or other specific safety information (eg, summary or 
listing of SAEs) from the sponsor will review and then file it along with the SRSD(s) for the 
study and will notify the IRB/EC, if appropriate according to local requirements.
8.3.5. 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 


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exposure include healthcare providers, family members, and others who may be exposed. An 
environmental exposure may include exposure during pregnancy, exposure during 
breastfeeding, and occupational exposure.
Any such exposure to the study intervention under study are reportable to Pfizer Safety 
within 24 hours of investigator awareness.
8.3.5.1. Exposure During Pregnancy
An EDP occurs if: 

A female participant is found to be pregnant while receiving or after discontinuing 
study intervention. 

A male participant who is receiving or has discontinued study intervention exposes a 
female partner prior to or around the time of conception.

A female is found to be pregnant while being exposed or having been exposed to 
study intervention due to 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.

A male family member or healthcare provider who has been exposed to the study 
intervention by ingestion then exposes 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 or a 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 a minimum 
of 28 calendar days after the last administration of study intervention.

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.


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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;

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.
8.3.5.2. Exposure During Breastfeeding
An exposure during breastfeeding occurs if: 

A female participant is found to be breastfeeding while receiving or after 
discontinuing study intervention.

A female is found to be breastfeeding while being exposed or having been exposed to 
study intervention (ie, environmental exposure). An example of environmental 
exposure during breastfeeding is a female family member or healthcare provider who 
reports that she is breastfeeding after having been exposed to the study intervention 
by ingestion.


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The investigator must report exposure during breastfeeding 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 exposure during 
breastfeeding 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 exposure during breastfeeding report is not created when a Pfizer drug specifically 
approved for use in breastfeeding women (eg, vitamins) is administered in accord with 
authorized use. However, if the infant experiences an SAE associated with such a drug, the 
SAE is reported together with the exposure during breastfeeding.
8.3.5.3. 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.
8.3.6. Cardiovascular and Death Events
Not applicable.
8.3.7. Disease-Related Events and/or Disease-Related Outcomes Not Qualifying as AEs 
or SAEs
Not applicable.
8.3.8. Adverse Events of Special Interest
AESIs include hemodynamic events, inflammatory events, and thyroid-related events.
Adverse events of special interest (AESIs) are examined as part of routine safety data review 
procedures throughout the clinical trial and as part of signal detection processes.
All AESIs must be reported as an AE or SAE following the procedures described in 
Sections 8.3.1 through 8.3.4. An AESI is to be recorded as an AE or SAE on the CRF. In 
addition, an AESI that is also an SAE must be reported using the CT SAE Report Form. 
8.3.8.1. Lack of Efficacy
The investigator must report signs, symptoms, and/or clinical sequelae resulting from lack of 
efficacy. Lack of efficacy or failure of expected pharmacological action is reportable to 
Pfizer Safety only if associated with an SAE.  


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8.3.9. Medical Device Deficiencies
Not applicable. 
8.3.10. 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.
Exposures to the study intervention under study may occur in clinical trial settings, such as 
medication errors.
Safety Event
Recorded on the CRF
Reported on the CT SAE Report 
Form to Pfizer Safety Within 
24 Hours of Awareness
Medication errors All (regardless of whether 
associated with an AE)
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.

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

The administration of study intervention consistent with the medication error 
descriptions in Section 6.4.
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.
In the event of a medication dosing error, the sponsor should be notified within 24 hours.
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 


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applicable, any associated AE(s), serious and nonserious, are recorded on the AE page of the 
CRF.
Medication errors should be reported to Pfizer Safety within 24 hours on a CT SAE Report 
Form only when associated with an SAE.
8.4. Pharmacokinetics
Blood samples of approximately 4 mL, to provide a minimum of 2 mL plasma, will be 
collected for measurement of plasma concentrations of PF-07321332 as specified in the SoA. 
Self-collected whole blood (Tasso device) may also be collected and used to measure 
concentrations of PF-07321332. 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 obtained ≤1 hour outside the scheduled nominal sampling time windows will not be 
captured as a protocol deviation, as long as the exact time of the collection is noted on the 
source document and the CRF. This protocol deviation window does not apply to samples to 
be collected more than 10 hours after dose administration at outpatient/follow-up visits with 
visit windows.
Samples will be used to evaluate the PK of PF-07321332. Samples collected for analyses of 
PF-07321332 concentration may also be used to evaluate safety or efficacy aspects related to 
concerns arising during or after the study, for metabolite identification and/or evaluation of 
the bioanalytical method, or for research related to the study intervention(s) and COVID-19. 
Samples may also be used to evaluate the PK of ritonavir.
Genetic analyses will not be performed on these samples unless consent for this was included 
in the informed consent. Participant confidentiality will be maintained.
Samples collected for measurement of concentrations of PF-07321332 will be analyzed using 
a validated analytical method in compliance with applicable SOPs.
The PK samples must be processed and shipped as indicated in the instructions provided to 
the investigator site to maintain sample integrity. Any deviations from the PK sample 
handling procedure (eg, sample collection and processing steps, interim storage or shipping 
conditions), including any actions taken, must be documented and reported to the sponsor. 
On a case-by-case basis, the sponsor may make a determination as to whether sample 
integrity has been compromised.
Drug concentration information that would unblind the study will not be reported to 
investigator sites or blinded personnel until the study has been unblinded.
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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.
8.6. Biomarkers
Collection of samples for biomarker research is also part of this study. 
The following samples for biomarker research are required and will be collected from all 
participants in this study as specified in the SoA:
•
Nasal swab will be collected to measure SARS CoV-2 viral load by RT-PCR. 
•
Nasal viral load samples may be used for SARS CoV-2 viral sequencing.
•
Nasal viral load samples may be used for SARS CoV-2 infectivity assays and 
phenotypic analyses. 
•
10 mL blood optimized for plasma may be utilized for proteomics and immunologic 
studies.
8.6.1. Specified Gene Expression (RNA) Research
Specified gene expression (RNA) research is not included in this study.
8.6.2. Specified Protein Research 
Blood will be collected for plasma biomarkers as specified in the SoA and may be used for 
proteomics, immunologic studies, as well as markers associated with coagulation, organ or 
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endothelial cell dysfunction. Storage and shipping instructions will be in accordance with the 
laboratory manual.
8.6.3. Specified Metabolomic Research
Specified metabolomic research is not included in this study.
8.6.4. SARS-CoV-2 Assessments
8.6.4.1. Rapid Antigen Assessments
Rapid antigen testing for SARS-CoV-2 will be performed as described in the SoA. 
Investigator sites will use test kits that are authorized for use in this study.
8.6.4.2. Viral Load Assessments
The first nasal swab will be self collected by the participant under observation by site staff to 
ensure correct collection methodology. Thereafter, nasal swabs will be collected by the HCP 
or self collected by the participant as specified in the SoA. On the days where there is an in-
person visit, the nasal swab should be collected by the HCP and the participants instructed to 
not collect the nasal swab prior to the visit. If, for any reason, a nasal swab was already 
collected in the morning of an in person visit, another swab for viral load assessment should 
not be collected on the same day and that would not be considered a protocol deviation.
Additional swabs may be required at the visit on days for which an in-person visit occurs (eg, 
COVID-19 Signs/Symptoms Onset visit), which should be collected by the HCP if not 
already self collected by the participant. 
Results of centrally read nasal swabs will not be available to the investigator. Therefore if 
COVID-19 symptoms occur during the study, investigators will make treatment decisions 
based on assessment of the participant’s symptoms, rapid antigen testing results, other locally 
available testing results (eg, RT-PCR) obtained and used outside this trial, and other relevant 
factors determined in the investigator’s clinical judgment. Results of these local tests will be 
recorded on the CRF.
Nasal swabs will be collected per the SoA, and may be analyzed to measure SARS-CoV-2
RNA by RT-PCR.
 
Storage and shipping instructions will be in accordance with the laboratory manual.
8.6.5. Assessments for Other Respiratory Pathogens
Nasal swabs that are collected as specified in the SoA may be sent to be analyzed for 
presence of SARS-CoV-2. Samples from symptomatic participants negative for SARS-CoV-
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2 will undergo qualitative assessment for presence of influenza or RSV. As stated above, 
results of centrally read nasal swabs may not be immediately available to the investigator. 
Participants who experience symptoms consistent with COVID-19 after the nasal swab 
collection period described in the SoA will undergo local testing for SARS-CoV-2 infection 
and other respiratory infections, per local standard of care. Results of these tests will be 
recorded in the CRF.
8.6.6. Retained Research Samples for Biomarkers
These Retained Research Samples will be collected in this study:

10 mL blood optimized for serum isolation Prep B2
Retained Research Samples will be collected as local regulations and IRB/ECs allow 
according to the SoA.  
Retained Research Samples may be used for research related to the study intervention(s) and 
COVID-19. Genes and other analytes (eg, proteins, RNA, nondrug metabolites) may be 
studied using the retained samples. 
See Appendix 5 for information regarding genetic research. Details on processes for 
collection and shipment of these samples can be found in the laboratory manual. 
8.7. Immunogenicity Assessments
Immunogenicity assessments are not included in this study.
8.8. Health Economics
Health economics/medical resource utilization and health economics parameters will be 
evaluated in this study (Section 8.1.2. and Section 8.1.3).
9. STATISTICAL CONSIDERATIONS
Detailed methodology for summary and statistical analyses of the data collected in this study 
is outlined here and further detailed in a SAP, which will be maintained by the sponsor. The 
SAP may modify what is outlined in the protocol where appropriate; however, any major 
modifications of the primary endpoint definitions or their analyses will also be reflected in a 
protocol amendment.
9.1. Statistical Hypotheses
The primary hypothesis is to test, in participants who have a negative RT-PCR at baseline, 
whether or not the risk ratio between 5-day and 10-day regimens of PF-07321332/ritonavir 


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versus placebo in the proportion of participants who develop symptomatic RT-PCR or rapid 
antigen test-confirmed infection through Day 14 is equal to 1:
Null hypothesis:  H0    
గುಷషబళయమభభయయమ
గ೛೗ೌ೎೐್೚
ൌ1           
Alternative hypothesis: Ha    
గುಷషబళయమభభయయమ
గ೛೗ೌ೎೐್೚
്1          
Where π PF-07321332 versus πplacebo are the symptomatic infection rate through Day 14 for 
5-day and 10-day regimens of PF-07321332 /ritonavir versus placebo groups in participants 
who have a negative RT-PCR result at baseline.
9.1.1. Estimands
9.1.1.1. Primary Estimand/Co-Primary Estimands
The primary estimand is the risk reduction between 5-day and 10-day regimens of 
PF-07321332/ritonavir versus placebo in the proportion of individuals who develop 
symptomatic RT-PCR or rapid antigen test-confirmed SARS-CoV-2 infection through 
Day 14 in adults who have a negative RT-PCR result at baseline and are household contacts 
of an individual with symptomatic COVID-19. This will be estimated without regard to 
adherence to randomized treatment.
9.1.1.2. Secondary Estimand
The estimand associated with the secondary objective is  
•
The risk reduction between 5-day and 10-day regimens of PF-07321332/ritonavir versus 
placebo in the proportion of individuals who develop symptomatic RT-PCR or rapid 
antigen test-confirmed SARS CoV-2 infection through Day 14 in adults who have a 
negative RT-PCR result at baseline, who are at increased risk of severe COVID-19 illness, 
and are household contacts of an individual with symptomatic COVID-19. This will be 
estimated without regard to adherence to randomized treatment.
Symptomatic RT-PCR or rapid antigen test-confirmed infection through Day 14 is 
considered the main clinical outcome measure so estimands for the measure in targeted 
populations are presented. Estimands for the other outcome measures/populations are 
considered supportive of the main outcome measures and are not presented.
9.1.2. Multiplicity Adjustment
There will be 2 group comparisons for the primary endpoint: 5-day regimen of 
PF-07321332/ritonavir versus placebo groups and 10-day regimen of PF-07321332/ritonavir 
versus placebo groups. Multiplicity adjustment for the primary endpoint will be made for 
multiple comparisons using Hochberg method.65
Following the positive test of the primary endpoint, the key secondary endpoint will be tested 
sequentially: proportion of participants with symptomatic RT-PCR or rapid antigen 


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test-confirmed SARS-CoV-2 infection through Day 14 in participants who have a negative 
RT-PCR result at baseline and are at increased risk of severe COVID-19 illness.
If the primary endpoint is significant for both treatment groups, the key secondary endpoint 
will be tested at full alpha level using Hochberg method65 to adjust for multiple comparisons 
for both treatment groups.
If one of PF-07321332/ritonavir arms is discontinued, sequential testing will be performed in 
the remaining PF-07321332/ritonavir arm in the order of primary endpoint and the key 
secondary endpoint. Details will be provided in the SAP or interim analysis plan.
9.2. Analysis Sets
For purposes of analysis, the following analysis sets are defined:
Participant Analysis Set
Description
Full Analysis Set (FAS)
All participants randomly assigned to study intervention.
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 study 
intervention they received.
Modified Intent-To-Treat
(mITT)
All participants randomly assigned to study intervention 
who take at least 1 dose of study intervention and have a 
negative RT-PCR result at baseline.  
Participants will be analyzed according to the study 
intervention they were randomized.
Modified Intent-To-
Treat1 (mITT1)
All participants randomly assigned to study intervention 
who take at least 1 dose of study intervention and have a 
positive RT-PCR result at baseline.  
Participants will be analyzed according to the study 
intervention they were randomized.
Modified Intent-To-
Treat2 (mITT2)
All participants randomly assigned to study intervention 
who take at least 1 dose of study intervention and have a 
negative RT-PCR result at baseline and are at increased 
risk of severe COVID-19 illness.
Participants will be analyzed according to the study 
intervention they were randomized.


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Participant Analysis Set
Description
Per-Protocol (PP)
All participants in the mITT set without important protocol 
deviations considered to impact the interpretation of the 
primary efficacy endpoint. Protocol deviations will be 
reviewed to generate the list of participants with significant 
deviations to be excluded from the PP analysis set. The PP 
exclusion criteria will be finalized prior to breaking the 
blind.
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
The number of participants randomized to the double-blind treatment phase, completing the 
study drug administration, and completing the study will be summarized from the FAS. The 
reason for discontinuations will be summarized by treatment group. 
Baseline demographic and other characteristics will be tabulated for the FAS and 
summarized by treatment group. Quantitative variables will be described by standard 
descriptive statistics (mean, standard deviation, minimum, and maximum), and qualitative 
variables will be summarized by frequency tables with number and proportion in each 
category.
For continuous endpoints, an MMRM or ANCOVA model will be used to analyze change 
from baseline, whichever is appropriate. Estimated mean differences between treatments 
groups will be calculated.
For categorical endpoints, proportion of participants for each category will be summarized 
for each group.
For count endpoints, the total number of the events and average number of events will be 
summarized for each group. 
Time to event will be summarized graphically using Kaplan-Meier plots for each of the 
treatment groups. Treatment comparisons will be conducted using Cox proportional hazard 
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Below are the combinations of RT-PCR and rapid antigen test results that may be available 
for a participant and how these results would be considered toward confirming SARS-CoV-2 
infection in analyses of the primary and relevant secondary endpoints.  

the first instance of a positive RT-PCR with either a positive or negative rapid antigen 
test, or

the first instance of a positive rapid antigen test with a negative RT-PCR test.
If only 1 test is available, infection is defined as a positive result (RT-PCR or rapid antigen 
test).
Considering the frequency (daily Days 1-14 and at COVID-19 signs and symptoms onset 
visits) and greater sensitivity for RT-PCR testing relative to the rapid antigen test, it is 
anticipated that the majority of primary endpoint events will be confirmed with a positive 
RT-PCR result.
9.3.2. Primary Endpoint(s)/Estimand(s) Analysis
The primary efficacy analysis will be conducted using the mITT analysis set. 
For the primary efficacy analysis, GEE will be used to analyze the proportion of participants 
with a negative RT-PCR result at baseline who develop a symptomatic RT-PCR or rapid 
antigen test-confirmed SARS-CoV-2 infection through Day 14 for each treatment group. The 
compound symmetry variance-covariance structure will be used to account for the correlation 
among the participants associated with the same index case. The risk ratio between 5-day 
regimen of PF-07321332/ritonavir versus placebo group and 10-day regimen of 
PF-07321332/ritonavir versus placebo group and the corresponding 95% CIs will be 
calculated based on the GEE model using a log link function. Comparisons between the 
5-day and 10-day regimens of PF-07321332/ritonavir versus placebo will be presented as a 
risk reduction with 95% CIs, which is calculated as 1 minus the risk ratio.
A symptomatic infection event is defined as having any SARS-CoV-2 symptoms 1 day prior 
to, on, or after the first RT-PCR or rapid antigen test-confirmed infection. For COVID-19 
related hospitalization or COVID-19-related death, it will be considered as achieving the 
event. 
Multiplicity adjustment for primary endpoint will be made for multiple comparisons using 
Hochberg method. 65
Significance level will be determined using the O’Brien-Fleming approach at the interim 
analysis and the final analysis. The overall type I error rate is maintained at 5% (2-sided).
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9.3.3. Key Secondary Efficacy Endpoint(s)/Estimand(s) Analysis
The key secondary efficacy endpoint is:

the proportion of participants with symptomatic RT-PCR or rapid antigen 
test-confirmed SARS-CoV-2 infection through Day 14 in adult participants who have 
a negative RT-PCR result at baseline and who are at increased risk of severe 
COVID-19 illness.
The analyses will be performed similarly to the primary efficacy analysis using mITT2 
population.
9.3.4. Secondary Endpoint(s)/Estimand(s) Analysis

Incidence of TEAEs.

Incidence of SAEs and AEs leading to discontinuation.

Proportion of participants with COVID-19 related hospitalization or death from any 
cause by Day 28 in adult participants who have a negative RT-PCR result at baseline 
and who are at increased risk of severe COVID-19 illness.

Proportion of participants with asymptomatic RT-PCR or rapid antigen 
test-confirmed SARS-CoV-2 infection through Day 14 for participants who have a 
negative RT-PCR result at baseline.

Time to RT-PCR or rapid antigen test-confirmed SARS-CoV-2 infection through Day 
14 for participants who have a negative RT-PCR result at baseline.

Proportion of participants with symptomatic RT-PCR or rapid antigen test-confirmed 
SARS-CoV-2 infection through Day 14 in participants who have a positive RT-PCR 
result at baseline.

Proportion of participants with symptomatic RT-PCR or rapid antigen test-confirmed 
SARS-CoV-2 infection through Day 14 for participants who have either a negative or 
positive RT-PCR result at baseline.

Proportion of participants with no, mild, moderate, or severe signs and symptoms 
attributed to COVID-19 through Day 28 for participants who have a negative 
RT-PCR result at baseline.

Number of days of symptomatic SARS-CoV-2 infection through Day 28 for 
participants who have a negative RT-PCR result at baseline.

PF-07321332 PK in plasma and whole blood (if feasible).

Proportion of participants with death (all-cause) through Day 38 for participants who 
have a negative RT-PCR result at baseline.

Viral titers measured via RT-PCR in nasal swabs over time for participants who have 
a negative RT-PCR result at baseline.


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•
Viral titers measured via RT-PCR in nasal swabs over time for participants who have 
a positive RT-PCR result at baseline.
•
Number of days of hospital and ICU stay in participants with COVID-19-related 
hospitalization through Day 28 for participants who have a negative RT-PCR at 
baseline.
•
Number of COVID-19 related medical visits through Day 28 for participants who 
have a negative RT-PCR at baseline.
Details on the definitions and analyses of secondary endpoints will be described in the SAP.
9.3.6. Other Safety Analyses
Safety analyses will be carried out for the Safety population.  
The safety assessments include AEs, laboratory assessments, physical examinations, and 
vital signs. No formal statistical analysis will be conducted on any of the other safety data 
listed above.
9.3.6.1. Laboratory
Clinical laboratory data will be subjected to clinical review, summarized by frequency of 
events and mean changes from baseline.
9.3.6.2. Physical Examination and Vital Signs
Physical examination and vitals will be descriptively summarized by treatment group.
9.3.7. Other Analyses 
Pharmacogenomic or biomarker data from Retained Research Samples (Section 8.5.2 and 
Section 8.6.5) may be collected during or after the trial and retained for future analyses; the 
results of such analyses are not planned to be included in the CSR. 
PRO data (WPAI, EQ-5D-5L, and Global Impression Questions) will be collected during the 
trial and are not planned to be included in the CSR.
9.3.7.1. PK Analyses
Descriptive statistics and graphical summaries of PF-07321332 concentrations will be 
generated. PK samples will be collected as described in the SoA. Additional PK sampling 
may be self collected in a subset of participants using Tasso, if feasible. Ritonavir 
concentrations may also be reported. PK data from this study may be combined with other 
studies and analyzed using population PK approaches. Results from any population PK 
analyses will be reported outside of the clinical study report.
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9.4. Interim Analyses
An interim analysis will be conducted for efficacy, futility, and sample size re-estimation and 
reviewed by an independent E-DMC after a prespecified accrual of participants (ie, before or 
at approximately 70% overall participants have completed the Day 14 assessments with a 
minimum number of 24 participants having symptomatic infection [mITT analysis set]). The 
nominal significance level for the interim and final analyses is determined by means of the 
Lan-DeMets procedure with an O’Brien-Fleming stopping boundary, with an overall 
two-sided type I error rate of 5%. O’Brien-Fleming approach provides relatively conservative 
stopping boundary for decision making, ie, the nominal level for interim analysis for efficacy 
and futility is 0.014 and 0.32. The nominal significance level for final analysis is 0.046. The 
actual stopping boundaries will depend on the exact number of participants included in the 
interim analysis.
At the predefined interim analysis, the sample size may be adjusted based on sample size 
re-estimation with maximum increase of 30%. A well-established method such as CHW66
will be used to control the Type I error probability. Besides stopping a 
PF-07321332/ritonavir arm for safety or futility, a PF-07321332/ritonavir arm (5-day or 
10-day regimen) may be discontinued based on overall evaluation of efficacy and safety 
profiles between the 2 arms.
Before any interim analysis is performed, the details of the objectives, decision criteria, 
dissemination plan, and method of maintaining the study blind as per Pfizer’s SOPs will be 
documented and approved in a DMC charter. In addition, the analysis details will be 
documented and approved in the SAP.
9.5. Sample Size Determination
Based on the results from Study C4671005, which showed PF-07321332/ritonavir treatment 
significantly reduced the risk of hospitalization or death from any cause by 89% compared 
with placebo in nonhospitalized symptomatic adult participants with COVID-19 who were at 
increased risk of progression to severe disease when they were treated within 3 days of 
symptom onset, and the high relative risk reduction (approximately 80%) observed in 
Regeneron REGEN-COV post-exposure prophylaxis study, the risk reduction between 
PF-07321332/ritonavir group versus placebo group is assumed to be 70%. The symptomatic 
infection rate assumption in the placebo group is adjusted to 4% based on the observed 
seropositivity rate in this study and the impact of seropositivity on the incidence of primary 
endpoint events in the REGEN-COV post-exposure prophylaxis study where the incidence of 
symptomatic infection was 2% in participants who were seropositive and 8% in those who 
were seronegative.2 As of January 2022, a large percentage of participants were observed to 
be seropositive. Based on a 2% placebo event rate for participants who were seropositive and 
8% placebo rate for participants who were seronegative observed in the REGEN-COV 
postexposure prophylaxis study,2 the expected placebo rate across the 2 groups is estimated 
to be approximately 3%. In addition, based upon emerging epidemiology data for the 
Omicron variant,34 which suggests higher infectivity than with prior variants, the placebo rate 
is adjusted to be 4%.


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Among baseline RT-PCR negative participants, assuming a 4% symptomatic infection rate in 
the placebo group, a 70% reduction in symptomatic infection (1.2% symptomatic infection 
rate) in the PF-07321332/ritonavir group (5-day and 10-day regimen), a sample size of 
821 participants per group (2463 participants total) will provide approximately 90% power 
for each comparison between 5-day and 10-day regimens of PF-07321332/ritonavir group 
versus placebo group under a 2-sided type-1 error rate of 5%. Assuming approximately 5% 
of participants with negative rapid antigen test result at screening will have a positive 
RT-PCR result at baseline, and assuming an approximately 10% dropout rate, the total 
sample size for this study will be approximately 2880 participants.
Study enrollment will stop once approximately 2463 participants are evaluable and at least 
34 participants had symptomatic infection for the primary analysis. However, enrollment 
may continue until the 70% interim analysis has been completed.


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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 (if applicable), European Medical Device Regulation 
2017/745 for clinical device research (if applicable), and all other applicable local 
regulations.
10.1.1.1. Reporting of Safety Issues and Serious Breaches of the Protocol or ICH GCP
In the event of any prohibition or restriction imposed (ie, clinical hold) by an applicable 
regulatory authority in any area of the world, or if the investigator is aware of any new 
information that might influence the evaluation of the benefits and risks of the study 
intervention, Pfizer should be informed immediately. 


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In addition, the investigator will inform Pfizer immediately of any urgent safety measures 
taken by the investigator to protect the study participants against any immediate hazard, and 
of any serious breaches of this protocol or of the ICH GCP guidelines that the investigator 
becomes aware of.
10.1.2. Financial Disclosure
Investigators and subinvestigators will provide the sponsor with sufficient, accurate financial 
information as requested to allow the sponsor to submit complete and accurate financial 
certification or disclosure statements to the appropriate regulatory authorities. Investigators 
are responsible for providing information on financial interests during the course of the study 
and for 1 year after completion of the study.
10.1.3. Informed Consent Process 
The investigator or his/her representative will explain the nature of the study, including the 
risks and benefits, to the participant or his/her legally authorized representative and answer 
all questions regarding the study. The participant or his/her legally authorized representative 
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 or their 
legally authorized representative 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 study participant or his or her legally authorized 
representative 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 or his or her legally authorized representative must be informed that his/her 
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 or his or her 
legally authorized representative.
The participant or his or her legally authorized representative must be informed that his/her 
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 or his or her legally 
authorized representative is fully informed about his or her right to access and correct his or 
her personal data and to withdraw consent for the processing of his or her personal data.


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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 or his or her legally authorized representative must be reconsented to the most 
current version of the ICD(s) during their participation in the study.
A copy of the ICD(s) must be provided to the participant or the participant’s legally 
authorized representative.
10.1.4. Data Protection
All parties will comply with all applicable laws, including laws regarding the implementation 
of organizational and technical measures to ensure protection of participant data.
Participants’ personal data will be stored at the study site in encrypted electronic form and 
will be password-protected 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 his or her 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.
10.1.5. Committees Structure
10.1.5.1. Data Monitoring Committee 
This study will use an E-DMC. The E-DMC is independent of the study team and includes 
only external members. The E-DMC charter describes the role of the E-DMC in more detail.
The E-DMC will be responsible for ongoing monitoring of the efficacy and safety of 
participants in the study according to the charter. The recommendations made by the E-DMC
will be forwarded to the appropriate authorized Pfizer personnel for review and final 
decision. Pfizer will communicate such decisions, which may include summaries of 
aggregate analyses of safety data to regulatory authorities, investigators, as appropriate. 


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In addition to up to weekly reviews of safety data, the E-DMC will review the following:

Sentinel cohort safety review: The E-DMC will review unblinded safety data after 
approximately the first 150 participants have completed Day 10 of the study, at which 
point enrollment will be paused pending E-DMC review of the safety data. After 
review of the sentinel cohort, the frequency of safety reviews may be reduced 
subsequently based on E-DMC recommendations.

Interim analysis: An interim analysis will be conducted for efficacy, futility, and 
sample size re-estimation and reviewed by the E-DMC after a prespecified accrual of 
participants (ie, before or at approximately 70% overall participants have completed 
the Day 14 assessments with a minimum number of 24 participants having 
symptomatic infection events [mITT analysis set]). 
The E-DMC will review all deaths that occur during the study. A pause in enrollment 
pending E-DMC review will occur if 2 participants experience a Grade 4 or higher AE that is 
deemed related to study intervention as determined by the investigator and if the sponsor 
agrees.
10.1.6. Dissemination of Clinical Study Data
Pfizer fulfills its commitment to publicly disclose clinical study results through posting the 
results of studies on www.clinicaltrials.gov (ClinicalTrials.gov), the EudraCT, and/or 
www.pfizer.com, and other public registries in accordance with applicable local 
laws/regulations. In addition, Pfizer reports study results outside of the requirements of local 
laws/regulations pursuant to its SOPs.
In all cases, study results are reported by Pfizer in an objective, accurate, balanced, and 
complete manner and are reported regardless of the outcome of the study or the country in 
which the study was conducted.
www.clinicaltrials.gov
Pfizer posts clinical trial results on www.clinicaltrials.gov for Pfizer-sponsored interventional 
studies (conducted in patients) that evaluate the safety and/or efficacy of a product, 
regardless of the geographical location in which the study is conducted. These results are 
submitted for posting in accordance with the format and timelines set forth by US law.
EudraCT
Pfizer posts clinical trial results on EudraCT for Pfizer-sponsored interventional studies in 
accordance with the format and timelines set forth by EU requirements.
www.pfizer.com
Pfizer posts public disclosure synopses (CSR synopses in which any data that could be used 
to identify individual participants have been removed) on www.pfizer.com for 


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Pfizer-sponsored interventional studies at the same time the corresponding study results are 
posted to www.clinicaltrials.gov.
Documents within marketing authorization packages/submissions
Pfizer complies with the European Union Policy 0070, the proactive publication of clinical 
data to the EMA website. Clinical data, under Phase 1 of this policy, includes clinical 
overviews, clinical summaries, CSRs, and appendices containing the protocol and protocol 
amendments, sample CRFs, and statistical methods. Clinical data, under Phase 2 of this 
policy, includes the publishing of individual participant data. Policy 0070 applies to new 
marketing authorization applications submitted via the centralized procedure since 
01 January 2015 and applications for line extensions and for new indications submitted via 
the centralized procedure since 01 July 2015.
Data sharing
Pfizer provides researchers secure access to patient-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. Patient-level data will be anonymized in accordance with 
applicable privacy laws and regulations. CSRs will have personally identifiable information 
redacted.
Data requests are considered from qualified researchers with the appropriate competencies to 
perform the proposed analyses. Research teams must include a biostatistician. Data will not 
be provided to applicants with significant conflicts of interest, including individuals 
requesting access for commercial/competitive or legal purposes.
10.1.7. Data Quality Assurance
All participant data relating to the study will be recorded on printed or electronic CRF unless 
transmitted to the sponsor or designee electronically (eg, laboratory data). The investigator is 
responsible for verifying that data entries are accurate and correct by physically or 
electronically signing the CRF.
Guidance on completion of CRFs will be provided in the CRF Completion Requirements 
document.
The investigator must ensure that the CRFs are securely stored at the study site in encrypted 
electronic form and are password protected to prevent access by unauthorized third parties.
QTLs are predefined parameters that are monitored during the study. Important deviations 
from the QTLs and any remedial actions taken will be summarized in the clinical study 
report.
The investigator must permit study-related monitoring, audits, IRB/EC review, and 
regulatory agency inspections and provide direct access to source data documents. This 


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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 retain  
notification in relation to the study. Furthermore, the investigator will cooperate with the 
sponsor or its agents to prepare the investigator site for the inspection and will allow the 
sponsor or its agent, whenever feasible, to be present during the inspection. The investigator 
site and investigator will promptly resolve any discrepancies that are identified between the 
study data and the participant's medical records. The investigator will promptly provide 
copies of the inspection findings to the sponsor or its agent. Before response submission to 
the regulatory authorities, the investigator will provide the sponsor or its agents with an 
opportunity to review and comment on responses to any such findings.
10.1.8. Source Documents
Source documents provide evidence for the existence of the participant and substantiate the 
integrity of the data collected. Source documents are filed at the investigator site.
Data reported on the CRF or entered in the eCRF that are from source documents must be 
consistent with the source documents or the discrepancies must be explained. The 
investigator may need to request previous medical records or transfer records, depending on 
the study. Also, current medical records must be available.
Definition of what constitutes source data and its origin can be found in the monitoring plan, 
which is maintained by the sponsor.


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Description of the use of the computerized system is documented in the Data Management 
Plan, which is maintained by the sponsor.
The investigator must maintain accurate documentation (source data) that supports the 
information entered in the CRF.
Study monitors will perform ongoing source data verification to confirm that data entered 
into the CRF by authorized site personnel are accurate, complete, and verifiable from source 
documents; that the safety and rights of participants are being protected; and that the study is 
being conducted in accordance with the currently approved protocol and any other study 
agreements, ICH GCP guidelines, and all applicable regulatory requirements.
10.1.9. 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. Study sites will be closed upon study 
completion. A study site is considered closed when all required documents and study 
supplies have been collected and a study-site closure visit has been performed.
The investigator may initiate study-site closure at any time upon notification to the sponsor 
or designee/CRO 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.


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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.
10.1.10. Publication Policy
The results of this study may be published or presented at scientific meetings by the 
investigator after publication of the overall study results or 1 year after the end of the study 
(or study termination), whichever comes first. 
The investigator agrees to refer to the primary publication in any subsequent publications, 
such as secondary manuscripts, and submits all manuscripts or abstracts to the sponsor 
30 days before submission. This allows the sponsor 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- or Pfizer 
intervention-related information necessary for the appropriate scientific presentation or 
understanding of the study results.
For all publications relating to the study, the investigator will comply with recognized ethical 
standards concerning publications and authorship, including those established by the 
International Committee of Medical Journal Editors.
The sponsor will comply with the requirements for publication of the overall study results 
covering all investigator sites. In accordance with standard editorial and ethical practice, the 
sponsor will support publication of multicenter studies only in their entirety and not as 
individual site data. In this case, a coordinating investigator will be designated by mutual 
agreement.
Authorship of publications for the overall study results will be determined by mutual 
agreement and in line with International Committee of Medical Journal Editors authorship 
requirements. 
If publication is addressed in the clinical study agreement, the publication policy set out in 
this section will not apply.
10.1.11. Sponsor’s Qualified Medical Personnel
The contact information for the sponsor's appropriately qualified medical personnel for the 
study is documented in the study contact list located in the supporting study 
documentation/study portal or other electronic system. 
To facilitate access to appropriately qualified medical personnel for study-related medical 
questions or problems, participants are provided with an Emergency Contact Card (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, (c) site emergency 
phone number active 24 hours/day, 7 days per week, and (d) Pfizer Call Center number.
The ECC is intended to augment, not replace, the established communication pathways 
between the investigator, site staff, and study team. The ECC is to be used by healthcare 


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professionals not involved in the research study only, as a means of reaching the investigator 
or site staff related to the care of a participant. The Pfizer Call Center number should only be 
used when the investigator and site staff cannot be reached. The Pfizer Call Center number is 
not intended for use by the participant directly; if a participant calls that number directly, he 
or she will be directed back to the investigator site.


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10.2. Appendix 2: Clinical Laboratory Tests
The following safety laboratory tests will be performed at times defined in the SoA section of 
this protocol. Additional laboratory results may be reported on these samples as a result of 
the method of analysis or the type of analyzer used by the clinical laboratory, or as derived 
from calculated values. These additional tests would not require additional collection of 
blood. Unscheduled clinical laboratory measurements may be obtained at any time during the 
study to assess any perceived safety issues.
Table 1.
Protocol-Required Safety Laboratory Assessments
Hematology
Chemistry
Other
Additional Tests (Needed 
for Hy’s Law)
Hemoglobin
Hematocrit
RBC count
Platelet count
WBC count
Total neutrophils (Abs)
Eosinophils (Abs)
Monocytes (Abs)
Basophils (Abs)
Lymphocytes (Abs)
BUN or urea
Creatinine a
Glucose
Calcium
Sodium
Potassium
Chloride
Total CO2
(bicarbonate)
AST, ALT
Total bilirubin
Alkaline phosphatase
Albumin
Total protein
Ferritin
hsCRP
Procalcitonin
LDH
CK
Haptoglobin
Thyroid function
TSH
T4 (free)
Coagulation 
PT/aPTT
Fibrinogen
D-dimer
SARS-CoV-2 
serology 
IgM, IgG
Other

FSHb

Pregnancy test 
(β-hCG)c
AST, ALT (repeat)
Total bilirubin (repeat)
Albumin 
Alkaline phosphatase 
(repeat)
Direct bilirubin
Indirect bilirubin
Creatine kinase
GGT
PT/INR
Total bile acids
Acetaminophen drug and/or 
protein adduct levels
a.
eGFR will be calculated using the method developed by the CKD-EPI using serum creatinine.52
b.
FSH is collected for confirmation of postmenopausal status only.
c.
Local urine testing will be standard for the protocol unless serum testing is required by local regulation 
or IRB/EC. Serum or urine -hCG for female participants of childbearing potential.
The investigator must review the laboratory report, document this review, and record any 
clinically relevant changes occurring during the study in the AE section of the CRF.  


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10.3. Appendix 3: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-Up, and Reporting
10.3.1. Definition of AE
AE Definition

An AE is any untoward medical occurrence in a patient or clinical study 
participant, temporally associated with the use of study intervention, whether or not 
considered related to the study intervention.

Note: An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease (new or exacerbated) 
temporally associated with the use of study intervention.
Events Meeting the AE Definition

Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) 
or other safety assessments (eg, ECG, radiological scans, vital sign measurements), 
including those that worsen from baseline, considered clinically significant in the 
medical and scientific judgment of the investigator. Any abnormal laboratory test 
results that meet any of the conditions below must be recorded as an AE:

Is associated with accompanying symptoms.

Requires additional diagnostic testing or medical/surgical intervention.

Leads to a change in study dosing (outside of any protocol-specified dose 
adjustments) or discontinuation from the study, significant additional 
concomitant drug treatment, or other therapy.

Exacerbation of a chronic or intermittent preexisting condition, including either an 
increase in frequency and/or intensity of the condition.

New condition detected or diagnosed after study intervention administration, even 
though it may have been present before the start of the study.

Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction.

Signs, symptoms, or the clinical sequelae of a suspected overdose of either study 
intervention or a concomitant medication. Overdose per se will not be reported as 
an AE or SAE unless it is an intentional overdose taken with possible 
suicidal/self-harming intent. Such overdoses should be reported regardless of 
sequelae.


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Events NOT Meeting the AE Definition

Any clinically significant abnormal laboratory findings or other abnormal safety 
assessments that are associated with the underlying disease, unless judged by the 
investigator to be more severe than expected for the participant’s condition.

The disease/disorder being studied or expected progression, signs, or symptoms of 
the disease/disorder being studied, unless more severe than expected for the 
participant’s condition.

Medical or surgical procedure (eg, endoscopy, appendectomy): the condition that 
leads to the procedure is the AE.

Situations in which an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital).

Anticipated day-to-day fluctuations of preexisting disease(s) or condition(s) present 
or detected at the start of the study that do not worsen.
10.3.2. Definition of an SAE
An SAE is defined as any untoward medical occurrence that, at any dose, meets one 
or more of the criteria listed below:
a.
Results in death
b. Is life-threatening
The term “life-threatening” in the definition of “serious” refers to an event in which the 
participant was at risk of death at the time of the event. It does not refer to an event that 
hypothetically might have caused death if it were more severe.
c.
Requires inpatient hospitalization or prolongation of existing hospitalization
In general, hospitalization signifies that the participant has been admitted (usually 
involving at least an overnight stay) at the hospital or emergency ward for observation 
and/or treatment that would not have been appropriate in the physician’s office or 
outpatient setting. Complications that occur during hospitalization are AEs. If a 
complication prolongs hospitalization or fulfills any other serious criteria, the event is 
serious. When in doubt as to whether “hospitalization” occurred or was necessary, the 
AE should be considered serious.


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Hospitalization for elective treatment of a preexisting condition that did not worsen 
from baseline is not considered an AE.
d. Results in persistent or significant disability/incapacity

The term disability means a substantial disruption of a person’s ability to conduct 
normal life functions.

This definition is not intended to include experiences of relatively minor medical 
significance, such as uncomplicated headache, nausea, vomiting, diarrhea, 
influenza, and accidental trauma (eg, sprained ankle), that may interfere with or 
prevent everyday life functions but do not constitute a substantial disruption.
e.
Is a congenital anomaly/birth defect
f.
Is a suspected transmission via a Pfizer product of an infectious agent, pathogenic 
or non-pathogenic, is considered serious.  
g.
The event may be suspected from clinical symptoms or laboratory findings indicating 
an infection in a participant exposed to a Pfizer product. The terms “suspected 
transmission” and “transmission” are considered synonymous. These cases are 
considered unexpected and handled as serious expedited cases by pharmacovigilance 
personnel. Such cases are also considered for reporting as product defects, if 
appropriate.
h. Other situations:

Medical or scientific judgment should be exercised by the investigator in deciding
whether SAE reporting is appropriate in other situations, such as significant 
medical events that may jeopardize the participant or may require medical or 
surgical intervention to prevent one of the other outcomes listed in the above 
definition. These events should usually be considered serious.

Examples of such events include invasive or malignant cancers, intensive treatment 
in an emergency room or at home for allergic bronchospasm, blood dyscrasias or 
convulsions that do not result in hospitalization, or development of drug 
dependency or drug abuse.
10.3.3. Recording/Reporting and Follow-Up of AEs and/or SAEs During the Active 
Collection Period 
AE and SAE Recording/Reporting
The table below summarizes the requirements for recording AEs on the CRF and for 
reporting SAEs on the CT SAE Report Form to Pfizer Safety throughout the active 


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collection period. These requirements are delineated for 3 types of events: (1) SAEs; (2) 
nonserious AEs; and (3) exposure to the study intervention under study during pregnancy 
or breastfeeding, and occupational exposure. 
It should be noted that the CT SAE Report Form 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.
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 or SAEs 
associated with exposure 
during pregnancy or 
breastfeeding
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 non-participant (not 
involving EDP or EDB).
None.  Exposure to a study 
non-participant is not 
collected on the CRF.
The exposure (whether or 
not there is an associated 
AE or SAE) must be 
reported.***
*
EDP (with or without an associated AE or SAE): any pregnancy information is reported to 
Pfizer Safety using 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. 


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
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.

It is not acceptable for the investigator to send photocopies of the participant’s 
medical records to Pfizer Safety in lieu of completion of the CT SAE Report 
Form/AE or SAE CRF page.

There may be instances when copies of medical records for certain cases are 
requested by Pfizer Safety. In this case, all participant identifiers, with the 
exception of the participant number, will be redacted on the copies of the medical 
records before submission to Pfizer Safety.

The investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information. Whenever possible, the diagnosis (not 
the individual signs/symptoms) will be documented as the AE or SAE.
Assessment of Intensity
The investigator will make an assessment of intensity for each AE and SAE reported 
during the study and assign it to 1 of the following categories, which are based on the 
Division of AIDS (DAIDS) Table for Grading the Severity of Adult and Pediatric Adverse 
Events,64 version 2.1 (July 2017):
GRADE
Clinical Description of Severity
1
MILD adverse event
2
MODERATE adverse event
3
SEVERE adverse event
4
POTENTIALLY LIFE-THREATENING event 
5
DEATH RELATED TO adverse event
An event is defined as “serious” when it meets at least 1 of the predefined outcomes as 
described in the definition of an SAE, NOT when it is rated as severe.
Assessment of Causality

The investigator is obligated to assess the relationship between study intervention 
and each occurrence of each AE or SAE. The investigator will use clinical 
judgment to determine the relationship.

A “reasonable possibility” of a relationship conveys that there are facts, evidence, 
and/or arguments to suggest a causal relationship, rather than a relationship cannot 
be ruled out.


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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 information, for marketed 
products, in his/her assessment.

For each AE or SAE, the investigator must document in the medical notes that 
he/she has reviewed the AE or SAE and has provided an assessment of causality.

There may be situations in which an SAE has occurred and the investigator has 
minimal information to include in the initial report to the sponsor. However, it is 
very important that the investigator always make an assessment of causality 
for every event before the initial transmission of the SAE data to the sponsor.

The investigator may change his/her opinion of causality in light of follow-up 
information and send an SAE follow-up report with the updated causality 
assessment.

The causality assessment is one of the criteria used when determining regulatory 
reporting requirements.

If the investigator does not know whether or not the study intervention caused the 
event, then the event will be handled as “related to study intervention” for reporting 
purposes, as defined by the sponsor. In addition, if the investigator determines that 
an SAE is associated with study procedures, the investigator must record this 
causal relationship in the source documents and CRF, and report such an 
assessment in the dedicated section of the CT SAE Report Form and in accordance 
with the SAE reporting requirements.
Follow-Up of AEs and SAEs

The investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations, as medically indicated or as requested by the 
sponsor, to elucidate the nature and/or causality of the AE or SAE as fully as 
possible. This may include additional laboratory tests or investigations, 
histopathological examinations, or consultation with other healthcare providers.

If a participant dies during participation in the study or during a recognized 
follow-up period, the investigator will provide Pfizer Safety with a copy of any 
postmortem findings, including histopathology.


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
New or updated information will be recorded in the originally submitted 
documents.

The investigator will submit any updated SAE data to the sponsor within 24 hours 
of receipt of the information.
10.3.4. Reporting of SAEs
SAE Reporting to Pfizer Safety via an Electronic Data Collection Tool

The primary mechanism for reporting an SAE to Pfizer Safety will be the 
electronic data collection tool.

If the electronic system is unavailable, then the site will use the paper SAE data 
collection tool (see next section) to report the event within 24 hours.

The site will enter the SAE data into the electronic system as soon as the data 
become available.

After the study is completed at a given site, the electronic data collection tool will 
be taken off-line to prevent the entry of new data or changes to existing data.

If a site receives a report of a new SAE from a study participant or receives updated 
data on a previously reported SAE after the electronic data collection tool has been 
taken off-line, then the site can report this information on a paper SAE form (see 
next section) or to Pfizer Safety by telephone.
SAE Reporting to Pfizer Safety via CT SAE Report Form

Facsimile transmission of the CT SAE Report Form is the preferred method to 
transmit this information to Pfizer Safety.

In circumstances when the facsimile is not working, notification by telephone is 
acceptable with a copy of the CT SAE Report Form sent by overnight mail or 
courier service.

Initial notification via telephone does not replace the need for the investigator to 
complete and sign the CT SAE Report Form pages within the designated reporting 
time frames.


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10.4. Appendix 4: Contraceptive and Barrier Guidance
10.4.1. Male Participant Reproductive Inclusion Criteria
Male participants are eligible to participate if they agree to the following requirements during 
the intervention period and for at least 28 days after the last dose of study intervention, which
corresponds to the time needed to eliminate reproductive safety risk of the study 
intervention(s):

Refrain from donating sperm.
PLUS either:

Be abstinent from heterosexual intercourse with a female of childbearing potential as 
their preferred and usual lifestyle (abstinent on a long-term and persistent basis) and 
agree to remain abstinent. 
OR

Must agree to use contraception/barrier as detailed below:

Agree to use a male condom when having sexual intercourse with a woman of 
childbearing potential 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
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 definitions below in Section 10.4.3).

OR

Is a WOCBP and using a contraceptive method that is highly effective (with a 
failure rate of <1% per year), as described below, 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 method that is user dependent is 
chosen, a second effective method of contraception, as described below, must also
be used. The investigator should evaluate the effectiveness of the contraceptive 
method in relationship to the first dose of study intervention.


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Because ritonavir may reduce the effect of estradiol-containing contraceptives when agents 
are coadministered, a barrier method or other nonhormonal method of contraception must 
also be used if the participant is using estradiol-containing contraceptives.
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 an alternate 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 50 years of age 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 nonestrogen hormonal highly effective contraception methods 


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if they wish to continue their HRT during the study. Otherwise, they must 
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.
1. Implantable progestogen-only hormone contraception associated with inhibition of 
ovulation.
2. Intrauterine device.
3. Intrauterine hormone-releasing system.
4. Bilateral tubal occlusion (eg, bilateral tubal ligation).
5. Vasectomized partner:

A vasectomized partner is a highly effective contraceptive method provided that 
the partner is the sole sexual partner of the woman of childbearing potential 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.
6. Combined (estrogen- and progestogen-containing) hormonal contraception associated 
with inhibition of ovulation:

Oral;

Intravaginal;

Transdermal.
7. Progestogen-only hormone contraception associated with inhibition of ovulation:

Oral;

Injectable.
8. Sexual abstinence:

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 


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evaluated in relation to the duration of the study and the preferred and usual 
lifestyle of the participant.
In addition, one of the following effective barrier methods must also be used when 
option 6 or 7 are chosen above:

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).
Because ritonavir may reduce the effect of estradiol-containing contraceptives when agents 
are coadministered, a barrier method or other non-hormonal method of contraception must 
also be used if the participant is using estradiol-containing contraceptives.


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CCI
CCI


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10.6. Appendix 6: Liver Safety: Suggested Actions and Follow-Up Assessments and 
Study Intervention Rechallenge Guidelines
Potential Cases of Drug-Induced Liver Injury
Humans exposed to a drug who show no sign of liver injury (as determined by elevations in 
transaminases) are termed “tolerators,” while those who show transient liver injury but adapt 
are termed “adaptors.” In some participants, transaminase elevations are a harbinger of a 
more serious potential outcome. These participants fail to adapt and therefore are 
"susceptible" to progressive and serious liver injury, commonly referred to as DILI. 
Participants who experience a transaminase elevation above 3 × ULN should be monitored 
more frequently to determine if they are “adaptors” or are “susceptible.”
In the majority of DILI cases, elevations in AST and/or ALT precede TBili elevations (>2 ×
ULN) by several days or weeks. The increase in TBili typically occurs while AST/ALT is/are 
still elevated above 3 × ULN (ie, AST/ALT and TBili values will be elevated within the same 
laboratory sample). In rare instances, by the time TBili 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 TBili 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 TBili baseline values within the normal range who 
subsequently present with AST OR ALT values >3 × ULN AND a TBili 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 TBili values above the ULN, the 
following threshold values are used in the definition mentioned above, as needed, 
depending on which values are above the ULN at baseline:

Preexisting AST or ALT baseline values above the normal range: AST or ALT 
values >2 times the baseline values AND >3 × ULN; or >8 × ULN (whichever is 
smaller).

Preexisting values of TBili above the normal range: TBili level increased from 
baseline value by an amount of at least 1 × ULN or if the value reaches 
>3 × ULN (whichever is smaller).


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Rises in AST/ALT and TBili 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 TBili 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 
TBili 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: ECG Findings of Potential Clinical Concern (No Longer Applicable)


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10.8. Appendix 8: Prohibited Concomitant Medications That May Result in DDI  
PF-07321332 and ritonavir are both primarily metabolized by CYP3A4. Therefore, 
concomitant use of any medications or substances that are strong inducers of CYP3A4 are 
prohibited within 28 days prior to dosing of study intervention and during study treatment.
Additionally, ritonavir and PF-07321332 are inhibitors of CYP3A4. Therefore, medications 
highly dependent on CYP3A4 for clearance and for which elevated plasma concentrations 
may be associated with serious and/or life-threatening events are not permitted during dosing 
of PF-07321332/ritonavir (at least 24 hours prior to the first dose of study intervention or as 
late as Day 1, prior to the first dose of study intervention – see below) and for 4 days after the 
last dose of PF-07321332/ritonavir. Ritonavir also appears to induce CYP3A, CYP1A2, 
CYP2C9, CYP2C19, and CYP2B6 as well as other enzymes, including glucuronosyl 
transferase. Since ritonavir 100 mg q12h is being used to boost the exposure of 
PF-07321332, no additional DDI is expected other than those associated with ritonavir 
100 mg q12h based on in vitro assessments. Thus, the prohibited concomitant medications 
and those to be used with caution are primarily based on the ritonavir label.
A nonexhaustive list of prohibited and precautionary medications is provided below. If a 
medication is not listed, it should not automatically be assumed it is safe to co-administer. 
Appropriately qualified site staff will review all concomitant medications to determine if they 
are prohibited.
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 judgement 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).  
This is not an all-inclusive list. Site staff should consult with the sponsor or designee with 
any questions regarding potential DDI.


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Prohibited Medications that are Strong Inducers of CYP450 3A4a
Due to prolonged induction of CYP450 3A4 participants must not use these medications within 28 days 
prior to randomization and during dosing of PF-07321332/placebo and ritonavir/placebo.
Drug Class
Specific Medication
Clinical Comments
Anti-cancer drugs
Apalutamide
Reduced concentrations of 
PF-07321332/ritonavir; may result in 
suboptimal concentrations.
Anticonvulsants
Phenytoin, Carbamazepine, 
Phenobarbital 
Antimycobacterials
Rifampin
Herbal Products
St. John’s Wort
Prohibited Medications Dependent on CYP450 3A4 for Clearance or with other Notable 
Interactionsa
These medications are prohibited for at least 24 hours prior to the first dose of PF-0321332/placebo and 
ritonavir/placebo, through 4 days after the last dose of PF-07321332/placebo and ritonavir/placebo. If a 
participant cannot temporarily interrupt the prohibited medication during this period, they should be 
considered ineligible.
Drug Class
Specific Medication
Clinical Comments
Alpha 1-Adrenoreceptor 
Antagonist
Alfuzosin
Risk of hypotension, syncope
Analgesics 
Piroxicam, Propoxyphene, 
Pethidine 
Analgesic concentrations may increase.
Antianginal
Ranolazine
Risk of cardiac arrhythmias 
Antiarrhythmics
Dronedarone , Amiodarone, 
Flecainide, Propafenone, Quinidine
Risk of cardiac arrhythmias
Anti-gout
Colchicine
Ritonavir 100 mg twice daily increased 
colchicine AUC 296% and Cmax 184%. 
Potential for serious and/or 
life-threatening reactions in patients 
with renal and/or hepatic impairment.
Antipsychotics
Clozapine, Lurasidone, Pimozide
Potential for increased levels of 
antipsychotics.
Ergot Derivatives
Dihydroergotamine, Ergotamine, 
Methylergonovine
Risk of acute ergot toxicity (peripheral 
vasospasm and ischemia of the 
extremities)
Lipid lowering drugs 
(HMG CoA Reductase 
Inhibitors)
Lovastatin, Simvastatin
Risk of rhabdomyolysis
PDE-5 Inhibitors for 
pulmonary arterial 
hypertension treatment
Sildenafil (Revatio) when used for 
pulmonary arterial hypertension
Risk of visual disturbances, 
Co-administration may result in visual 
abnormalities, hypotension, prolonged 
erection, and syncope.
Sedatives/
Hypnotics
oral Midazolam, Triazolam
Risk of prolonged sedation, respiratory 
depression, or hypnotic concentrations  
a.
Note: If a drug is not listed, it should not automatically be assumed it is safe to co-administer


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Prohibited Medications Dependent on CYP450 3A4 for Clearance or with other Notable Interactionsa
These medications are prohibited from the first dose of PF-07321332/placebo and ritonavir/placebo, through 
4 days after the last dose of PF-07321332/placebo and ritonavir/placebo. If a participant cannot temporarily 
interrupt the prohibited medication during this period, they should be considered ineligible.   
Drug Class 
Specific Medication 
Clinical Comments 
Alpha 1-Adrenoreceptor 
Antagonist 
Tamsulosin, Silodosin, Doxazosin 
(>2 mg daily), Terazosin (>5 mg 
daily), 
Risk of hypotension, syncope 
Analgesics
Opioid Dependence 
Treatment
Methadone 
Fentanyl, Oxycodone
Buprenorphine 
Lofexidine 
Moderate to weak decreases in 
methadone concentrations have been 
observed. 
Analgesic concentrations may increase.
Co-administration may increase 
concentrations of Buprenorphine and 
Lofexidine.
Anticancer drugs
Abemaciclib, 
Ceritinib,
Dasatinib, 
Encorafenib,
Ibrutinib, 
Ivosidenib, 
Neratinib, 
Nilotinib, 
Venetoclax,
Vinblastine, 
Vincristine
Co-administration contraindicated due to 
potential loss of virologic response and 
possible resistance.
Avoid co-administration of Encorafenib 
or Ivosidenib due to potential risk of 
serious adverse events such as QT 
interval prolongation. Avoid use of 
Neratinib, Venetoclax or Ibrutinib.
Co-administration of Vincristine and 
Vinblastine may lead to significant 
hematologic or gastrointestinal side 
effects.
For further information, refer to 
individual product label for anticancer 
drug.
Anticoagulants/ 
antiplatelet
Rivaroxaban, 
Warfarin 
Possible increased risk of bleeding 
Possible decreased warfarin effects. 
Closely monitor INR if co-administration 
with Warfarin is necessary.


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Prohibited Medications Dependent on CYP450 3A4 for Clearance or with other Notable Interactionsa
These medications are prohibited from the first dose of PF-07321332/placebo and ritonavir/placebo, through 
4 days after the last dose of PF-07321332/placebo and ritonavir/placebo. If a participant cannot temporarily 
interrupt the prohibited medication during this period, they should be considered ineligible.   
Drug Class 
Specific Medication 
Clinical Comments 
Antidepressant 
Bupropion
Trazodone
Monitor for an adequate clinical response 
to Bupropion. 
Adverse reactions of nausea, dizziness, 
hypotension, and syncope have been 
observed following co-administration of 
Trazodone and Ritonavir. A lower dose 
of Trazodone should be considered. 
Refer to Trazadone product label for 
further information.
Anti-infective 
(antibacterials)
Erythromycin 
Co-administration may increase 
erythromycin concentrations.
Clarithromycin
Co-administration may increase 
clarithromycin concentrations.
Antimycobacterials
Bedaquiline 
Co-administration contraindicated due to 
potential loss of virologic response and 
possible resistance. Alternate 
antimycobacterial drugs such as 
Rifabutin should be considered.
(antifungals) 
Isavuconazole
Itraconazole 
Posaconazole 
Ketoconazole 
Voriconazole
Refer to Ketoconazole, 
Isavuconazonium Sulfate, and 
Itraconazole product labels for further 
information.
Co-administration of Ritonavir with 
Voriconazole may result in reduction in 
Voriconazole levels. 
Antihistamines 
Astemizole, Terfenadine 
Risk of cardiac arrhythmias 
Antipsychotics 
Quetiapine 
Risperidone, Perphenazine, 
Aripiprazole, Brexpiprazole, 
Cariprazine, Iloperidone, 
Thioridazine, Ziprasidone 
Co-administration may increase 
Quetiapine and increase risk of 
quetiapine-related toxicity.  
Potential for increased levels of 
antipsychotics. 
Cardiac Medications 
(beta blockers) 
Carvedilol, Metoprolol, Timolol 
Co-administration may increase 
concentration of Carvedilol, Metoprolol, 
Timolol. 


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Prohibited Medications Dependent on CYP450 3A4 for Clearance or with other Notable Interactionsa
These medications are prohibited from the first dose of PF-07321332/placebo and ritonavir/placebo, through 
4 days after the last dose of PF-07321332/placebo and ritonavir/placebo. If a participant cannot temporarily 
interrupt the prohibited medication during this period, they should be considered ineligible.   
Drug Class 
Specific Medication 
Clinical Comments 
Calcium channel blockers  Diltiazem, Verapamil, Nifedipine, 
amlodipine (> 5 mg daily), 
felodipine, nicardipine 
Co-administration may increase 
concentrations of calcium channel 
blockers. The impact on the PR interval 
of co-administration of ritonavir with 
other drugs that prolong the PR interval 
(including calcium channel blockers) has 
not been evaluated.  A dose decrease 
may be needed for these drugs when 
co-administered with PAXLOVID.
Cardiac glycosides 
Digoxin 
Caution should be exercised when 
co-administering PAXLOVID with 
digoxin, with appropriate monitoring of 
serum digoxin levels. 
Refer to the digoxin product label for 
further information.
Eplerenone 
Co-administration increases eplerenone 
concentrations. 
Ivabradine 
Co-administration increases ivabradine 
concentrations. 
Corticosteroids 
(inhaled or intranasal) 
(systemic) 
(Local injections, 
including intra-articular, 
epidural, or intra-orbital)
Budesonide, 
Ciclesonide, 
Mometasone
Betamethasone 
Budesonide 
Betamethasone, 
Methylprednisolone, Triamcinolone 
Co-administration can increase 
concentration of Budesonide, 
Ciclesonide, and Mometasone and can 
result in adrenal insufficiency and 
Cushing’s syndrome. 
Co-administration can increase 
concentration of Betamethasone, and 
Budesonide and can result in adrenal 
insufficiency and Cushing’s syndrome. 
Co-administration can increase 
Betamethasone, Methylprednisolone, 
and Triamcinolone concentrations and 
can result in adrenal insufficiency and 
Cushing’s syndrome
Endothelin receptor 
antagonists 
Bosentan 
Bosentan should be discontinued at least 
36 hours prior to the initiation of 
ritonavir. 
Hepatitis C direct acting 
antivirals (DAAs) 
Elbasvir/Grazoprevir,
Glecaprevir/Pibrentasvir
Increased Grazoprevir concentrations 
can result in ALT elevations.
It is not recommended to co-administer 
ritonavir with Glecaprevir/Pibrentasvir. 


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Prohibited Medications Dependent on CYP450 3A4 for Clearance or with other Notable Interactionsa
These medications are prohibited from the first dose of PF-07321332/placebo and ritonavir/placebo, through 
4 days after the last dose of PF-07321332/placebo and ritonavir/placebo. If a participant cannot temporarily 
interrupt the prohibited medication during this period, they should be considered ineligible.   
Drug Class 
Specific Medication 
Clinical Comments 
Ombitasvir/Paritaprevir/Ritonavir 
and Dasabuvir
Sofosbuvir/Velpatasvir/Voxilaprevir
Refer to the 
Ombitasvir/Paritaprevir/Ritonavir and 
Dasabuvir label for further information.
Refer to the 
Sofosbuvir/Velpatasvir/Voxilaprevir 
product label for further information.
Patients on ritonavir-containing HCV 
regimens should continue their treatment 
as indicated. Monitor for increased 
PAXLOVID or HCV drug adverse 
events with concomitant use.
HIV Antiretrovirals 
Protease Inhibitors 
Integrase Inhibitors 
Lopinavir, Amprenavir, Indinavir, 
Nelfinavir, Atazanavir, Darunavir, 
Fosamprenavir, Saquinavir, 
Tipranavir. 
Ritonavir or cobicistat containing 
combination products 
Elvitegravir 
Co-administration may increase HIV 
protease inhibitor concentrations. 
Risk of increased rate of adverse 
reactions. Appropriate doses of 
additional Ritonavir in combination with 
ritonavir-containing combination 
products with respect to safety and 
efficacy have not been established. 
Co-administration will increase 
Elvitegravir concentrations. 
Hormonal contraceptive
Ethinyl Estradiol
An additional, non-hormonal method of 
contraception should be considered.
Lipid lowering drugs 
(HMG-CoA Reductase 
Inhibitors) 
Atorvastatin (>20 mg daily), 
Rosuvastatin (>10 mg daily) 
Lomitapide 
Risk of rhabdomyolysis 
Co-administration may increase 
concentration of Lomitapide. 


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Prohibited Medications Dependent on CYP450 3A4 for Clearance or with other Notable Interactionsa
These medications are prohibited from the first dose of PF-07321332/placebo and ritonavir/placebo, through 
4 days after the last dose of PF-07321332/placebo and ritonavir/placebo. If a participant cannot temporarily 
interrupt the prohibited medication during this period, they should be considered ineligible.   
Drug Class 
Specific Medication 
Clinical Comments 
Hypoglycemics 
Glipizide, Tolbutamide 
Repaglinide 
Saxagliptin (>2.5 mg daily) 
Potentially decrease glipizide and 
Tolbutamide concentrations. 
Potentially increase Repaglinide 
concentrations.  
Co-administration may increase 
Saxagliptin concentration. 
Immunosuppressants 
Cyclosporine, Tacrolimus, 
Sirolimus, Everolimus 
Co-administration may increase 
immunosuppressant concentrations.  
Therapeutic concentration monitoring is 
recommended for immunosuppressants.
Long-Acting Beta-
Adrenoceptor Agonist 
Salmeterol 
The combination may result in increased 
concentrations of Salmeterol and 
increased risk of cardiovascular adverse 
events, including QT prolongation, 
palpitations and sinus tachycardia. 
Neuroleptics
Pimozide 
Risk of cardiac arrhythmias  
Sedatives/ 
Hypnotics 
Midazolam (parenteral), 
Alprazolam, Bromazepam, 
Brotizolam, Clonazepam, 
Cloniprazepam, Delorazepam, 
Diazepam, Etizolam, Eszopiclone, 
Halazepam, Lormetazepam, 
Nitrazepam, Nordiazpam, 
Quazepam, Suvorexant, 
Temazepam, Zaleplon, Zolpidem
Clorazepate, Estazolam, 
Flurazepam, 
Zolpidem (> 5mg daily) 
Risk of prolonged sedation, respiratory 
depression, or hypnotic concentrations 
Co-administration with Ritonavir may 
increase dose of Clorazepate, Estazolam, 
and Flurazepam. 
Co-administration may increase 
zolpidem concentration  
a.
Note: If a drug is not listed, it should not automatically be assumed it is safe to co-administer. 


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Precautionary Medications
Medications may be used with caution and require oversight by the investigator when co-administered 
with PF-07321332/ritonavira
Drug Class
Specific Medication
Clinical Comments
Antidepressant
Citalopram, Escitalopram, 
Sertraline, 
No data available
Co-administration may decrease Sertraline 
and Bupropion concentrations.
Antihypertensive 
Angiotensin receptor 
blockers: 
Losartan, Valsartan 
Co-administration with Ritonavir increases 
the level/effect of Losartan by affecting 
hepatic/intestinal enzyme CYP3A4 
metabolism. Ritonavir increases the 
level/effect of Valsartan by decreasing 
hepatic clearance. To be used with caution. 
Antiparasitic:
Atovaquone
Quinine
Co-administration with Ritonavir may 
decrease the concentration of Atovaquone.
Co-administration with Ritonavir may 
decrease concentration of Quinine.
Antipsychotic: 
Haloperidol 
Co-administration with ritonavir increases 
the level/effect of Haloperidol by affecting 
hepatic/intestinal CYP3A4 metabolism. 
Haloperidol and Ritonavir both increase 
QTc interval. To be used with caution. 
Bronchodilator:
Theophylline
Co-administration with Ritonavir may 
decrease Theophylline concentration.
Corticosteroids 
Fluticasone 
Ritonavir twice daily increases Fluticasone 
AUC 350-fold 
HIV Antivirals
Non-nucleoside 
reverse transcriptase 
inhibitors
CCR5-antagonist
Integrase inhibitors
Delavirdine
Maraviroc
Raltegravir
Co-administration may increase Ritonavir 
concentration.
Co-administration may increase Maraviroc 
concentration.
Raltegravir concentrations may be 
decreased.
Hypoglycemics
Canagliflozin
Co-administration may decrease
Canagliflozin concentration.
Narcotic and 
Treatment for Opioid 
Dependence
Tramadol
Co-administration may increase 
concentration of Tramadol.


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Medications may be used with caution and require oversight by the investigator when co-administered 
with PF-07321332/ritonavira
Drug Class
Specific Medication
Clinical Comments
PDE-5 Inhibitors for 
treatment of erectile 
dysfunction
Sildenafil– ED (max dose 25 mg 
every 48 hours)
Avanafil
Tadalafil (max dose 10 mg every 72 
hours)
Vardenafil (max dose 2.5 mg every 72 
hours)
Risk of visual disturbances, hypotension, 
prolonged erection, and syncope
Steroids (systemic)
Dexamethasone
Prednisone
Co-administration with ritonavir may 
increase dose of Dexamethasone and 
Prednisone and may increase the risk for 
development of systemic corticosteroid 
effects including Cushing’s syndrome and 
adrenal suppression.
Stimulant
Methamphetamine
Co-administration with Ritonavir may 
increase concentration of  
Methamphetamine.
a.
Note: If a drug is not listed, it should not automatically be assumed it is safe to co-administer


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10.9. Appendix 9: Signs and Symptoms Consistent With COVID-19
Table 2.
Signs and Symptoms Consistent With COVID-19
Daily Sign and Symptom Collection53
Exclusion 
Criterion #2
Daily Signs and 
Symptom 
Collection
Targeted 
Symptoms For 
Analysis
Cough
X
X
X
Shortness of breath or difficulty breathing 
X
X
X
Fever (documented temperature >38˚C [100.4˚F]) or 
subjective fever (eg, feeling feverish)
X
Feeling feverish
X
X
X
Chills or shivering
X
X
X
Fatigue (low energy or tiredness)
X
X
X
Muscle or body aches
X
X
X
Diarrhea (loose or watery stools)
X
X
X
Nausea (feeling like you wanted to throw up)
X
X
X
Vomiting (throw up)
X
X
X
Headache
X
X
X
Sore throat
X
X
X
Stuffy or runny nose
X
X
X
Loss of smell 
X
X
X
Loss of taste
X
X
X


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10.10. Appendix 10: High-Risk Close Contact Behaviors
High-risk close contact is defined as any of the following exposures without the consistent 
appropriate use of recommended personal protective equipment (eg, face mask)44:

Provided direct care for the index case

Had close direct physical contact with the index case

Lived with the index case

Had close indoor contact (within 2 m), with or without direct physical contact, for at 
least 1 hour

Had direct contact with infectious body fluids, including oral secretions, respiratory 
secretions, or stool.


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10.11. Appendix 11: Risk Factors Associated With Severe COVID-19 Illness67

≥60 years of age

BMI >25

Current smoker (cigarette smoking within the past 30 days) and history of at least 
100 lifetime cigarettes

Immunosuppressive disease (eg, bone marrow or organ transplantation or primary 
immune deficiencies) OR prolonged use of immune-weakening medications:
o
Has received corticosteroids equivalent to prednisone ≥20mg daily for at least 
14 consecutive days within 30 days prior to study entry
o
Has received treatment with biologics (eg, infliximab, ustekinumab), 
immunomodulators (eg, methotrexate, 6MP, azathioprine), or cancer 
chemotherapy within 90 days prior to study entry’
o
HIV infection with CD4 cell count <200 mm3 and a viral load less than 
400 copies/mL.

Chronic lung disease (if asthma, requires daily prescribed therapy)

Known diagnosis of hypertension

CVD, defined as history of any of the following: myocardial infarction, stroke, TIA, 
HF, angina with prescribed nitroglycerin, CABG, PCI, carotid endarterectomy, and 
aortic bypass

Type 1 or Type 2 diabetes mellitus

CKD 

Sickle cell disease

Neurodevelopmental disorders (eg, cerebral palsy, Down's syndrome) or other 
conditions that confer medical complexity (eg, genetic or metabolic syndromes and 
severe congenital anomalies);

Active cancer, other than localized skin cancer, including those requiring treatment as 
long as the treatment is not among the prohibited medications that must be 
administered/continued during the study period;

Medical-related technological dependence (eg, CPAP [not related to COVID-19]).


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10.12. Appendix 12: Country Specific Requirements
10.12.1. Japan
A Protocol Administrative Change Letter was issued on 22 July 2021 to provide Japan 
country specific guidance regarding Exclusion Criterion #5 .
Exclusion Criterion #5: Known HIV infection with a viral load >400 copies/mL or taking 
prohibited medications for HIV treatment (from known medical history within past 6 months 
of the screening visit).
If HIV infection is known by medical interview or examination results (if any), the 
investigators must consult with the patient’s HIV treatment specialist to confirm that the HIV 
RNA level has been monitored at an appropriate frequency and the HIV RNA level has been 
≤400 copies/mL during the past 6 months before the screening visit in order to assess the 
study eligibility of that patient.
Rationale: There is a risk for patients with uncontrolled HIV to develop resistance to 
ritonavir which is being administered with PF-07321332. According to the HIV treatment 
guideline in Japan, even if there is an occasional increase in the amount of HIV RNA in the 
blood to about 20-500 copies/mL, the same treatment may be continued. The guideline 
recommends a resistance test when HIV RNA levels exceed 500 copies/mL.
10.12.2. Bulgaria
A Protocol Administrative Change Letter was issued on 26 Oct 2021 to provide Bulgaria 
country specific guidance regarding exclusion criteria 3 and 5 on participants with known 
hepatitis B or C infection (chronic or active) or poorly controlled HIV (viral load >400 
copies/mL within the last 6 months).
Per guidance from Bulgarian regulatory authorities, hepatitis B and C and HIV testing must 
be performed for all participants being evaluated for participation in Study C4671006 to 
objectively confirm that participants do not have active or chronic hepatitis B or C or poorly 
controlled HIV infection as specified in protocol exclusion criteria 3 and 5. Required viral 
testing should be performed at the local laboratory and results are to be retained in participant 
source documents. If results for the required testing are not available within the protocol 
specified Screening period (24 hours prior to randomization), the participant will not be 
eligible to participate in the study.
Revised note on Clinical Laboratory Tests from section 1.3 (additions in bold):

Local testing for hepatitis B, hepatitis C and HIV is required to confirm 
participant eligibility per exclusion criteria 3 and 5.


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10.12.3. Ukraine
A Protocol Administrative Change Letter was issued on 22 Dec 2021 to provide Ukraine 
country specific guidance regarding nasal swab collection.
As per Ministry of Health of Ukraine Order # 722 dated 28-Mar-2020, requirement is made 
to have diagnostic tests for COVID-19 performed by a healthcare professional. The change 
being made in this letter is to shift from nasal swab self collection by the participants to nasal 
swab collection performed by a healthcare professional.
Revised note on Nasal Swab from section 1.3 (deletions in strikethrough)

At baseline, a nasal swab will be self collected by the participant to determine RT-
PCR status (+ or -); this test will not be used to determine study eligibility. The 
sample will be collected under observation by site staff to ensure correct collection 
method. Thereafter, nasal swabs will be self collected by the participant at about the 
same time each day, preferably in the morning. 

Nasal swabs will be self collected from Day 1 to 14 including days when a study visit 
occurs (**including at unplanned visits).
Revised first paragraph from section 8.6.4.2 (deletions in strikethrough, additions in bold): 
The first nasal swab will be self collected by the participant under observation by site staff to 
ensure correct collection method. Thereafter, Nasal swabs will be self collected by a 
healthcare professional the participant at about the same time each day, preferably in the 
morning. If an in-person visit occurs on the same day as self collection of the nasal swab, the 
nasal swab self-collection should be done prior to the visit. 
Additional swabs may be required at the visit on days for which an in-person visit occurs (eg, 
COVID-19 Signs/Symptoms Onset visit). Participants A healthcare professional should 
collect conduct the nasal swab self-collection for Viral Load Assessment by central lab 
prior to any other swab on the days described in the SoA, including those for which an in-
person visit is scheduled.
It is noted that the PACL dated 14 December 2021 is not applicable in Ukraine.


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10.13. Appendix 13: Glossary of Terms
Term
Definition68-70
Close contact
Someone who has been within 6 feet (1.8 meters) of an infected 
person (laboratory-confirmed or a clinically compatible illness) 
for a cumulative total of 15 minutes or more over a 24-hour 
period (for example, 3 individual 5-minute exposures for a total 
of 15 minutes in one day). 
Contact
Exposure to a source of an infection; a person who has been 
exposed
Confirmed COVID-19 
case
Report of person with COVID-19 and meeting confirmatory 
evidence.
Exposure
Having come into contact with a cause of, or possessing a 
characteristic that is a determinant of, a particular health 
problem
High-risk group
A group of persons whose risk for a particular disease, injury, 
or other health condition is greater than that of the rest of their 
community or population
Household
A group of people (two or more) living in the same residence
Including, but not limited to:

Two or more people living together in a domestic 
residence (residential institutions, such as boarding 
schools, dormitories, hotels or prisons will be excluded) 
and 

A dwelling or group of dwellings with a shared kitchen 
or common opening onto a shared household space
Household contact
Any person who has resided in the same household (or other 
closed setting) as a confirmed COVID-19 case
Incubation period
Period of time between exposure to an infection and onset of 
symptoms
Index case
The first case or instance of a patient coming to the attention of 
health authorities. For this study, the index case is the 
individual with the first confirmed SARS-CoV-2 infection in 
the household that the participant resides in. This individual is 
presumed to be the source case.
Isolation
The separation of a person or group of people known or 
reasonably believed to be infected with a communicable disease 
and potentially infectious from those who are not infected to 
prevent spread of the communicable disease. Isolation for 


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Term
Definition68-70
public health purposes may be voluntary or compelled by 
federal, state, or local public health order.
Multigenerational 
household
Households that consist of more than 2 generations living under 
the same roof. Many researchers also include households with a 
grandparent and at least one other generation.
Quarantine
The separation of a person or group of people reasonably 
believed to have been exposed to a communicable disease but
not yet symptomatic from others who have not been so exposed 
to prevent the possible spread of the communicable disease. 
Quarantine may be voluntary or compelled by federal, state, or 
local public health order.
Secondary attack rate
A measure of the frequency of new cases of a disease among 
the contacts of known patients
Source Case
The case or instance of a patient responsible for transmitting 
infection to others; the instance of a patient who gives rise to an 
outbreak or epidemic


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10.14. Appendix 14: Abbreviations
The following is a list of abbreviations that may be used in the protocol.
Abbreviation
Term
3CL
3C-like protein
6MP
mercaptopurine
Abs
absolute
AE
adverse event
AESI
adverse events of special interest
ALT
alanine aminotransferase
ANCOVA
analysis of covariance
APTT
activated partial thromboplastin time
ARDS
acute respiratory distress syndrome
AST
aspartate aminotransferase
AUC
area under the concentration-time curve
AV
atrioventricular
-hCG
beta-human chorionic gonadotropin
BID
twice a day
BMI
body mass index
bpm
beats per minute
BUN
blood urea nitrogen
CABG
coronary artery bypass graft
CCR5
chemokine receptor type 5
CD4
cluster of differentiation 4
CDC
United States Centers for Disease Control and Prevention
CFR
Code of Federal Regulations
CHW
Cui, Hung, and Wang
CI
confidence interval
CIOMS
Council for International Organizations of Medical Sciences
CK
creatine kinase
CKD
chronic kidney disease
CKD-EPI
chronic kidney disease epidemiology 
Cmax
maximum observed concentration
CO2
carbon dioxide (bicarbonate)
CONSORT
Consolidated Standards of Reporting Trials
COVID-19
coronavirus disease 2019
CPAP
continuous positive airway pressure
CRF
case report form
CRO
contract research organization
CSR
Clinical Study Report
CT
clinical trial
Ctrough
predose concentration
CVD
cardiovascular disease


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Abbreviation
Term
CYP
cytochrome P450
DAA
direct acting antivirals
DAIDS
Division of AIDS
DDI
drug-drug interaction 
DILI
drug-induced liver injury
DMC
Data Monitoring Committee
DNA
deoxyribonucleic acid
dNHBE
differentiated normal human bronchial epithelial cells
DU
dispensable unit
EC
ethics committee
EC90
concentration required for 90% effect
ECC
emergency contact card
ECDC
European Centre for Disease Prevention and Control
ECG
electrocardiogram
eCRF
electronic case report form
ED
erectile dysfunction
EDB
exposure during breastfeeding
E-DMC
external data monitoring committee
EDP
exposure during pregnancy
eGFR
epidermal growth factor receptor
EMA
European Medicines Agency
EQ-5D
EuroQol-5 Dimensions
EQ-5D-3L
EuroQol-5 Dimensions 3-Levels
EQ-5D-5L
EuroQol-5 Dimensions 5-Levels
ET
early termination
EU
European Union
EUA
Emergency Use Authorization
EudraCT
European Clinical Trials Database
FAS
full analysis set
FDA
Food and Drug Administration
FIH
first-in-human
FSH
follicle-stimulating hormone
fu
fraction of unbound drug in serum or plasma
GCP
Good Clinical Practice
GEE
Generalized estimating equation
GGT
gamma-glutamyl transferase
GLP
Good Laboratory Practice
Ha
alternative hypothesis
HCoV
human coronavirus
HCP
health care professional; health care provider
HCV
hepatitis C virus
HDPE
high-density polyethylene


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Abbreviation
Term
HF
heart failure
HIV
human immunodeficiency virus
H0
Null hypothesis
HR
heart rate
HRT
hormone replacement therapy
hsCRP
high-sensitivity C-reactive protein
HTA
health technologies assessment
IB
Investigator’s Brochure
ICD
informed consent document
ICH
International Council for Harmonisation
ICU
intensive care unit
ID
identification
IMP
investigational medicinal product
IND
Investigational New Drug
INR
international normalized ratio
IP manual
investigational product manual
IPAL
Investigational Product Accountability Log
IRB
Institutional Review Board
IRT
Interactive Response Technology
IV
intravenous
IWR
interactive Web-based response
LDH
lactate dehydrogenase
LFT
liver function test
mAb
monoclonal antibody
MAD
multiple ascending dose
mITT
modified intent-to-treat
MMRM
mixed-effect model repeated measure
MRC-5
human lung epithelial cells-5
msec
millisecond
NA
not applicable
NCT
national clinical trial
NHP
non-human primate
NIH
National Institutes of Health
NIMP
noninvestigational medicinal product
NP 
nasopharyngeal
PACL
protocol administrative change letter
PCI
percutaneous coronary intervention
PDE-5
phosphodiesterase
PK
pharmacokinetic(s)
PP
Per-protocol
PRO
patient-reported outcome
PT
prothrombin time


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Abbreviation
Term
PVC
premature ventricular contraction
q12h
every 12 hours
QSP
Quantitative Systems Pharmacology
QT
time from the beginning of the QRS complex to the end of the T 
wave
QTc
corrected QT
QTcF
corrected QT using Fridericia’s formula
QTL
quality tolerance limit
RBC
red blood cell
RNA
ribonucleic acid
RSV
respiratory syncytial virus
RT-PCR
reverse transcription polymerase chain reaction
RT-qPCR
real-time quantitative polymerase chain reaction
SAD
single ascending dose
SAE
serious adverse event
SAP
Statistical Analysis Plan
SARS-CoV-2
severe acute respiratory syndrome coronavirus 2
SC
subcutaneous
SoA
schedule of activities
SoC
standard of care
SOC
System Organ Class
SOP
standard operating procedure
SRSD
single reference safety document
SUSAR
Suspected Unexpected Serious Adverse Reaction
T4
thyroxine
TBili
total bilirubin
TEAE
treatment-emergent adverse event
TIA
transient ischemic attack
TSH
thyroid-stimulating hormone
ULN
upper limit of normal
US
United States
USPI
United States Prescribing Information; United States Package 
Insert
VAS
visual analog scale
WBC
white blood cell
WHO
World Health Organization
WOCBP
woman/women of childbearing potential
WPAI
Work Productivity and Activity Impairment Questionnaire
WPAI-GH
Work Productivity and Activity Impairment Questionnaire-General
Health


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10.15. Appendix 14: Protocol Amendment History
Amendment 1 (20 August 2021)
The Protocol Amendment Summary of Changes Table for the current amendment is located 
directly before the table of contents (TOC).  The protocol amendment summary of changes 
tables for past amendment(s) can be found below:
Overall Rationale for the Amendment 1: 
The protocol was amended to modify the eligibility criteria for the study to exclude Rapid 
Antigen Test positive participants, modify the primary analysis set, and provide clearer 
guidance for assessment of participants who develop symptomatic SARS-CoV-2 infection. 
Section # and Name
Description of Change
Brief Rationale
3. Objectives, Endpoints, 
and Estimands
9. Statistical 
Considerations
Primary analysis set limited to 
participants who have a negative 
RT-PCR result at baseline.
Primary and secondary 
estimand/endpoints adapted to 
include adults who have a 
negative RT-PCR result at 
baseline, as applicable.
Additional detail provided in 
description of primary and key 
secondary analyses including 
intercurrent event.
By excluding participants with a 
positive RT-PCR result at baseline 
from the primary analysis set, this 
analysis more accurately reflects 
postexposure prophylaxis.
Addition of intercurrent events 
provides greater clarity to the 
analysis of primary and key 
secondary endpoints.
1. Protocol Summary
4.1 Overall Design
9.5. Sample Size 
Determination
Increased sample size
Increased sample size accounts for 
participants who have a negative 
screening antigen test, but who 
subsequently have a positive 
RT-PCR result at baseline. 
4.1. Overall Design
Removal of stratification 
variable based on rapid antigen 
test.
Removal of this stratum accounts 
for exclusion of participants who 
have a positive screening antigen
test. 
1. Protocol Summary
4.1. Overall Design
10.1.5.1. Data 
Monitoring Committee
Enrollment pause for unblinded 
E-DMC safety data review of 
sentinel cohort
E-DMC meeting frequency 
specified.
Enrollment pause allows time for 
E-DMC review of sentinel cohort 
safety data prior to further 
enrollment. 
E-DMC meeting frequency 
provides greater clarity in the 
protocol. 


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Section # and Name
Description of Change
Brief Rationale
1. Protocol Summary
4.1. Overall Design
10.1.5.1. Data 
Monitoring Committee
9.4. Interim Analyses
Futility assessment incorporated 
into interim analysis.
More details on interim analysis 
including stopping boundaries 
and discontinuation of treatment 
groups
Futility assessment provides for 
the E-DMC to discontinue one or 
both active treatment groups. 
1.3 Schedule of 
Activities
4.2. Overall Design
8.1.2. Daily Signs and 
Symptoms of COVID-19
8.1.3. COVID-19 Related 
Medical Visit Details
8.2.4. Vital Signs
Addition of COVID-19 Signs/ 
Symptoms Onset visit, including 
triggers for the visit and 
assessments to be performed.
Addition of this visit provides 
guidance for assessment of 
participants who develop 
COVID-19 symptoms.
5.1. Inclusion Criteria 
Participants must have a negative 
screening SARS-CoV-2 rapid 
antigen test to be included in the 
study.
Exclusion of participants with a 
positive screening antigen test will 
reduce enrollment of participants 
with positive baseline RT-PCR 
results. 
10.9. Signs and 
Symptoms Attributable 
to COVID-19
Addition of loss of taste and loss 
of smell to exclusionary 
symptoms and to symptoms that 
will be assessed in efficacy 
analyses.
Loss of taste/smell is a frequent 
first symptom associated with 
SARS-CoV-2 infection.
5.2. Exclusion Criteria
Exclusion of participants with 
history of positive test for anti-
SARS-CoV-2 antibody. 
Exclusion of participants with 
history of positive SARS-CoV-2 
antibody test will reduce factors 
that may obscure treatment effect. 
5.2. Exclusion Criteria
Addition of approved, authorized 
or investigational 
anti-SARS-CoV-2 treatments to 
the list of prohibited medications 
for study entry.
Increases focus of eligibility on 
postexposure prophylaxis.
9.1.2. Multiplicity 
Adjustment
Clarification that if one of the 
PF-07321332/ritonavir groups is 
discontinued, sequential testing 
Increase clarity on multiplicity 
adjustment if one of the 


PF-07321332
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PFIZER CONFIDENTIAL
Page 129
Section # and Name
Description of Change
Brief Rationale
will be performed in the 
remaining 
PF-07321332/ritonavir group in 
the order of the primary endpoint 
and key secondary endpoint.
PF-07321332/ritonavir groups is 
discontinued.
10.12.2. Japan
Japan country-specific 
requirement for consultation on 
HIV RNA monitoring.
Inclusion of this consultation 
incorporates country-specific 
changes to the global protocol. 
6.8 Concomitant Therapy
Clarification that participants 
who develop COVID-19 may 
receive SoC therapy.
Clarification ensures appropriate 
treatment of participants. 
1.3. Schedule of 
Activities
8.2.6. Clinical Safety 
Laboratory Assessments
Investigators are instructed to 
contact the Medical Monitor if 
baseline lab results meet 
exclusion criteria.
Enables investigator to review 
disposition and follow-up with the 
Medical Monitor for participants 
with baseline laboratory 
abnormalities.
1.3. Schedule of 
Activities
Day 14 and Day 38 will be 
in-person visits for all 
participants.
Provides for collection of blood for 
serology testing for all 
participants, but maintains reflex 
testing for safety laboratory tests.
Collection of blood samples for 
SARS-CoV-2 serology on 
Day 14 and Day 38 for all 
participants.
Increases understanding of 
exposure and immune response to 
SARS-CoV-2 infection.
1.3. Schedule of 
Activities
8.6.5. Assessments for 
Other Respiratory 
Pathogens
Additional testing for respiratory 
pathogens at central laboratory 
for protocol-required nasal swabs 
and additional local testing per 
local standard of care.
Allows identification of other 
respiratory pathogens besides 
SARS-CoV-2
1.3. Schedule of 
Activities
8.6 Biomarkers
8.6.4.2. Viral Load 
Assessments
Removal of NP swabs.
Instruction that first nasal swab 
is to be self collected by 
participant under observation of 
site staff.
NP swabs removed to use a 
consistent swab source (nasal).
First nasal swab will be 
self collected by participant under 
observation of site staff to ensure 
correct collection method.
8.6.4.2. Viral Load 
Assessments
SARS-CoV-2 positive nasal 
swab samples will undergo 
additional testing.
Increases understanding of 
SARS-CoV-2 kinetics in study 
participants.


PF-07321332
Protocol C4671006
Final Protocol Amendment 2, 25 January 2022
PFIZER CONFIDENTIAL
Page 130
Section # and Name
Description of Change
Brief Rationale
1.3. Schedule of 
Activities
Updates to description of visit 
conditions in footnotes.
Increases clarity for study conduct.
1.3 Schedule of 
Activities
Added footnote describing the 
study intervention dispensation.
Increases clarity for study conduct.
6.3.2. Blinding of the 
Sponsor
Description of sponsor blinding 
and unblinded team.
Increases clarity for study conduct.
6.2. Preparation, 
Handling, Storage, and 
Accountability
Guidance added regarding 
shipping study intervention by 
courier and temperature 
monitoring for ground 
transportation.
Increases clarity for study conduct.
1.3. Schedule of 
Activities
Allowance for investigators to 
change a telemedicine visit to in-
person at their discretion.
Increases clarity for study conduct.
8.2.2. Height and Weight
Height may be self reported.
Consistency with other C467 
Phase 2/3 studies.
Protocol Title
1. Protocol Summary
2. Introduction
3. Objectives, Endpoints, 
and Estimands
Index cases described as 
individuals with “symptomatic 
COVID-19”.
Document clarity and consistency
8. Study Assessments 
and Procedures
Correct total blood sampling 
volume.
Document clarity and consistency.
10.4.3. Woman of 
Childbearing Potential
FSH is used to confirm 
postmenopausal state in women 
under 50 years of age.
Document clarity and consistency.
Title Page
Phase 3 was updated to Phase 
2/3.
Document clarity and consistency.
Throughout
Editorial changes and correction 
of typographical errors.
Document clarity and consistency.


PF-07321332
Protocol C4671006
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PFIZER CONFIDENTIAL
Page 131
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Final Protocol Amendment 2, 25 January 2022
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Protocol C4671006
Final Protocol Amendment 2, 25 January 2022
PFIZER CONFIDENTIAL
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SAP_001.pdf: 
Protocol C4671006 (PF-07321332) Statistical Analysis Plan
PFIZER CONFIDENTIAL 
Page 1
Protocol C4671006
A PHASE 2/3, RANDOMIZED, DOUBLE-BLIND, DOUBLE-DUMMY,
PLACEBO-CONTROLLED STUDY TO EVALUATE THE SAFETY 
AND EFFICACY OF 2 REGIMENS OF ORALLY ADMINISTERED 
PF-07321332/RITONAVIR IN PREVENTING SYMPTOMATIC 
SARS-COV-2 INFECTION IN ADULT HOUSEHOLD CONTACTS OF 
AN INDIVIDUAL WITH SYMPTOMATIC COVID-19
Statistical Analysis Plan 
(SAP)
Version:
3
Date:
15 Apr 2022


Protocol C4671006 (PF-07321332) Statistical Analysis Plan
PFIZER CONFIDENTIAL 
Page 2
TABLE OF CONTENTS
LIST OF TABLES.....................................................................................................................5
LIST OF FIGURES ...................................................................................................................5
APPENDICES ...........................................................................................................................5
1. VERSION HISTORY............................................................................................................6
2. INTRODUCTION .................................................................................................................9
2.1. Study Objectives, Endpoints, and Estimands............................................................9
2.1.1. Primary Estimand .......................................................................................10
2.1.2. Secondary Estimand ...................................................................................10
2.2. Study Design ...........................................................................................................10
2.3. Sample Size Determination.....................................................................................12
3. ENDPOINTS AND BASELINE VARIABLES: DEFINITIONS AND 
CONVENTIONS ................................................................................................................13
3.1. Primary Endpoint ....................................................................................................13
3.2. Secondary Endpoint(s) ............................................................................................13
3.4. Baseline Variables...................................................................................................14
3.5. Stratification Variables............................................................................................14
3.6. Safety Endpoints .....................................................................................................14
3.6.1. Adverse Events...........................................................................................15
3.6.2. Laboratory Data..........................................................................................15
3.6.3. Vital Signs ..................................................................................................15
4. ANALYSIS SETS (POPULATIONS FOR ANALYSIS)...................................................15
5. GENERAL METHODOLOGY AND CONVENTIONS....................................................17
5.1. Hypotheses and Decision Rules ..............................................................................17
5.2. General Methods .....................................................................................................17
5.2.1. Multiplicity Adjustment..............................................................................18
5.2.2. Analyses for Binary Endpoints...................................................................18
5.2.3. Analyses for Continuous Endpoints ...........................................................18
5.2.4. Analyses for Categorical Endpoints ...........................................................18
5.2.5. Analyses for Count Endpoints....................................................................19
5.2.6. Analyses for Time-to-Event Endpoints ......................................................19
CCI


Protocol C4671006 (PF-07321332) Statistical Analysis Plan
PFIZER CONFIDENTIAL 
Page 3
5.3. Methods to Manage Missing Data ..........................................................................19
6. ANALYSES AND SUMMARIES ......................................................................................19
6.1. Primary Endpoint ....................................................................................................19
6.1.1. Primary Endpoint/Estimand Analysis.........................................................19
6.1.1.1. Main Analysis ...........................................................................19
6.1.1.2. Sensitivity Analyses ..................................................................20
6.2. Secondary Endpoint(s) ............................................................................................21
6.2.1. Incidence of Treatment Emergent Adverse Events (TEAEs).....................21
6.2.2. Incidence of SAEs and AEs Leading to Discontinuations .........................21
6.2.3. Proportion of Participants with Symptomatic, RT-PCR or Rapid 
Antigen Test-confirmed SARS-CoV-2 Infection through Day 14 for 
Participants who have a Negative RT-PCR Result at Baseline and who 
are at Increased Risk of Severe COVID-19 Illness .........................................21
6.2.4. Proportion of Participants with COVID-19 Related Hospitalization 
or Death from Any Cause by Day 28 for Participants who have a 
Negative RT-PCR Result at Baseline and who are at Increased Risk of 
Severe COVID-19 Illness ................................................................................22
6.2.5. Proportion of Participants with Asymptomatic RT-PCR or Rapid 
Antigen Test-confirmed SARS-CoV-2 Infection through Day 14 for 
Participants who have a Negative RT-PCR Result at Baseline.......................22
6.2.6. Time to RT-PCR or Rapid Antigen Test-confirmed SARS-CoV-2 
Infection through Day 14 for Participants who have a Negative RT-PCR 
Result at Baseline.............................................................................................22
6.2.7. Proportion of Participants with Symptomatic RT-PCR or Rapid 
Antigen Test-confirmed SARS-CoV-2 Infection through Day 14 for 
Participants who have a Positive RT-PCR Result at Baseline.........................23
6.2.8. Proportion of Participants with Symptomatic RT-PCR or Rapid 
Antigen Test-confirmed SARS-CoV-2 Infection through Day 14 for 
Participants who have a Negative or Positive RT-PCR Result at 
Baseline............................................................................................................23
6.2.9. Proportion of Participants with No, Mild, Moderate or Severe 
Signs/symptoms Attributed to COVID-19 through Day 28 in 
Participants who have a Negative RT-PCR Result at Baseline.......................23
6.2.10. Number of Days of Symptomatic SARS-CoV-2 Infection through 
Day 28 for Participants who have a Negative RT-PCR Result at 
Baseline............................................................................................................24
6.2.11. PF-07321332 Plasma PK in Plasma and Whole Blood (if feasible) ........24


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6.2.12. Proportion of Participants with Death (all-cause) through Day 38 
for Participants who have a Negative RT-PCR Result at Baseline .................24
6.2.13. Viral Titers (quantitative RT-PCR) Measured in Nasal Swabs Over 
Time for Participants who have a Negative RT-PCR Result at Baseline........24
6.2.14. Viral Titers (quantitative RT-PCR) Measured in Nasal Swabs Over 
Time for Participants who have a Positive RT-PCR Result at Baseline..........25
6.2.15. Number of Days of Hospital and ICU Stay in Participants with 
COVID-19 Related Hospitalization through Day 28 for Participants who 
have a Negative RT-PCR Result at Baseline...................................................25
6.2.16. Number of COVID-19 Related Medical Visits throught Day 28 for 
Participants who have a Negative RT-PCR Result at Baseline.......................25
6.4. Subset Analyses.......................................................................................................26
6.5. Baseline and Other Summaries and Analyses.........................................................26
6.5.1. Baseline and Other Characteristics Summaries..........................................26
6.5.2. Study Conduct and Participant Disposition................................................27
6.5.3. Study Treatment Exposure .........................................................................27
6.5.4. Prior and Concomitant Medications...........................................................27
6.5.5. Medical History ..........................................................................................27
6.6. Safety Summaries and Analyses .............................................................................27
6.6.1. Adverse Events...........................................................................................27
6.6.2. Laboratory Data..........................................................................................27
6.6.3. Vital Signs ..................................................................................................28
7. INTERIM ANALYSES.......................................................................................................28
CCI


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7.1. Interim Analyses and Summaries............................................................................28
7.2. Data Monitoring Committee ...................................................................................28
8. REFERENCES ....................................................................................................................29
9. APPENDICES .....................................................................................................................30
LIST OF TABLES
Table 1.
Summary of Changes..................................................................................6
LIST OF FIGURES
Figure 1.
C4671006 Study Design...........................................................................12
APPENDICES
Appendix 1. Summary of Efficacy Analyses...........................................................................30
Appendix 2. Data Derivation Details.......................................................................................43
Appendix 2.1. Definition and Use of Visit Windows in Reporting.........................................43
Appendix 3. Signs and Symptoms Consistent With COVID-19.............................................44
Appendix 4. Risk Factors Associated With Severe COVID-19 Illness...................................45
Appendix 5. List of Abbreviations...........................................................................................47
Appendix 6. List of Pre-specified AESIs.................................................................................48


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1. VERSION HISTORY
Table 1.
Summary of Changes
Version/
Date
Associated 
Protocol 
Amendment
Rationale
Specific Changes
Version 1/
9 Sep, 2021
Protocol 
amendment 1
Original SAP
NA
Version 2/
23 Feb 2022
Protocol 
amendment 2
Protocol 
amendment 2 
changes,  FDA 
request and other 
clarification

Updated Section 2.1, 3.1, 3.2, 5,1, 5.2, 6.1 and 
6.2 to include rapid antigen test in the definition 
of confirmed SARS-CoV-2 infection for the 
primary objective/estimand/endpoint and 
relevant secondary 
obejective/estimand/endpoints.

Updated Section 2.1, 3.2 and 6.2 to include viral 
titers assessment in participants with a positive 
RT-PCR result at baseline as the secondary 
objective/endpoint and the corresponding 
analysis method.

Updated Section 2.3 sample size to reflect the 
adjustment of the relative risk reduction and the 
placebo event rate.

Updated Section 4 on mITT related analysis 
sets. 

Added more information in Section 5.2 for 
region combination due to limited number of 
participants enrolled in Brazil and the 
description of analysis model in general.

Added the method of handling missing data for 
symptomatic and asymptomatic infection in 
Section 5.3.

Updated/added more information for the 
primary efficacy analysis in Section 6.1.1.1 
including the endpoint defnition, the handling of 
model convergence, and the clarification of 
handling intercurrent events, and subgroup 
analyses.  

Added more sensitivity analyses in 
Section 6.1.1.2.

Updated the definition of Asymptomatic 
infection through Day 14 in Section 6.2.5 to 
align with symptomatic infection defintion.  

Added more details for the analysis of sense of 
taste and sense of smell in Section 6.2.9.

Added more details for PK analysis in 
Section 6.2.11.


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•
Updated/added more analyses for viral titer in 
Section 6.2.13.
•
Added subgroup analyses in Section 6.4.
•
Medical history was moved from safety 
endpoint Section 3.6 and Section 6.6 to baseline 
and demo characteristics Section 6.5.
•
Updated the visit window for baseline in 
Section 3.4 and Appendix 2.1 and Add the 
handling of multiple measurements on the same 
day in Appendix 2.1.
•
Updated Section 7.1 for the timing of the 
planned interim analysis from 45% to 70% of 
enrolment and corresponding alpha levels.
•
Updated references in Section 8.
•
Updated Appendix 1 to align with the analysis 
updates/changes in SAP main body.
•
Clarified in Appendix 4 for the definition of the 
presence of risk factor/increased risk of severe 
COVID-19 illness.
•
Added the list of pre-specified AESI in 
Section 6.6.1 and Appendix 6.
Version 3/
15 Apr 2022
Protocol 
amendment 2
FDA feedback and 
other update/ 
clarification
•
Updated/added more information for analysis 
sets in Section 4 including mITT3 population 
definition, SAS treatment group assigment, 
handling of data cleaning and duplicate 
enrollment for efficacy and safety analyses. 
•
Added sensitivity analyses in Section 6.1.1.2 for 
primary endpoint and in Section 6.2.3, 6.2.7 and 
6.2.8 for secondary endpoints.
•
Added additional efficacy endpoints and/or 
analyses for mITT1 and mITT3 populations
in Section
 6.2.7,
and 6.4.
•
Added more information on handling of model 
convergence and updated age subgroup 
categories in Section 6.4.
•
Clarified and added more details/summary on 
baseline and other summary in Section 6.5.
•
Clarified vital sign analysis in Section 6.6.3.
CCI
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CCI
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
Add the statement of Interim analysis 
completion in Section 7.1.

Updated Appendix 1 to align with the analysis 
updates/changes in SAP main body.

Add the handling of multiple measurements on 
the same day for vital sign and lab data in 
Appendix 2.1.

Editorial changes/clarification in Section 5.2.6, 
Section 6.2.13 and Section 6.2.15.


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2. INTRODUCTION
PF-07321332, a potent and selective SARS-CoV-2 3CL protease inhibitor, is being 
investigated as oral antiviral postexposure prophylaxis for adult household contacts of an 
individual with symptomatic COVID-19.
The purpose of this study is to evaluate the efficacy and safety of PF-07321332/ritonavir as 
postexposure prophylaxis for adult household contacts of an individual with symptomatic 
COVID-19.
2.1. Study Objectives, Endpoints, and Estimands
Primary Efficacy Objective: 
To compare the efficacy of 5-day and 10-day regimens of PF-07321332/ritonavir versus 
placebo in preventing symptomatic RT-PCR or rapid antigen test- confirmed SARS-CoV-2 
infection in adult participants who have a negative RT-PCR result at baseline and who are 
household contacts of an individual with symptomatic COVID-19.
Secondary Objective:
To describe the safety and tolerability of 5-day and 10-day regimens of 
PF-07321332/ritonavir relative to placebo in adult participants who have a negative or 
positive RT-PCR result at baseline and who are household contacts of an individual with 
symptomatic COVID-19.
To compare the efficacy of 5-day and 10-day regimens of PF-07321332/ritonavir versus 
placebo in preventing symptomatic RT-PCR or rapid antigen test- confirmed SARS-CoV-2 
infection in adult participants who have a negative RT-PCR result at baseline, who are at 
increased risk of severe COVID-19 illness, and who are household contacts of an individual 
with symptomatic COVID-19.
To compare the efficacy of 5-day and 10-day regimens of PF-07321332/ritonavir versus 
placebo in preventing SARS-CoV-2 infection in adult participants who have a negative or 
positive RT-PCR result at baseline and who are household contacts of an individual with 
symptomatic COVID-19.
To compare the efficacy of 5-day and 10-day regimens of PF-07321332/ritonavir versus 
placebo in the duration and severity of COVID-19 related signs and symptoms in adult 
participants who have a negative RT-PCR result at baseline and who are household contacts 
of an individual with symptomatic COVID-19.
To determine the PK of PF-07321332 in adult participants who have a negative or positive 
RT-PCR result at baseline and who are household contacts of an individual with 
symptomatic COVID-19.


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To describe all-cause mortality in adult participants who have a negative RT-PCR result at 
baseline and who are household contacts of an individual with symptomatic COVID-19.
To describe the viral load in nasal samples over time in adult participants who have a 
negative or positive RT-PCR result at baseline and who are household contacts of an 
individual with symptomatic COVID-19.
To describe hospitalizations in adult participants who have a negative RT-PCR result at 
baseline and who are household contacts of an individual with symptomatic COVID-19.
To describe COVID-19 related medical visits in adult participants who have a negative 
RT-PCR result at baseline and who are household contacts of an individual with 
symptomatic COVID-19.
2.1.1. Primary Estimand
The risk reduction between 5-day and 10-day regimens of PF-07321332/ritonavir versus
placebo in the proportion of individuals who develop symptomatic RT-PCR or rapid antigen 
test- confirmed SARS-CoV-2 infection through Day 14 in adults who have a negative 
RT-PCR result at baseline and are household contacts of an individual with symptomatic 
COVID-19. This will be estimated without regard to adherence to randomized treatment.
2.1.2. Secondary Estimand
The risk reduction between 5-day and 10-day regimens of PF-07321332/ritonavir versus
placebo in the proportion of individuals who develop symptomatic RT-PCR or rapid antigen 
test- confirmed SARS-CoV-2 infection through Day 14 in adults who have a negative 
RT-PCR result at baseline, who are at increased risk of severe COVID-19 illness, and who 
are household contacts of an individual with symptomatic COVID-19. This will be estimated 
without regard to adherence to randomized treatment.
Symptomatic RT-PCR or rapid antigen test- confirmed infection through Day 14 is 
considered the main clinical outcome measure so estimands for the measure in targeted 
populations are presented. Estimands for the other outcome measures/populations are 
considered supportive of the main outcome measures and are not presented.
2.2. Study Design
This Phase 2/3, randomized, double-blind, double-dummy, placebo-controlled study will
compare the efficacy of 2 regimens of PF 07321332/ritonavir versus placebo in
approximately 2880 participants who have a negative screening SARS-CoV-2 rapid antigen
test result and are asymptomatic household contacts of individuals who are symptomatic and
recently tested positive for SARS-CoV-2 (index case: defined as patient with symptomatic
COVID-19). Index cases may be participants in Phase 2/3 safety and efficacy studies of
PF-07321332/ritonavir (C4671002 and C4671005), but this is not required. Eligible
participants for this study will be randomly assigned (1:1:1) within 96 hours after collection
of the index case’s first positive SARS-CoV-2 test to receive:


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
PF-07321332/ritonavir q12h for 5 days followed by matching placebo q12h for 
5 days; or

PF-07321332/ritonavir q12h for 10 days; or

Matching placebo for PF-07321332/ritonavir q12h for 10 days.
Randomization will be stratified based on the presence of risk factors associated with severe
COVID-19 illness and geographic region at screening. Throughout the study period, 
provision will be made to allow study visits to be conducted at a participant’s home or at 
another nonclinic location approved by the investigator where possible when participants 
are unwilling or unable to attend a clinic visit at the investigational site.
Participants will be screened within 24h before randomization. The total duration of the 
study is up to 42 days and includes screening, study intervention through Day 10, efficacy
assessments through Day 14, and a safety follow-up period through Day 38 [±3 days].
An independent E-DMC will review unblinded data to ensure the safety of participants on an
ongoing basis throughout the duration of the study. In addition to up to weekly reviews of
safety data, the E-DMC will review the following:

Sentinel cohort safety review: The E-DMC will review unblinded safety data after
approximately the first 150 participants have completed Day 10 of the study, at which
point enrollment will be paused pending E-DMC review of the safety data. After
review of the sentinel cohort, the frequency of safety reviews may be reduced
subsequently based on E-DMC recommendations.

Interim analysis: An interim analysis will be conducted for efficacy, futility, and
sample size re-estimation and reviewed by an E-DMC after a prespecified accrual of
participants (ie, before or at approximately 70% participants have complete the
Day 14 assessments with a minimum number of 24 participants having symptomatic 
infection [mITT analysis set]).
Subsequent to the planned interim analysis, there will be a single analysis for reporting the
results of this study after all participants have had their last study visit. The study schematic 
is provided in Figure 1.


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Figure 1.
C4671006 Study Design
2.3. Sample Size Determination
Based on the results from Study C4671005, which showed PF-07321332/ritonavir treatment 
significantly reduced the risk of hospitalization or death from any cause by 89% compared 
with placebo in nonhospitalized symptomatic adult participants with COVID-19 who were at 
increased risk of progression to severe disease when they were treated within 3 days of 
symptom onset, and the high relative risk reduction (approximately 80%) observed in 
Regeneron REGEN-COV post-exposure prophylaxis study, the risk reduction between 
PF-07321332/ritonavir group versus placebo group is assumed to be 70%. The symptomatic 
infection rate assumption in the placebo group is adjusted to 4% based on the observed 
seropositivity rate in this study and the impact of seropositivity on the incidence of primary 
endpoint events in the REGEN-COV post-exposure prophylaxis study where the incidence of 
symptomatic infection was 2% in participants who were seropositive and 8% in those who 
were seronegative.1 As of January 2022, a large percentage of participants were observed to 
be seropositive. Based on a 2% placebo event rate for participants who were seropositive 
and 8% placebo rate for participants who were seronegative observed in the REGEN-COV 
postexposure prophylaxis study 1 the expected placebo rate across the 2 groups is estimated 
to be approximately 3%. In addition, based upon emerging epidemiology data for the 
Omicron variant,2,3 which suggests higher infectivity than with prior variants, the placebo 
rate is adjusted to be 4%.
Among baseline RT-PCR negative participants, assuming a 4% symptomatic infection rate in 
the placebo group, a 70% reduction in symptomatic infection (1.2% symptomatic infection 
rate) in the PF-07321332/ritonavir group (5-day and 10-day regimen), a sample size of 
821 participants per group (2463 participants total) will provide approximately 90% power 
for each comparison between 5-day and 10-day regimens of PF-07321332/ritonavir group 
versus placebo group under a 2-sided type-1 error rate of 5%. Assuming approximately 
5% of participants with negative rapid antigen test result at screening will have a positive 
RT-PCR result at baseline, and assuming an approximately 10% dropout rate, the total 
sample size for this study will be approximately 2880 participants.
Study enrollment will stop once approximately 2463 participants are evaluable and at least 
34 participants had symptomatic infection for the primary analysis. However, enrollment 
may continue until the 70% interim analysis has been completed.


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3. ENDPOINTS AND BASELINE VARIABLES: DEFINITIONS AND 
CONVENTIONS
3.1. Primary Endpoint

Proportion of participants who develop a symptomatic, RT-PCR or rapid antigen 
test- confirmed SARS-CoV-2 infection through Day 14 for participants who have a 
negative RT-PCR result at baseline.
3.2. Secondary Endpoint(s)

Incidence of treatment emergent adverse events (TEAEs).

Incidence of Serious Adverse Events (SAEs) and Adverse Events (AEs) leading to 
discontinuations.

Proportion of participants with symptomatic, RT-PCR or rapid antigen 
test- confirmed SARS-CoV-2 infection through Day 14 for participants who have a 
negative RT-PCR result at baseline and who are at increased risk of severe 
COVID-19 illness.

Proportion of participants with COVID-19 related hospitalization or death from any 
cause by Day 28 for participants who have a negative RT-PCR result at baseline and 
who are at increased risk of severe COVID-19 illness.

Proportion of participants with asymptomatic RT-PCR or rapid antigen 
test- confirmed SARS-CoV-2 infection through Day 14 for participants who have a 
negative RT-PCR result at baseline.

Time to RT-PCR or rapid antigen test- confirmed SARS-CoV-2 infection through Day 
14 for participants who have a negative RT-PCR result at baseline.

Proportion of participants with symptomatic RT-PCR or rapid antigen test- confirmed 
SARS-CoV-2 infection through Day 14 for participants who have a positive RT-PCR 
result at baseline.

Proportion of participants with symptomatic RT-PCR or rapid antigen test- confirmed 
SARS-CoV-2 infection through Day 14 for participants who have a negative or 
positive RT-PCR result at baseline.

Proportion of participants with no, mild, moderate, or severe signs and symptoms 
attributed to COVID-19 through Day 28 for participants who have a negative 
RT-PCR result at baseline.

Number of days of symptomatic SARS-CoV-2 infection through Day 28 for 
participants who have a negative RT-PCR result at baseline.


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•
PF-07321332 PK in plasma and whole blood (if feasible).
•
Proportion of participants with death (all-cause) through Day 38 for participants 
who have a negative RT-PCR result at baseline.
•
Viral titers measured via RT-PCR in nasal swabs over time for participants who have 
a negative RT-PCR result at baseline.
•
Viral titers measured via RT-PCR in nasal swabs over time for participants who have 
a positive RT-PCR result at baseline.
•
Number of days of hospital and ICU stay in participants with COVID-19-related 
hospitalization through Day 28 for participants who have a negative RT-PCR result 
at baseline.
•
Number of COVID-19 related medical visits through Day 28 for participants who 
have a negative RT-PCR result at baseline.
3.4. Baseline Variables
Baseline visit (Day 1) will be defined as the latest measurement between Day -2 and Day 1. 
3.5. Stratification Variables
Randomization will be stratified based on the presence of risk factors associated with severe
COVID-19 illness (Appendix 4) and geographic region at screening.
3.6. Safety Endpoints
The safety endpoints of this study are: 
•
Incidence of TEAEs;
CCI


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
Incidence of SAEs and AEs leading to discontinuations;

Laboratory assessments;

Vital signs.
Clinical Data Interchange Standards Consortium (CDISC) and Pfizer Standards (CaPs) will
be used for the analysis of standard safety data.
3.6.1. Adverse Events
An AE is any untoward medical occurrence in a study participant administered a product or 
medical device; the event need not necessarily have a causal relationship with the treatment 
or usage. An adverse event is considered a TEAE if the event started on or after the study 
medication start date and time.
3.6.2. Laboratory Data
Laboratory data includes hemotology, chemistry and other safety tests. To determine if there 
are any clinically significant laboratory abnormalities, the hematological and chemistry and 
other safety tests will be assessed against the criteria specified in the Pfizer reporting
standards. This assessment will take into account whether each participant’s baseline test 
results are within or outside the laboratory reference range for particular laboratory 
parameter.
3.6.3. Vital Signs
Vital signs measurements include temperature, pulse rate, respiratory rate, and blood 
pressure. Participants attending a COVID-19 Signs/Symptoms Onset visit will also have 
oxygen saturation measured.
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.
Population
Description
Full Analysis Set (FAS)
All participants randomly assigned to study intervention
regardless of whether or not study intervention was 
administered.
Safety Analysis Set (SAS) All participants randomly assigned to study intervention and 
who take at least 1 dose of study intervention.
Participants will be analyzed according to the intervention they 
actually received. A randomized but not treated participant will 
be excluded from the safety analyses.  


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Population
Description
Modified Intent-To-Treat 
(mITT)
All participants randomly assigned to study intervention who 
take at least 1 dose of study intervention and have a negative 
RT-PCR result at baseline.
Participants will be analyzed according to the study 
intervention they were randomized.
Modified Intent-To-Treat 
(mITT1)
All participants randomly assigned to study intervention who 
take at least 1 dose of study intervention and have a positive 
RT-PCR result at baseline.
Participants will be analyzed according to the study 
intervention they were randomized.
Modified Intent-To-Treat 
(mITT2)
All participants randomly assigned to study intervention who 
take at least 1 dose of study intervention and have a negative 
RT-PCR result at baseline and are at increased risk of severe 
COVID-19 illness (Appendix 4).
Participants will be analyzed according to the study 
intervention they were randomized.
Modified Intent-To-Treat 
(mITT3)
All participants randomly assigned to study intervention who 
take at least 1 dose of study intervention and have a negative,
positive or missing RT-PCR result at baseline.
Participants will be analyzed according to the study 
intervention they were randomized.
Per-Protocol (PP)
All participants in the mITT set without important protocol 
deviations considered to impact the interpretation of the 
primary efficacy endpoint. Protocol deviations will be reviewed 
to generate the list of participants with significant deviations to 
be excluded from the PP analysis set. The PP exclusion criteria 
will be finalized prior to breaking the blind.
The primary population for efficacy analysis is mITT.  
The primary population for safety analysis is SAS, where participants will be analyzed 
according to the intervention they actually received. If a participant receives PF-07321332
kit(s) (containing PF-07321332 or matching placebo) different from the kit(s) assigned by 
randomization, the participant will be analyzed according to the actually received kits. A
participant who first receives matching placebo for PF-07321332 and then PF-07321332 will 
be analyzed as in 5-day treatment group.


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For efficacy related analysis (mITT, mITT1, mITT2, mITT3 and PP), participants with data 
cleaned for reporting purposes will be included in the analysis. A sensitivity analysis for the 
primary endpoint will be performed in mITT population regardless of data cleaning level. For 
safety analysis (SAS), all safety data will be included regardless of data cleaning level.
For efficacy related analysis (mITT, mITT1, mITT2, mITT3 and PP), if a participant 
enters/is randomized into the study multiple times, the data associated with first 
randomization will be included in the analysis. Sensitivity analyses for the primary endpoint 
and secondary endpoints will be performed using all efficacy data by considering all 
randomized participants as independent participants. For safety analysis (SAS), all safety
data will be included by considering all randomized participants as independent participants. 
5. GENERAL METHODOLOGY AND CONVENTIONS
The final analysis will be performed after dataset release.
5.1. Hypotheses and Decision Rules
The primary hypothesis is to test, in participants who have a negative RT-PCR at baseline,
whether or not the risk ratio between 5-day and 10-day regimens of PF-07321332/ritonavir
versus placebo in the proportion of participants who develop symptomatic RT-PCR or rapid 
antigen test-confirmed infection through Day 14 is equal to 1:
Ho:   πPF-7321332 /πplacebo = 1
versus 
Ha:  π PF-7321332 / πplacebo ്1
Where π PF-7321332 and πplacebo are the symptomatic infection rate through Day 14 for 5-day 
and 10-day regimens of PF-07321332/ritonavir versus placebo groups in participants who 
have a negative RT-PCR result at baseline. The hypotheses will be tested at an overall 
significant level of 5% (2-sided).
5.2. General Methods
All data will be presented by treatment group. Descriptive statistics will be provided for 
efficacy endpoints.
The number of participants randomized to the double-blind treatment phase, completing the 
study drug administration, and completing the study will be summarized from the FAS. The 
reason for discontinuations will be summarized by treatment group.
Baseline demographic and other characteristics will be tabulated for the FAS and
summarized by treatment group. Quantitative variables will be described by standard
descriptive statistics (mean, standard deviation, minimum, and maximum), and qualitative
variables will be summarized by frequency tables with number and proportion in each
category (with the corresponding sample sizes).


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Due to limited number of participants enrolled in Brazil, Brazil region will be combined with 
rest of the World region when appropriate.
Unless otherwise specified, the analysis model will include the fixed effects of treatment, 
geographic regions and presence of risk factors associated with severe COVID-19 illness.
5.2.1. Multiplicity Adjustment
There will be 2 group comparisons for the primary endpoint: 5-day regimen of
PF-07321332/ritonavir versus placebo groups and 10-day regimen of PF-07321332/ritonavir
versus placebo groups. Multiplicity adjustment for the primary endpoint will be made for
multiple comparisons using Hochberg method.4
Following the positive test of the primary endpoint, the following key secondary endpoint
will be tested: proportion of participants with symptomatic RT-PCR or rapid antigen test-
confirmed SARS-CoV-2 infection through Day 14 in participants who have a negative
RT-PCR result at baseline and who are at increased risk of severe COVID-19 illness.
If the primary endpoint is significant for both treatment groups, the key secondary endpoint 
will be tested at an overall level of 5% (2-sided) using Hochberg methodto adjust for 
multiple comparisons for both treatment groups.
If one of PF-07321332/ritonavir regimens is discontinued, sequential testing will be 
performed in the remaining PF-07321332/ritonavir regimen in the order of primary endpoint 
and the key secondary endpoint.
5.2.2. Analyses for Binary Endpoints
For binary endpoints (ie, participants with or without symptomatic or asymptomatic 
infection), the proportion of participants with the event will be summarized for each group. 
Treatment comparison between the groups will be presented as the risk ratio/reduction of 
proportions with its 95% confidence intervals using a similar analysis method as the primary 
endpoint. For other binary endpoints, logistic regression model will be preformed when
applicable.
5.2.3. Analyses for Continuous Endpoints
For continuous endpoints (ie, viral titer), descriptive statistics will be summarized for each 
group at each visit. The plot of mean over time will be generated when applicable.
5.2.4. Analyses for Categorical Endpoints
For categorical endpoints (ie, participants with no, mild, moderate or severe signs/symptoms 
attributed to COVID-19), proportion of participant for each category will be summarized for 
each group.


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5.2.5. Analyses for Count Endpoints
For count endpoints (ie, number of COVID-19 related medical visits through Day 28), a 
negative-binomial regression model analysis will be performed using the log-total number of 
days of data collection as the participant offset variable.
5.2.6. Analyses for Time-to-Event Endpoints
For time-to-event endpoints, Kaplan-Meier analysis will provide tabular summaries of the
Kaplan-Meier curves including the median, quartiles (if applicable)for each treatment group. 
In addition, the KM curves will be presented graphically. If significant covariates are 
identified, Cox proportional hazard model will be performed.
5.3. Methods to Manage Missing Data
For the primary endpoint/relevant secondary endpoints (symptomatic infection and 
asymptomtic infection through Day 14), if a participant has both RT-PCR and rapid antigen 
test results missing at Day 14, the participant is considered to have confirmed-infection at 
Day 14 if either RT-PCR or RAT test is positive at Day 15 or Day16 (if Day 15 missing).
For safety data, missing and partial dates will be programmatically handled according to 
Pfizer standards. 
6. ANALYSES AND SUMMARIES
6.1. Primary Endpoint
6.1.1. Primary Endpoint/Estimand Analysis
6.1.1.1. Main Analysis
The primary endpoint is the proportion of participants who develop a symptomatic, RT-PCR 
or rapid antigen test-confirmed SARS-CoV-2 infection through Day 14 for participants who 
have a negative RT-PCR result at baseline in the mITT population.
For the primary efficacy analysis, GEE will be used to analyze the proportion of participants
who develop a symptomatic RT-PCR or rapid antigen test-confirmed SARS-CoV-2 infection 
through Day 14 for each treatment group. The analysis model will include the fixed effects of 
treatment, geographic regions and presence of risk factors associated with severe COVID-19 
illness(Appendix 4). The compound symmetry variance-covariance structure will be used to
account for the correlation among the participants associated with the same index case. If the 
covariance structure fails to converge, independent variance-covariance structure or 
generalized linear model assuming independence may be considered, whichever is 
applicable. The risk ratio between 5-day regimen of PF-07321332/ritonavir versus placebo 
group and 10-day regimen of PF-07321332/ritonavir versus placebo group and the
corresponding 95% confidence intervals (CIs) will be calculated based on the 
GEE/generalized linear model using a log link function. Comparisons between the 5-day and 
10-day regimens of PF-07321332/ritonavir versus placebo will be presented as risk 
reductions with 95% CIs, which are calculated as 1 minus the risk ratio.


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A symptomatic infection event through Day 14 is defined as having any symptoms consistent 
with COVID-19 (Appendix 3 and FDA guidance5) within 14 days of an RT-PCR or rapid 
antigen test-confirmed infection through Day 14. Symptoms consistent with COVID-19 will 
be collected through self-reported participant diary. Multiplicity adjustment for primary 
endpoint will be made for multiple comparisons using Hochberg method. 
Significance level will be determined using the O’Brien-Fleming approach at the interim
analysis and the final analysis. The overall type I error rate is maintained at 5% (2-sided).
Handling of missing data is provided in Section 5.3. Handling of anticipated intercurrent 
events is provided below:

Discontinuation of assigned treatment: Participants who discontinue assigned 
treatment will be handled similarly as the participants who complete assigned 
treatment.

Use of an additional or alternative treatment: Treatment with additional or alternative
treatments does not imply or infer that a participant has a symptomatic infection. 
Thus, participants with additional or alternative treatment will not be handled 
differently than those participants not receiving additional or alternative treatment.

Termination event: COVID-19 related hospitalization or COVID-19 related death
through Day 14will be considered as achieving the primary endpoint. COVID-19 
related hospitalization or COVID-19 related death after Day 14 happening within 
14 days of an RT-PCR or rapid antigen test-confirmed infection through Day 14 will 
be considered as achieving the primary endpoint.
Among participants with symptomatic infection through Day 14, participants will be grouped 
into symptomatic RT-PCR test confirmed infection and symptomatic rapid antigen test 
confirmed infection and summarized for each treatment group. Symptomatic RT-PCR test 
confirmed infection is defined as having symptomatic infection where infection is first 
confirmed by RT-PCR positivity. Symptomatic rapid antigen test confirmed infection is 
defined as having symptomatic infection where infection is first confirmed by rapid antigen 
test positivity. If infection is confirmed by RT-PCR test positivity and rapid antigen test 
positivity on the same day, participants will be assigned into symptomatic RT-PCR test 
confirmed infection group.
In addition, participants with symptomatic infection through Day 14 will be summarized by 
variant type for each treatment group if data available.
6.1.1.2. Sensitivity Analyses
The following sensitivity analyses will be performed for the primary efficacy endpoint:

Using PP analysis set.


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•
Excluding all participants from Site
.
•
If a participant has received therapeutic monoclonal antibody or other treatment 
approved under EUA for SARS-CoV-2 and has positive RT-PCR or rapid antigen test
through Day 14, the participant will be considered as achieving the primary endpoint.
•
If a participant having SARS-CoV-2 Symptom on or before Day 14 and all RT-PCR 
or rapid antigen test are missing on or after the symptom day through Day 14, the 
participant is considered as achieving the primary endpoint.
•
Using mITT population regardless of data cleaning level.
•
Using mITT population by considering all randomized participants as independent 
participants.
•
Symptomatic infection is based on an RT-PCR test-confirmed infection through 
Day 14.
•
If meeting one of the following criteria, participants will be considered as achieving 
the primary endpoint:
•
Participants who report symptoms consistent with COVID-19 by Day 14 and are 
missing infection status for four or more days through Day 14;
•
Participants who have a positive RT-PCR or RAT result by Day 14 and are 
missing four or more daily symptom diary entries through Day 14;
•
Participants who are lost to follow-up through Day 14.
6.2. Secondary Endpoint(s)
6.2.1. Incidence of Treatment Emergent Adverse Events (TEAEs)
The incidence of TEAEs will be summarized by treatment group, by system organ class 
(SOC) and preferred term (PT) using the SAS population.  
6.2.2. Incidence of SAEs and AEs Leading to Discontinuations
The incidence of SAEs and AEs leading to discontinuation will be summarized by treatment 
group using the SAS population.
6.2.3. Proportion of Participants with Symptomatic, RT-PCR or Rapid Antigen 
Test-confirmed SARS-CoV-2 Infection through Day 14 for Participants who have a 
Negative RT-PCR Result at Baseline and who are at Increased Risk of Severe 
COVID-19 Illness
The proportion of participants with symptomatic RT-PCR or rapid antigen test-confirmed 
SARS-CoV-2 infection through Day 14 who have a negative RT-PCR result at baseline and 
CCI


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who are at increased risk of severe COVID-19 illness will be analyzed using a similar 
analysis method as the primary endpoint. The analysis model will include the fixed effects of 
treatment and geographic regions. The analyses will be done using mITT2 population.
In addition, sensitivity analysis will be performed for mITT2 population by considering all 
randomized participants as independent participants.
6.2.4. Proportion of Participants with COVID-19 Related Hospitalization or Death from 
Any Cause by Day 28 for Participants who have a Negative RT-PCR Result at Baseline
and who are at Increased Risk of Severe COVID-19 Illness
The proportion of participants with COVID-19 related hospitalization or death from any 
cause by Day 28 in participants who have a negative RT-PCR result at baseline will be
summarized and analyzed using logistic regression model if applicable. The analyses will be 
done using mITT2 population.
6.2.5. Proportion of Participants with Asymptomatic RT-PCR or Rapid Antigen 
Test-confirmed SARS-CoV-2 Infection through Day 14 for Participants who have a 
Negative RT-PCR Result at Baseline
The proportion of participants with asymptomatic RT-PCR or rapid antigen test-confirmed 
SARS-CoV-2 infection through Day 14 in participants who have a negative RT-PCR result at 
baseline will be analyzed using a similar analysis method as the primary endpoint. An
asymptomatic infection event through Day 14 is defined as having no symptoms consistent 
with COVID-19 within 14 days of an RT-PCR or rapid antigen test-confirmed infection
through Day 14. The analyses will be done using mITT population.
6.2.6. Time to RT-PCR or Rapid Antigen Test-confirmed SARS-CoV-2 Infection 
through Day 14 for Participants who have a Negative RT-PCR Result at Baseline
For this analysis, time to RT-PCR or rapid antigen test-confirmed SARS-CoV-2 infection
will be measured from the first dose of study medication in days. 

For participants with RT-PCR or rapid antigen test-confirmed SARS-CoV-2 infection 
(event), time to event will be calculated as: (Event Date) – (First Dose Date) + 1.

For participants that either completes Day 14 of study or discontinues from study 
before Day 14 without RT-PCR or rapid antigen test-confirmed SARS-CoV-2 
infection (censored), censoring date will be calculated as (Censoring/last available 
RT-PCR or rapid antigen test Date) – (First Dose Date) +1 or Day 14 whichever 
occurs first.
Time to RT-PCR or rapid antigen test-confirmed SARS-CoV-2 infection will be summarized 
graphically using Kaplan-Meier plots for each of the treatment groups, the analyses will be 
done using mITT population.


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If significant covariates are identified,  Cox proportional hazard model will be performed 
using mITT population.where the estimate of the hazard ratio for treatment (each 
PF-07321332/ritonavir group vs Placebo), 95% CI and p-value will be provided.
6.2.7. Proportion of Participants with Symptomatic RT-PCR or Rapid Antigen 
Test-confirmed SARS-CoV-2 Infection through Day 14 for Participants who have a 
Positive RT-PCR Result at Baseline
The proportion of participants with symptomatic RT-PCR or rapid antigen test-confirmed 
SARS-CoV-2 infection through Day 14 in participants who have a positive RT-PCR result at 
baseline will be analyzed using a similar analysis method as the primary endpoint in mITT1 
population.
In addition, sensitivity analysis will be performed for mITT1 population by considering all 
randomized participants as independent participants.
6.2.8. Proportion of Participants with Symptomatic RT-PCR or Rapid Antigen 
Test-confirmed SARS-CoV-2 Infection through Day 14 for Participants who have a 
Negative or Positive RT-PCR Result at Baseline
The proportion of participants with symptomatic RT-PCR or rapid antigen test-confirmed 
SARS-CoV-2 infection through Day 14 in participants who have a negative or positive 
RT-PCR result at baseline will be analyzed using a similar analysis method as the primary 
endpoint.  The analyses will be done using mITT3 population.
In addition, sensitivity analysis will be performed for mITT3 population by considering all 
randomized participants as independent participants.
6.2.9. Proportion of Participants with No, Mild, Moderate or Severe Signs/symptoms 
Attributed to COVID-19 through Day 28 in Participants who have a Negative RT-PCR 
Result at Baseline
Participants will record a daily severity rating of their symptom severity over the past 
24 hours based on a 4-point scale in which 0 is reported if no symptoms were present; 1 if 
mild; 2 if moderate; and 3 if severe.
Vomiting and diarrhea will each be rated on a 4-point frequency scale where 0 is reported for 
no occurrence, 1 for 1 to 2 times, 2 for 3 to 4 times, and 3 for 5 or greater. Vomiting and 
diarrhea rated on a 4-point frequency scale will be mapped to 4-point severity rating 
accordingly. 
Sense of smell and sense of taste will each be rated on a 3-point Likert scale where 0 is 
reported if the sense of smell/taste was the same as usual, 1 if the sense of smell/taste was 
less than usual, and 2 for no sense of smell/taste.  
Among the 12 sign/symptoms with 4 grading levels, the proportion of participants with no, 
mild, moderate or severe post-baseline signs/symptoms will be summarized for each
treatment group by RT-PCR or rapid antigen test results during the study and by total. For 


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participants with multiple symptoms and severity, participants will be assigned to the 
severity category based on the maximum severity across symptoms. In addition, the 
proportion of participants with any severe post-baseline signs/symptoms attributed to 
COVID-19 through Day 28 will be summarized with number and percent of participants by 
treatment group. Treatment comparisons between between each PF-07321332/ritonavir 
group versus placebo group will be presented as odds ratios with 95% CI and P-value based 
on logistic regression model.
For the 2 signs/symptoms with 3 grading levels (ie, sense of taste and sense of smell), similar 
analyses will be provided based on 3 grading levels. 
The analyses will be done using mITT population. 
6.2.10. Number of Days of Symptomatic SARS-CoV-2 Infection through Day 28 for
Participants who have a Negative RT-PCR Result at Baseline
The number of days of symptomatic SARS-CoV-2 infection through Day 28 in participants 
who have a negative RT-PCR result at baseline will be summarized using mITT population.
6.2.11. PF-07321332 Plasma PK in Plasma and Whole Blood (if feasible)
The PK analysis will be performed and summarized descriptively by GPD Clinical 
Pharmacology. PF-07321332/ritonavir plasma and blood (if feasible) PK concentrations will 
be descriptively summarized for each time point and treatment group.
6.2.12. Proportion of Participants with Death (all-cause) through Day 38 for
Participants who have a Negative RT-PCR Result at Baseline
The proportion of participants with death (all-cause) through Day 38 will be summarized by 
treatment group using mITT population. Treatment comparisons between each
PF-07321332/ritonavir group versus placebo group will be presented as odds ratios with 
95% CIs and P-value based on logistic regression model (if data permit).
6.2.13. Viral Titers (quantitative RT-PCR) Measured in Nasal Swabs Over Time for 
Participants who have a Negative RT-PCR Result at Baseline
The viral load in nasal samples over time will be evaluated daily.Viral load data will be 
transformed to a Log10 bases scale. Viral load (Log10 base transformed) for each day will be 
summarized using mITT population. The proportion of RT-PCR positivity over time will 
also be summarized using the mITT population.
For participants with viral titer above the limit of detection (detectable) in the mITT 
population, viral load (Log10 base transformed) for will be summarized daily. The mean 
value over time will be plotted.
For participants with viral titer above the limit of detection (detectable) in the mITT 
population, peak viral load (Log10 base transformed) for will be summarized for each 
treatment group.


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For participants with any positive RT-PCR test result (at or above the limit of quantification) 
in the mITT population, first positive viral load (Log10 base transformed) for will be 
summarized for each treatment group.
6.2.14. Viral Titers (quantitative RT-PCR) Measured in Nasal Swabs Over Time for 
Participants who have a Positive RT-PCR Result at Baseline
The viral load in nasal samples over time will be summarized daily for the mITT1
population. The mean value over time will be plotted.
6.2.15. Number of Days of Hospital and ICU Stay in Participants with COVID-19 
Related Hospitalization through Day 28 for Participants who have a Negative RT-PCR 
Result at Baseline
The number of Days of hospitalizations/ICU visits through Day 28 will be summarized by 
each treatment group using mITT population.
6.2.16. Number of COVID-19 Related Medical Visits throught Day 28 for Participants 
who have a Negative RT-PCR Result at Baseline
The number of COVID-19 related medical visits through Day 28 visit will be summarized by 
each treatment group using mITT population. The endpoint will also be analyzed with a
negative-binomial regression model, using the log-total number of days of data collection as
the participant offset variable (if data permit). Treatment group comparison each
PF-07321332/ritonavir group versus placebo group will be based on estimated rate of 
medical visits.
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6.4. Subset Analyses
Subgroup analyses of the primary endpoint in mITT analysis set will include:
•
By age group (18 to 44, 45 to 59 , and ≥60);
•
Sex;
•
Race;
•
Geographic regions;
•
Presence of risk factors associated with severe COVID-19 illness;
•
Pre or post emergence of the omicron variant (Participant randomized before 
Dec 20 2021 vs on or after Dec 20 2021);
•
Baseline serology status.
In addition, the subgroup analysis for pre or post emergence of the omicron variant will be 
performed for mITT1 and mITT3 population.
The analysis model for subgroup analyses including fixed effects and variance-covariance 
structure will be similar to the primary analysis. For subgroup analysis or analysis similar to 
primary analysis, if model fails to converge, the following fixed effects could be considered 
sequentially with different variance-covariance structure: 1) treatment and geographic 
regions 2) treatment and presence of risk factors associated with severe COVID-19 
3) treatment.
6.5. Baseline and Other Summaries and Analyses
6.5.1. Baseline and Other Characteristics Summaries
The baseline and demographic characteristics will be summarized by treatment group within
the FAS and other analysis set as appropriate. This will include age, gender, race, height, and
baseline weight, etc. Other characteristics including index and household characteristics will 
also be summarized by treatment group within the FAS. 
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6.5.2. Study Conduct and Participant Disposition
Study conduct and participant disposition will be summarized within the FAS population. 
The number of participants randomized, treated, completing and discontinuing from the
study, as well as the number of participants in each analysis set will be summarized by 
treatment group. For participants who did not complete the study, the reasons for withdrawal
from the study will be presented.
In addition, participants who were excluded from the PP analysis set will be listed with 
reasons.
6.5.3. Study Treatment Exposure
Duration of treatment and compliance will be summarized within SAS population.  
The duration of treatment will be calculated as follows:
Duration of treatment = Date of last dose of study drug - date of first dose of study drug +1.
6.5.4. Prior and Concomitant Medications 
The frequency of prior and concomitant medications will be summarized by treatment based
on the WHO-drug coding dictionary within SAS population in accordance with CDISC and 
CaPs.
6.5.5. Medical History
Medical history data will be displayed in listings by participant in accordance with the Pfizer 
Data Standards for safety reporting.
6.6. Safety Summaries and Analyses
Standard summary tables and listings will be generated using Pfizer’s Clinical Data Analysis 
and Reporting System (CDARS) for the following parameters: AEs, laboratory data and vital 
signs.
6.6.1. Adverse Events
All AEs will be coded according to the Medical Dictionary for Regulatory Activities 
(MedDRA) and will be summarized by treatment group within SAS population. A list of 
pre-specified AESIs is provided in Appendix 6.
6.6.2. Laboratory Data
Descriptive statistics will be summarized by treatment group as well as mean change from
baseline for laboratory parameters within SAS population.
All laboratory data will be reported in accordance with CDISC and CaPs for safety reporting.


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6.6.3. Vital Signs
Vital sign measurements will be displayed in listings by participant for each sample 
collection date and time. 
Vital sign data including temperature, pulse rate, respiratory rate, and blood pressure will be
descriptively summarized by treatment group within SAS population and reported in 
accordance with the Pfizer Data Standards for safety reporting.
7. INTERIM ANALYSES
7.1. Interim Analyses and Summaries
An interim analysis will be conducted for efficacy, futility, and sample size re-estimation and 
reviewed by an independent E-DMC after a prespecified accrual of participants (ie, before or 
at approximately 70% overall participants have completed the Day 14 assessments with a 
minimum number of 24 participants having symptomatic infection [mITT analysis set]). The 
nominal significance level for the interim and final analyses is determined by means of the 
Lan-DeMets procedure with an O’Brien-Fleming stopping boundary, with an overall 
two-sided type I error rate of 5%. O’Brien-Fleming approach provides relatively conservative 
stopping boundary for decision making, ie, the nominal level for interim analysis for efficacy 
and futility is 0.014 and 0.32, respectively. The nominal significance level for final analysis 
is 0.046. The actual stopping boundaries will depend on the exact number of participants 
included in the interim analysis.
At the predefined interim analysis, the sample size may be adjusted based on sample size
re-estimation with maximum increase of 30%. A well-established method such as CHW6 will 
be used to control the Type I error probability. Besides stopping a PF-07321332/ritonavir 
arm for safety or futility, a PF-07321332/ritonavir arm (5-day or 10-day regimen) may be 
discontinued based on overall evaluation of efficacy and safety profiles between the 2 arms.
Before any interim analysis is performed, the details of the objectives, decision criteria,
dissemination plan, and method of maintaining the study blind as per Pfizer’s SOPs will be
documented and approved in a DMC charter.
The interim analysis was performed as planned above. The DMC recommendation was to 
continue study as designed.
7.2. Data Monitoring Committee
This study will use a E-DMC. The E-DMC is independent of the study team and includes 
only external members. The E-DMC charter describes the role of the DMC in more detail.
The E-DMC will be responsible for ongoing monitoring of the efficacy and safety of 
participants in the study according to the charter. The recommendations made by the E-DMC 
will be forwarded to the appropriate authorized Pfizer personnel for review and final 
decision. Pfizer will communicate such decisions, which may include summaries of 
aggregate analyses of safety data to regulatory authorities, investigators, as appropriate. 


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8. REFERENCES
1.
O'Brien MP, Forleo-Neto E, Musser BJ, et al. Subcutaneous REGEN-COV Antibody 
Combination to Prevent Covid-19. N Engl J Med. 2021;385(13):1184-95.
2.
World Health Organization. 2019-nCoV outbreak is an emergency of international 
concern. 31 Jan 2020. Available from: https://www.euro.who.int/en/health-
topics/health-emergencies/coronavirus-covid-19/news/news/2020/01/2019-ncov-
outbreak-is-an-emergency-of-international-concern. Accessed on: 22 March 2020.
3.
World Health Organization. WHO Situation Report 51 Coronavirus disease 2019 
(COVID-19). 11 March 2020. Available from: https://www.who.int/docs/default-
source/coronaviruse/situation-reports/20200311-sitrep-51-covid-
19.pdf?sfvrsn=1ba62e57_10. Accessed on: 22 March 2021.
4.
Benjamini Y, & Hochberg, Y. Controlling the false discovery rate: a practical and
powerful approach to multiple testing. Journal of the Royal Statistical Society
1995;57:289–300.
5.
US Food and Drug Administration. Assessing COVID-19-Related Symptoms in 
Outpatient Adult and Adolescent Subjects in Clinical Trials of Drugs and Biological 
Products for COVID-19 Prevention or Treatment. 2020. Available from: 
https://www.fda.gov/regulatory-information/search-fda-guidance-documents/assessing-
covid-19-related-symptoms-outpatient-adult-and-adolescent-subjects-clinical-trials-
drugs. Accessed on: 25 Mar 2021.
6.
Cui L, Hung HM, Wang SJ. Modification of sample size in group sequential 
clinicaltrials. Biometrics. 1999;55(3):853-7.


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9. APPENDICES
Appendix 1. Summary of Efficacy Analyses
Endpoint
Analysis Type
Population
Data Inclusion and Rules for 
Handling Intercurrent Events 
and Missing Data 
Analysis Model
Proportion of participants 
who develop a 
symptomatic, RT-PCR or 
rapid antigen test-
confirmed SARS-CoV-2 
infection through Day 14
for participant who have a 
negative RT-PCR result at 
baseline.
Primary Efficacy 
analysis 
mITT
All data collected will be
included. Intercurrent event of 
COVID-19 related 
hospitalization or 
COVID-19-related death will be 
handled based on 
Section 6.1.1.1.
Missing data will be handled
based on Section 5.3.
GEE/Generalized 
linear model
Descriptive statistics
Proportion of participants 
who develop a 
symptomatic, RT-PCR or 
rapid antigen 
test-confirmed 
SARS-CoV-2 infection
through Day 14 who have 
a negative RT-PCR result 
at baseline.
Sensitivity analysis for 
primary endpoint
PP
All data collected will be 
included. Intercurrent event of 
COVID-19 related 
hospitalization or 
COVID-19-related death will be 
handled based on 
Section 6.1.1.1.
Missing data will be handled 
based on Section 5.3.
GEE/Generalized 
linear model
Proportion of participants 
who develop a 
symptomatic, RT-PCR or 
rapid antigen 
Sensitivity analysis for 
primary endpoint
mITT excluding 
Site 1483
All data collected will be 
included. Intercurrent event of 
COVID-19 related 
hospitalization or 
GEE/Generalized 
linear model


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Endpoint
Analysis Type
Population
Data Inclusion and Rules for 
Handling Intercurrent Events 
and Missing Data 
Analysis Model
test-confirmed SARS-
CoV-2 infection through 
Day 14 who have a 
negative RT-PCR result at 
baseline.
COVID-19-related death will be 
handled based on 
Section 6.1.1.1.
Missing data will be handled 
based on Section 5.3.
Proportion of participants 
who develop a 
symptomatic, RT-PCR or 
rapid antigen 
test-confirmed 
SARS-CoV-2 infection
through Day 14 who have 
a negative RT-PCR result 
at baseline.
Sensitivity analysis for 
primary endpoint
mITT
All data collected will be 
included. Intercurrent event of 
COVID-19 related 
hospitalization or 
COVID-19-related death will be 
handled based on 
Section 6.1.1.1.
If a participant has received 
therapeutic monoclonal 
antibody or other treatment 
approved under EUA for 
SARS-CoV-2 and has positive 
RT-PCR or rapid antigen test
through Day 14, the participant 
will be considered as achieving 
the primary endpoint.
Missing data will be handled 
based on Section 5.3.
GEE/Generalized 
linear model


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Endpoint
Analysis Type
Population
Data Inclusion and Rules for 
Handling Intercurrent Events 
and Missing Data 
Analysis Model
Proportion of participants 
who develop a 
symptomatic, RT-PCR or 
rapid antigen test-
confirmed SARS-CoV-2 
infection through Day 14 
who have a negative 
RT-PCR result at baseline.
Sensitivity analysis for 
primary endpoint
mITT
All data collected will be 
included. Intercurrent event of 
COVID-19 related 
hospitalization or 
COVID-19-related death will be 
handled based on 
Section 6.1.1.1. 
Missing data will be handled 
based on Section 5.3. 
If a participant having 
SARS-CoV-2 Symptom on or 
before Day 14 and all RT-PCR 
or rapid antigen test are missing 
on or after the symptom day 
through Day 14, the participant 
is considered to achieve the 
primary endpoint.
GEE/Generalized 
linear model
Proportion of participants 
who develop a 
symptomatic, RT-PCR or 
rapid antigen test-
confirmed SARS-CoV-2 
infection through Day 14 
who have a negative 
RT-PCR result at baseline.
Sensitivity analysis for 
primary endpoint
mITT regardless 
of data cleaning 
level
All data collected will be 
included. Intercurrent event of 
COVID-19 related 
hospitalization or 
COVID-19-related death will be 
handled based on 
Section 6.1.1.1. 
GEE/Generalized 
linear model


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Endpoint
Analysis Type
Population
Data Inclusion and Rules for 
Handling Intercurrent Events 
and Missing Data 
Analysis Model
Missing data will be handled 
based on Section 5.3. 
Proportion of participants 
who develop a 
symptomatic, RT-PCR or 
rapid antigen test-
confirmed SARS-CoV-2 
infection through Day 14 
who have a negative 
RT-PCR result at baseline.
Sensitivity analysis for 
primary endpoint
mITT by 
considering all 
randomized 
participants as 
independent 
participants
All data collected will be 
included. Intercurrent event of 
COVID-19 related 
hospitalization or 
COVID-19-related death will be 
handled based on 
Section 6.1.1.1. 
Missing data will be handled 
based on Section 5.3. 
GEE/Generalized 
linear model
Proportion of participants 
who develop a 
symptomatic, RT-PCR 
confirmed SARS-CoV-2 
infection through Day 14 
who have a negative 
RT-PCR result at baseline.
Sensitivity analysis for 
primary endpoint
mITT
All data collected will be 
included. Intercurrent event of 
COVID-19 related 
hospitalization or 
COVID-19-related death will be 
handled based on 
Section 6.1.1.1. 
Missing data will be handled 
based on Section 5.3 (RT-PCR 
data only). 
Symptomatic infection is based 
on an RT-PCR test-confirmed 
infection through Day 14.
GEE/Generalized 
linear model


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Endpoint
Analysis Type
Population
Data Inclusion and Rules for 
Handling Intercurrent Events 
and Missing Data 
Analysis Model
Proportion of participants 
who develop a 
symptomatic, RT-PCR or 
rapid antigen test-
confirmed SARS-CoV-2 
infection through Day 14 
who have a negative 
RT-PCR result at baseline.
Sensitivity analysis for 
primary endpoint
mITT
All data collected will be 
included. Intercurrent event of 
COVID-19 related 
hospitalization or 
COVID-19-related death will be 
handled based on 
Section 6.1.1.1. 
If meeting one of the following 
criteria, participants will be 
considered as achieving the 
primary endpoint: participants 
who report symptoms consistent 
with COVID-19 by Day 14 and 
are missing infection status for 
four or more days through 
Day 14; participants who have a 
positive RT-PCR or RAT result 
by Day 14 and are missing four 
or more daily symptom diary 
entries through Day 1; 
participants who are lost to 
follow-up through Day 14.
GEE/Generalized 
linear model
Proportion of participants 
who develop a 
symptomatic, RT-PCR or 
rapid antigen test-
Subgroup analyses for 
the primary endpoint
mITT
All data collected will be 
included. Intercurrent event of 
COVID-19 related 
hospitalization or 
GEE/Generalized 
linear model


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Endpoint
Analysis Type
Population
Data Inclusion and Rules for 
Handling Intercurrent Events 
and Missing Data 
Analysis Model
confirmed SARS-CoV-2 
infection through Day 14 
who have a negative 
RT-PCR result at baseline.
COVID-19-related death will be 
handled based on 
Section 6.1.1.1. 
Missing data will be handled 
based on Section 5.3. 
Subset analysis define in 
Section 6.4. 
Proportion of participants 
with symptomatic 
RT-PCR or rapid antigen 
test-confirmed 
SARS-CoV-2 infection 
through Day 14 for 
participant who have a 
negative RT-PCR result at 
baseline and who are at 
increased risk of severe 
COVID-19 illness.
Secondary analysis 
mITT2
All data collected will be 
included. For Intercurrent event 
of COVID-19 related 
hospitalization or 
COVID-19-related death will be 
handled based on 
Section 6.1.1.1.
Missing data will be handled 
based on Section 5.3.
GEE/Generalized 
linear model
Proportion of participants 
with symptomatic 
RT-PCR or rapid antigen 
test-confirmed 
SARS-CoV-2 infection 
through Day 14 for 
participant who have a 
Sensitivity analysis for 
sencondary endpoint
mITT2 by 
considering all 
randomized 
participants as 
independent 
participants
All data collected will be 
included. For Intercurrent event 
of COVID-19 related 
hospitalization or 
COVID-19-related death, it will 
be handled based on
Section 6.1.1.1.
GEE/Generalized 
linear model


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Endpoint
Analysis Type
Population
Data Inclusion and Rules for 
Handling Intercurrent Events 
and Missing Data 
Analysis Model
negative RT-PCR result at 
baseline and who are at 
increased risk of severe 
COVID-19 illness.
Missing data will be handled 
based on Section 5.3.
Proportion of participants 
with COVID-19 related 
hospitalization or death 
from any cause by Day 28 
for participant who have a 
negative RT-PCR result at 
baseline and who are at 
increased risk of severe 
COVID-19 illness.
Secondary analysis
mITT2
All data collected will be 
included regardless of 
intercurrent events.
Missing data will not be 
imputed.
Descriptive statistics
Logistic regression 
model if applicable
Proportion of participants 
with asymptomatic 
RT-PCR or rapid antigen 
test-confirmed
SARS-CoV-2
infection through Day 14 
for participants who have 
a negative RT-PCR result 
at baseline.
Secondary analysis
mITT
All data collected will be 
included regardless of 
intercurrent events.
Missing data will be handled 
based on Section 5.3. 
GEE/Generalized 
linear model
Time to RT-PCR or rapid 
antigen test-confirmed 
SARS-CoV-2 infection 
Secondary analysis
mITT
All data collected will be 
included regardless of 
intercurrent events.
KM plot; Cox 
proportional hazard 
model as needed.


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Endpoint
Analysis Type
Population
Data Inclusion and Rules for 
Handling Intercurrent Events 
and Missing Data 
Analysis Model
through Day 14 for 
participants who have a 
negative RT-PCR result at 
baseline.
Missing data will not be 
imputed.
Proportion of participants 
with symptomatic 
RT-PCR or rapid antigen 
test-confirmed 
SARS-CoV-2 infection 
through Day 14 in 
participant who have a 
positive RT-PCR result at 
baseline.
Secondary analysis
mITT1 
All data collected will be 
included. Intercurrent event of 
COVID-19 related 
hospitalization or 
COVID-19-related death will be 
handled based on 
Section 6.1.1.1.
Missing data will be handled 
based on Section 5.3.
GEE/Generalized 
linear model
Proportion of participants 
with symptomatic 
RT-PCR or rapid antigen 
test-confirmed 
SARS-CoV-2 infection 
through Day 14 in 
participant who have a 
positive RT-PCR result at 
baseline.
Sensitivity analysis for 
sencondary endpoint
mITT1 by 
considering all 
randomized 
participants as 
independent 
participants
All data collected will be 
included. Intercurrent event of 
COVID-19 related 
hospitalization or 
COVID-19-related death will be 
handled based on 
Section 6.1.1.1.
Missing data will be handled 
based on Section 5.3.
GEE/Generalized 
linear model
Proportion of participants 
with symptomatic 
RT-PCR or rapid antigen 
Subgroup analyses on 
pre or post emergence 
mITT1
All data collected will be 
included. Intercurrent event of 
COVID-19 related 
GEE/Generalized 
linear model


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Endpoint
Analysis Type
Population
Data Inclusion and Rules for 
Handling Intercurrent Events 
and Missing Data 
Analysis Model
test-confirmed 
SARS-CoV-2 infection 
through Day 14 in 
participant who have a 
positive RT-PCR result at 
baseline.
of the omicron variant 
for secondary endpoint
hospitalization or 
COVID-19-related death will be 
handled based on 
Section 6.1.1.1. 
Missing data will be handled 
based on Section 5.3. 
Proportion of participants 
with symptomatic 
RT-PCR or rapid antigen 
test-confirmed 
SARS-CoV-2 infection 
through Day 14 in 
participant who have a 
negative or positive 
RT-PCR result at baseline.
Secondary analysis
mITT3
All data collected will be 
included. Intercurrent event of 
COVID-19 related 
hospitalization or 
COVID-19-related death will be 
handled based on 
Section 6.1.1.1.
Missing data will be handled 
based on Section 5.3.
GEE/Generalized 
linear model
Proportion of participants 
with symptomatic 
RT-PCR or rapid antigen 
test-confirmed 
SARS-CoV-2 infection 
through Day 14 in 
participant who have a 
negative or positive 
RT-PCR result at baseline.
Sensitivity analysis for 
sencondary endpoint
mITT3 by 
considering all 
randomized 
participants as 
independent 
participants
All data collected will be 
included. Intercurrent event of 
COVID-19 related 
hospitalization or 
COVID-19-related death will be 
handled based on 
Section 6.1.1.1.
Missing data will be handled 
based on Section 5.3.
GEE/Generalized 
linear model


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Endpoint
Analysis Type
Population
Data Inclusion and Rules for 
Handling Intercurrent Events 
and Missing Data 
Analysis Model
Proportion of participants 
with symptomatic 
RT-PCR or rapid antigen 
test-confirmed 
SARS-CoV-2 infection 
through Day 14 in 
participant who have a 
negative or positive 
RT-PCR result at baseline.
Subgroup analyses on 
pre or post emergence 
of the omicron variant 
for secondary endpoint
mITT3
All data collected will be 
included. Intercurrent event of 
COVID-19 related 
hospitalization or 
COVID-19-related death will be 
handled based on 
Section 6.1.1.1. 
Missing data will be handled 
based on Section 5.3. 
GEE/Generalized 
linear model
Proportion of participants 
with no, mild, moderate, 
or severe signs and 
symptoms attributed to 
COVID-19 through 
Day 28 for participants 
who have a negative 
RT-PCR result at baseline.
Secondary analysis
mITT
All data collected will be 
included regardless of 
intercurrent events. Missing 
data will not be imputed.
Descriptive statistics 
Logistic regression 
model
Number of days of 
symptomatic 
SARS-CoV-2 infection 
through Day 28 for 
participants who have a 
negative RT-PCR result at 
baseline.
Secondary analysis 
mITT
All data collected will be 
included regardless of 
intercurrent events. Missing 
data will not be imputed.
Descriptive statistics


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Endpoint
Analysis Type
Population
Data Inclusion and Rules for 
Handling Intercurrent Events 
and Missing Data 
Analysis Model
Proportion of participants 
with death (all-cause) 
through Day 38 for 
participants who have a 
negative RT-PCR result at 
baseline.
Secondary analysis
mITT
All data collected will be 
included regardless of 
intercurrent events. 
Missing data will not be 
imputed.
Descriptive statistics 
Logistic regression 
model if applicable
Viral titers measured via 
RT-PCR in nasal swabs 
over time for participants 
who have a negative 
RT-PCR result at baseline.
Secondary analysis
mITT
All data collected will be 
included regardless of 
intercurrent events. 
Missing data will not be 
imputed. 
Descriptive statistics
Viral titers measured via 
RT-PCR in nasal swabs 
over time for participants 
who have a positive 
RT-PCR result at baseline.
Secondary analysis
mITT1
All data collected will be 
included regardless of 
intercurrent events. 
Missing data will not be 
imputed. 
Descriptive statistics
Number of days of 
hospital and ICU stay in 
participants with 
COVID-19-related 
hospitalization through 
Day 28 for participants
who have a negative 
RT-PCR result at baseline.
Secondary analysis
mITT
All data collected will be 
included regardless of 
intercurrent events. Missing 
data will not be imputed.
Descriptive statistics


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Endpoint
Analysis Type
Population
Data Inclusion and Rules for 
Handling Intercurrent Events 
and Missing Data 
Analysis Model
Number of COVID-19 
related medical visits 
through Day 28 for 
participants who have a 
negative RT-PCR result at 
baseline.
Secondary analysis
mITT
All data collected will be 
included regardless of 
intercurrent events. Missing 
data will not be imputed.
Descriptive statistics  
negative binomial 
model
CCI


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Endpoint
Analysis Type
Population
Data Inclusion and Rules for 
Handling Intercurrent Events 
and Missing Data 
Analysis Model
CCI


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Appendix 2. Data Derivation Details
Appendix 2.1. Definition and Use of Visit Windows in Reporting
For safety endpoints, the following table defines the visit label, target day and visit windows:
Visit Label 
Target Day
Definition [Day window]
Baseline
Day 1
Day -2 to Day 1
Day 5
Day 5
Days 2 to Day 7
Day 10
Day 10
Days 8 to Day 11
Day 14
Day 14
days 12 to 26
Day 38
Day 38
days 27 and beyond
These visit windows may be revised for analysis and reporting purpose when deemed 
appropriate. 
If two or more measurements fall into the same visit window, keep the one closest to the 
Target Day. If two measuremets are equal distance from the Target Day in absolute value, 
the later visit should be used. 
For lab data, if there are multiple measurements on the same day, the latest measurement will 
be used.
For vital sign data, if there are multiple measurements on the same day, the average value 
will be used.
For viral load data collected daily, if there are multiple measurements on the same day, the 
extreme/the largest value will be used.


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Appendix 3. Signs and Symptoms Consistent With COVID-19
Daily Sign and Symptom Collection
Exclusion 
Criterion #2
Daily Signs and 
Symptom Collection
Cough
X
X
Shortness of breath or difficulty breathing 
X
X
Fever (documented temperature >38°C [100.4°F]) or 
subjective fever (eg, feeling feverish)
X
Feeling feverish
X
X
Chills or shivering
X
X
Fatigue (low energy or tiredness)
X
X
Muscle or body aches
X
X
Diarrhea (loose or watery stools)
X
X
Nausea (feeling like you wanted to throw up)
X
X
Vomiting (throw up)
X
X
Headache
X
X
Sore throat
X
X
Stuffy or runny nose
X
X
Loss of smell 
X
X
Loss of taste
X
X


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Appendix 4. Risk Factors Associated With Severe COVID-19 Illness 

≥60 years of age.

BMI >25 kg/m2.

Current smoker (cigarette smoking within the past 30 days) and history of at least 
100 lifetime cigarettes.

Immunosuppressive disease (eg, bone marrow or organ transplantation or primary 
immune deficiencies) OR prolonged use of immune-weakening medications:

Has received corticosteroids equivalent to prednisone ≥20 mg daily for at least 
14 consecutive days within 30 days prior to study entry;

Has received treatment with biologics (eg, infliximab, ustekinumab), 
immunomodulators (eg, methotrexate, 6MP, azathioprine), or cancer 
chemotherapy within 90 days prior to study entry;

HIV infection with CD4 cell count <200 mm3 and a viral load less than 
400 copies/mL.

Chronic lung disease (if asthma, requires daily prescribed therapy).

Known diagnosis of hypertension.

CVD, defined as history of any of the following: myocardial infarction, stroke, TIA, 
HF, angina with prescribed nitroglycerin, CABG, PCI, carotid endarterectomy, and 
aortic bypass.

Type 1 or Type 2 diabetes mellitus.

CKD.

Sickle cell disease.

Neurodevelopmental disorders (eg, cerebral palsy, Down's syndrome) or other 
conditions that confer medical complexity (eg, genetic or metabolic syndromes and 
severe congenital anomalies).

Active cancer, other than localized skin cancer, including those requiring treatment as 
long as the treatment is not among the prohibited medications that must be 
administered/continued during the study period.

Medical-related technological dependence (eg, CPAP [not related to COVID-19]).


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If a participant meets at least one of the above criteria, the participant is considered as having
the presence of risk factors associated with severe COVID-19 illness (increased risk of 
severe COVID-19 illness).


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Appendix 5. List of Abbreviations
Abbreviation
Term
AE
adverse event
AESI
adverse events of special interest
CDARS
Clinical Data Analysis and Reporting System (of US Food and Drug 
Administration)
CDISC
Clinical Data Interchange Standards Consortium 
CaPs
Clinical Data Interchange Standards Consortium and Pfizer Standards
CI
Confidence Interval
DMC
data monitoring committee
E-DMC
external data monitoring committee 
FAS
full analysis set
FDA
Food and Drug Administration (United States)
GEE 
Generalized estimating equation
ITT
intent-to-treat
MedDRA
Medical Dictionary for Regulatory Activities 
mITT
modified intent-to-treat
NA
not applicable
PK
pharmacokinetic(s)
PP
per-protocol
SAE
serious adverse event
SAP
statistical analysis plan
SAS
safety analysis set
SOP
standard operating procedure


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Appendix 6. List of Pre-specified AESIs