Clinical trial NCT05011513
Conditions: COVID-19
Keywords: SARS-CoV-2 Infection
Sponsor: Pfizer
Start date: 2021-08-25; Completion date: 2022-07-25
Enrollment: 1440 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The primary hypothesis to be tested is whether or not there is a difference in time to sustained alleviation of all targeted COVID-19 signs and symptoms through Day 28 between PF-07321332/ritonavir and placebo.

Detailed description:
Throughout the study period, provision will be made to allow study visits to be conducted at a participant's home or at another non-clinic location, if available. The total study duration is up to 24 weeks.

Arms: arm 1: Orally administered PF-07321332+ritonavir arm 2: Orally administered Placebo
Interventions: intervention 1: PF-07321332 intervention 2: Ritonavir intervention 3: Placebo intervention 4: Placebo
Intervention descriptions: intervention 1: PF-07321332 (tablet) intervention 2: Ritonavir (capsule) intervention 3: Placebo (tablet) intervention 4: Placebo (capsule)

Protocol documents:
Prot_000.pdf: 
PF-07321332
Protocol C4671002
Final Protocol Amendment 6, 09 June 2022
PFIZER CONFIDENTIAL
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AN INTERVENTIONAL EFFICACY AND SAFETY, PHASE 2/3, DOUBLE-BLIND, 
2-ARM STUDY TO INVESTIGATE ORALLY ADMINISTERED 
PF-07321332/RITONAVIR COMPARED WITH PLACEBO IN NONHOSPITALIZED
SYMPTOMATIC ADULT PARTICIPANTS WITH COVID-19 WHO ARE AT LOW 
RISK OF PROGRESSING TO SEVERE ILLNESS
Study Intervention Number:
PF-07321332
Study Intervention Name:
nirmatrelvir
US IND Number:
EudraCT Number:
2021-002857-28
ClinicalTrials.gov ID:  
NCT05011513
Protocol Number:
C4671002
Phase:
2/3
Brief Title: A Phase 2/3 Efficacy and Safety Study of PF-07321332/Ritonavir in 
Nonhospitalized Low-Risk Adult Participants With 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.
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Document History
Document 
Version Date
Amendment 6
09 June 2022
Amendment 5
21 January 2022
Amendment 4
23 November 2021
Protocol Amendment Change Letter
27 September 2021
Protocol Amendment Change Letter
31 August 2021
Protocol Amendment Change Letter
13 August 2021
Amendment 3
03 August 2021
Protocol Amendment Change Letter
22 July 2021
Amendment 2
19 July 2021
Amendment 1
02 July 2021
Original protocol
18 June 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 6 (09 June 2022)
Overall Rationale for the Amendment: 
Study C4671002 enrolled participants who had risk factors for severe COVID-19 illness and 
who were vaccinated against the SARS-CoV-2 virus as well as participants who did not have 
risk factors for severe COVID-19 illness and who were not vaccinated. Data from this study
are required to support regulatory submissions, thereby necessitating an interim analysis 
utilizing the 19 December 2021 dataset. This dataset had not been analyzed previously 
because the protocol was amended to increase the sample size and extend  enrollment to 
assess the potential benefit of participants at low risk of progression to severe COVID-19 in 
the clinically relevant endpoint of COVID-19 related hospitalization or death from any cause 
(Protocol Amendment 5, 21 January 2022). This third interim analysis (100% planned 
enrollment through Protocol Amendment 4) did not include any data from participants who 
entered the study under Protocol Amendment 5. Finally, this amendment defines the second 
interim analysis (80% of planned enrollment through Protocol Amendment 4) that was 


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PFIZER CONFIDENTIAL
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conducted following the first interim analysis (45% planned enrollment through Protocol 
Amendment 4).
In addition, hypertension was added as a potential risk and hemodynamic and inflammatory 
effects, TSH and T4 (free) elevations were removed as potential risks.
Protocol Amendment Summary of Changes Table
Section # and 
Name
Description of 
Change
Brief Rationale
Substantial or 
Nonsubstantial
Section 9.4. Interim 
Analyses
Section 1.1. Synopsis
Section 4.1. Overall 
Design
At the conclusion of the first 
interim analysis (45% planned 
enrollment through Protocol 
Amendment 4), the E-DMC 
requested an additional second 
interim analysis (80% planned 
enrollment through Protocol 
Amendment 4).  A third 
interim analysis (100% 
planned enrollment through 
Protocol Amendment 4) is 
being added to support 
regulatory filings utilizing the 
dataset from 
19 December 2021.
Clarified other sections of the 
protocol to differentiate the  
interim analyses conducted.
This dataset includes 
participants who had risk 
factors for severe COVID-19 
illness and who were 
vaccinated against the SARS-
CoV-2 virus as well as 
participants who did not have 
risk factors for severe 
COVID-19 illness and who 
were not vaccinated. The data 
were never released nor 
analyzed previously.
Substantial
Section 2.3.1. Risk 
Assessment
Added hypertension as a 
potential risk and removed 
hemodynamic and 
inflammatory effects, and TSH 
and T4 (free) elevations as 
potential risks.
Program level decision related 
to emerging safety data.
Substantial
Section 1.2. Schema
Corrected spelling in the study 
schema.
Correction to typo
Nonsubstantial
Section 2.2. Background
Updated the indication for use 
of remdesivir and added 
reference.
Updated the EUA status of PF-
07321332/ritonavir and 
molnupiravir.
Added clarification regarding 
reproductive studies conducted 
with molnupiravir.
For investigator awareness
Nonsubstantial
Section 5.2. .Exclusion 
Criteria
Included molnupiravir in 
Exclusion Criterion #15 which 
had been omitted in the 
previous amendment.
To bring into alignment with 
Section 6.8 of the protocol.
Nonsubstantial


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TABLE OF CONTENTS
LIST OF TABLES.....................................................................................................................9
1. PROTOCOL SUMMARY...................................................................................................10
1.1. Synopsis ..................................................................................................................10
1.2. Schema ....................................................................................................................15
1.3. Schedule of Activities .............................................................................................16
2. INTRODUCTION ...............................................................................................................24
2.1. Study Rationale .......................................................................................................24
2.2. Background .............................................................................................................24
2.2.1. Nonclinical Studies of PF-07321332..........................................................25
2.2.2. Clinical Overview.......................................................................................26
2.3. Benefit/Risk Assessment.........................................................................................27
2.3.1. Risk Assessment.........................................................................................28
2.3.2. Benefit Assessment.....................................................................................30
2.3.3. Overall Benefit/Risk Conclusion................................................................30
3. OBJECTIVES, ENDPOINTS, AND ESTIMANDS ...........................................................31
4. STUDY DESIGN.................................................................................................................32
4.1. Overall Design.........................................................................................................32
4.2. Scientific Rationale for Study Design.....................................................................34
4.2.1. Diversity of Study Population ....................................................................35
4.2.2. Choice of Contraception/Barrier Requirements .........................................35
4.3. Justification for Dose ..............................................................................................35
4.4. End of Study Definition ..........................................................................................36
5. STUDY POPULATION......................................................................................................36
5.1. Inclusion Criteria.....................................................................................................36
5.2. Exclusion Criteria....................................................................................................37
5.3. Lifestyle Considerations..........................................................................................40
5.3.1. Contraception..............................................................................................40
5.4. Screen Failures ........................................................................................................40
5.5. Criteria for Temporarily Delaying 
Enrollment/Randomization/Administration of Study Intervention...........................40
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6. STUDY INTERVENTION(S) AND CONCOMITANT THERAPY.................................41
6.1. Study Intervention(s) Administered........................................................................41
6.1.1. Administration............................................................................................42
6.2. Preparation, Handling, Storage, and Accountability...............................................43
6.2.1. Preparation and Dispensing........................................................................44
6.3. Measures to Minimize Bias: Randomization and Blinding.....................................44
6.3.1. Allocation to Study Intervention ................................................................44
6.3.2. Blinding of the Sponsor..............................................................................45
6.3.3. Breaking the Blind......................................................................................45
6.4. Study Intervention Compliance...............................................................................45
6.5. Dose Modification...................................................................................................46
6.6. Continued Access to Study Intervention After the End of the Study......................46
6.7. Treatment of Overdose............................................................................................46
6.8. Concomitant Therapy..............................................................................................47
6.8.1. Rescue Medicine.........................................................................................47
7. DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL...........................................................................48
7.1. Discontinuation of Study Intervention ....................................................................48
7.1.1. Potential Cases of Decreased eGFR ...........................................................48
7.2. Participant Discontinuation/Withdrawal From the Study.......................................49
7.2.1. Withdrawal of Consent...............................................................................49
7.3. Lost to Follow-Up ...................................................................................................50
8. STUDY ASSESSMENTS AND PROCEDURES...............................................................50
8.1. Efficacy Assessments..............................................................................................51
8.1.1. Participant Diary.........................................................................................51
8.1.2. COVID-19-Related Medical Visit Details..................................................51
8.1.3. Daily Signs and Symptoms of COVID-19 .................................................52
8.1.4. Oxygen Support Details..............................................................................52
8.1.5. PRO Assessments.......................................................................................52
8.1.5.1. WPAI Questionnaire .................................................................52
8.1.5.2. EQ-5D-5L Scale........................................................................53
8.1.5.3. Global Impression Questions ....................................................53


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8.1.6. Exit Interview .............................................................................................53
8.2. Safety Assessments .................................................................................................53
8.2.1. Medical History ..........................................................................................53
8.2.2. Height and Weight......................................................................................54
8.2.3. Targeted Physical Examinations.................................................................54
8.2.4. Vital Signs ..................................................................................................54
8.2.5. Clinical Safety Laboratory Assessments ....................................................54
8.2.6. Pregnancy Testing ......................................................................................55
8.3. Adverse Events, Serious Adverse Events, and Other Safety Reporting .................55
8.3.1. Time Period and Frequency for Collecting AE and SAE Information.......56
8.3.1.1. Reporting SAEs to Pfizer Safety...............................................57
8.3.1.2. Recording Nonserious AEs and SAEs on the CRF...................57
8.3.2. Method of Detecting AEs and SAEs ..........................................................57
8.3.3. Follow-Up of AEs and SAEs......................................................................57
8.3.4. Regulatory Reporting Requirements for SAEs...........................................57
8.3.5. Environmental Exposure, Exposure During Pregnancy or 
Breastfeeding, and Occupational Exposure.....................................................58
8.3.5.1. Exposure During Pregnancy......................................................58
8.3.5.2. Exposure During Breastfeeding ................................................59
8.3.5.3. Occupational Exposure .............................................................60
8.3.6. Cardiovascular and Death Events...............................................................60
8.3.7. Disease-Related Events and/or Disease-Related Outcomes Not 
Qualifying as AEs or SAEs..............................................................................60
8.3.8. Adverse Events of Special Interest.............................................................60
8.3.8.1. Lack of Efficacy........................................................................61
8.3.9. Medical Device Deficiencies......................................................................61
8.3.10. Medication Errors.....................................................................................61
8.4. Pharmacokinetics ....................................................................................................62
8.5. Genetics...................................................................................................................63
8.5.1. Specified Genetics ......................................................................................63
8.6. Biomarkers ..............................................................................................................63
8.6.1. Specified Gene Expression (RNA) Research .............................................63
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8.6.3. Specified Metabolomic Research ...............................................................64
8.6.4. Viral Load Assessments .............................................................................64
8.7. Immunogenicity Assessments.................................................................................64
8.8. Health Economics ...................................................................................................64
9. STATISTICAL CONSIDERATIONS ................................................................................64
9.1. Statistical Hypotheses .............................................................................................65
9.1.1. Estimands....................................................................................................65
9.1.1.1. Primary Estimand/Co-Primary Estimands ................................65
9.1.1.2. Secondary Estimands ................................................................66
9.2. Analysis Sets ...........................................................................................................67
9.3. Statistical Analyses .................................................................................................67
9.3.1. General Considerations...............................................................................68
9.3.2. Primary Endpoint(s)/Estimand(s) Analysis ................................................68
9.3.2.1. Supplemental Analyses .............................................................69
9.3.3. Secondary Endpoint(s)/Estimand(s) Analysis............................................70
9.3.5. Other Safety Analyses ................................................................................71
9.3.5.1. Laboratory Test Results ............................................................72
9.3.5.2. Physical Examination and Vital Signs ......................................72
9.3.5.3. Persistent Symptoms of COVID-19..........................................72
9.3.6. Other Analyse(s).........................................................................................72
9.3.6.1. PK Analyses ..............................................................................72
9.4. Interim Analyses .....................................................................................................72
9.5. Sample Size Determination.....................................................................................74
10. SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS..........................................................................................................75
10.1. Appendix 1: Regulatory, Ethical, and Study Oversight Considerations...............75
10.1.1. Regulatory and Ethical Considerations ....................................................75
10.1.1.1. Reporting of Safety Issues and Serious Breaches of the 
Protocol or ICH GCP.........................................................................75
10.1.2. Financial Disclosure .................................................................................76
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10.1.3. Informed Consent Process ........................................................................76
10.1.4. Data Protection .........................................................................................77
10.1.5. Committees Structure ...............................................................................77
10.1.5.1. Data Monitoring Committee ...................................................77
10.1.6. Dissemination of Clinical Study Data ......................................................78
10.1.7. Data Quality Assurance ............................................................................79
10.1.8. Source Documents....................................................................................81
10.1.9. Study and Site Start and Closure ..............................................................81
10.1.10. Publication Policy...................................................................................82
10.1.11. Sponsor’s Qualified Medical Personnel .................................................83
10.2. Appendix 2: Clinical Laboratory Tests .................................................................84
10.3. Appendix 3: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-Up, and Reporting .....................................................................85
10.3.1. Definition of AE .......................................................................................85
10.3.2. Definition of an SAE ................................................................................86
10.3.3. Recording/Reporting and Follow-Up of AEs and/or SAEs During 
the Active Collection Period............................................................................87
10.3.4. Reporting of SAEs....................................................................................91
10.4. Appendix 4: Contraceptive and Barrier Guidance ................................................92
10.4.1. Male Participant Reproductive Inclusion Criteria....................................92
10.4.2. Female Participant Reproductive Inclusion Criteria.................................92
10.4.3. Woman of Childbearing Potential ............................................................93
10.4.4. Contraception Methods.............................................................................94
10.6. Appendix 6: Liver Safety: Suggested Actions and Follow Up Assessments 
and Study Intervention Rechallenge Guidelines .......................................................97
10.7. Appendix 7: ECG Findings of Potential Clinical Concern (No Longer 
Applicable) ................................................................................................................99
10.8. Appendix 8: Prohibited Concomitant Medications That May Result in DDI.....100
10.9. Appendix 9: Signs and Symptoms Attributable to COVID-19...........................109
10.10. Appendix 10: Country-Specific Requirements .................................................110
10.10.1. France ...................................................................................................110
10.10.2. Japan .....................................................................................................110
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10.11. Appendix 11: Protocol Amendment History.....................................................112
10.12. Appendix 12: Abbreviations .............................................................................121
11. REFERENCES ................................................................................................................125
LIST OF TABLES
Table 1
Protocol-Required Safety Laboratory Assessments .................................84
Table 2.
Signs and Symptoms Attributable to COVID-19 ...................................109


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1. PROTOCOL SUMMARY 
1.1. Synopsis 
An Interventional Efficacy and Safety, Phase 2/3, Double-Blind, 2-Arm Study to Investigate 
Orally Administered PF-07321332/Ritonavir Compared With Placebo in Nonhospitalized 
Symptomatic Adult Participants with COVID-19 who are at Low Risk of Progressing to 
Severe Illness.
Brief Title: A Phase 2/3 Efficacy and Safety Study of PF-07321332/Ritonavir in 
Nonhospitalized Low-Risk Adult Participants With COVID-19. 
Rationale: The purpose of this study is to evaluate the efficacy and safety of 
PF-07321332/ritonavir for the treatment of nonhospitalized, symptomatic, adult participants 
with COVID-19 who are at low risk of progression to severe illness.
Objectives, Endpoints, and Estimands 
Objectives
Endpoints
Estimands
Primary: 
Primary:
Primary: 
To compare the efficacy of 
PF-07321332/ritonavir to 
placebo for the treatment of 
symptomatic COVID-19 in 
nonhospitalized adult 
participants with COVID-19 
who are at low risk of 
progression to severe disease.
Time (days) to sustained alleviation of 
all targeted COVID-19 
signs/symptoms through Day 28.
The difference in median time 
(days) to sustained alleviation 
of all targeted COVID-19 
signs and symptoms through 
Day 28 between 
PF-07321332/ritonavir and 
placebo in nonhospitalized 
adult patients with 
COVID-19 who are at low 
risk of progression to severe 
disease at baseline and were 
treated ≤5 days after 
COVID-19 symptom onset.
This will be estimated 
irrespective of adherence to 
randomized treatment. 
Secondary: 
Secondary:
Secondary: 
To describe the safety and 
tolerability of 
PF-07321332/ritonavir relative 
to placebo in the treatment of 
nonhospitalized symptomatic 
adult participants with 
COVID-19 who are at low risk 
of progression to severe disease.
Incidence of TEAEs.
Incidence of SAEs and AEs leading to 
discontinuations.
Not Applicable.
To compare 
PF-07321332/ritonavir versus 
placebo for COVID-19-related 
hospitalization and all-cause 
mortality in nonhospitalized 
adult participants with 
COVID-19 who are at low risk 
of progression to severe disease.
Proportion of participants with 
COVID-19-related hospitalization or 
death from any cause through Day 28. 
The difference in 
proportions of patients 
experiencing COVID-19-
related hospitalization or 
death from any cause 
through Day 28 in 
nonhospitalized adult 
patients with COVID-19 


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Objectives
Endpoints
Estimands
Proportion of participants with death 
(all cause) through Week 24.
who are at low risk of 
progression to severe 
disease and were treated 
≤5 days after COVID-19 
symptom onset. This will 
be estimated without 
regard to adherence to 
randomized treatment.
Not Applicable
To compare 
PF-07321332/ritonavir versus 
placebo for COVID-19-related 
medical visits in nonhospitalized 
adult participants with 
COVID-19 who are at low risk 
of progression to severe disease.
Number of COVID-19 related 
medical visits through Day 28.
The difference in the 
estimated rate of the number 
of COVID-19-related medical 
visits through Day 28 in 
nonhospitalized adult patients 
with COVID-19 who are at 
low risk of progression to 
severe disease and were 
treated ≤5 days after 
COVID-19 symptom onset. 
This will be estimated 
without regard to adherence 
to randomized treatment.
Number of days in hospital and ICU 
stay in participants with 
COVID-19-related hospitalization 
through Day 28.
The difference in the 
estimated rate of number of 
days in hospital and ICU stay 
in patients with 
COVID-19-related 
hospitalization through 
Day 28 in nonhospitalized 
adult patients with 
COVID-19 who are at low 
risk of progression to severe 
disease and were treated 
≤5 days after COVID-19 
symptom onset. This will be 
estimated without regard to 
adherence to randomized 
treatment.
To compare 
PF-07321332/ritonavir to 
placebo for the duration and 
severity of signs and symptoms 
in nonhospitalized symptomatic 
adult participants with COVID-
19 who are at low risk of 
progression to severe disease.
Proportion of participants with severe 
signs/symptoms attributed to 
COVID-19 through Day 28.
Time (days) to sustained resolution of 
all targeted COVID-19 
signs/symptom through Day 28.
Duration of each targeted COVID-19 
sign/symptom.
Progression to a worsening status in 
1 or more self-reported 
COVID-19-associated symptoms 
through Day 28.
Proportion of participants with a 
resting peripheral oxygen saturation 
≥95% at Days 1 and 5.
Not Applicable.


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Objectives
Endpoints
Estimands
To determine the PK of 
PF-07321332 in nonhospitalized 
adult participants with 
COVID-19 who are at low risk 
of progression to severe disease.
PF-07321332 PK in plasma and 
whole blood (if feasible).
Not Applicable.
To describe the viral load in 
nasal samples over time in 
nonhospitalized adult 
participants with COVID-19 
who are at low risk of 
progression to severe disease.
Viral titers measured via RT-PCR in 
NP/nasal swabs over time.
Not Applicable.
Overall Design
Brief Summary
This Phase 2/3, randomized, double-blind, placebo-controlled study in nonhospitalized 
symptomatic adult participants with COVID-19 who are at low risk of progressing to severe 
illness will determine the efficacy, safety, and tolerability of PF-07321332/ritonavir 
compared with placebo. Eligible participants with a confirmed diagnosis of SARS-CoV-2 
infection will be randomized (1:1) to receive PF-07321332/ritonavir or placebo orally q12h 
for 5 days (10 doses total). Randomization will be stratified by geographic region, by 
vaccination status and by COVID-19 symptom onset (≤3 days vs 3 to 5 days).
Number of Participants
Approximately 1980 participants will be randomly assigned to study intervention. 
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
Participants will be screened within 48 hours before randomization. Eligible participants will 
receive PF-07321332 plus ritonavir or placebo orally q12h for 5 days. The total study 
duration is up to 24 weeks, with study intervention through Day 5 or Day 6, efficacy 
assessments through Day 28, a safety follow-up period through Day 34, and long-term 
follow-up at Weeks 12 and 24. 


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Data Monitoring Committee or Other Independent Oversight Committee: Yes
An independent E-DMC will review unblinded data to ensure the safety of participants 
throughout the duration of the study, as specified in the E-DMC Charter. In addition to up to 
weekly reviews of safety, the E-DMC will review the following:

Sentinel cohort safety review: The E-DMC will review unblinded safety data after 
approximately the first 100 randomized participants have completed through Day 10. 
Whether enrollment is paused for this review will depend on the successful completion of 
the Study C4671005 sentinel cohort (after approximately the first 60 randomized 
participants have completed through Day 10). If the C4671005 sentinel cohort safety 
review has successfully completed and no clinically significant safety signals have been 
identified prior to enrollment of the first 100 participants in this Study C4671002, the 
study will continue without pause.  Otherwise, enrollment of Study C4671002 will be 
paused pending the E-DMC review of safety data. After review of the sentinel cohort in 
this Study C4671002, the frequency of safety reviews may be reduced subsequently 
based on E-DMC recommendations.

Proof-of-concept assessment: Viral load data when 25% (approximately 200 participants 
in the primary analysis set with evaluable data) complete the Day 5 assessments. 
Enrollment will not be paused during review of these data, but may be paused or stopped 
following E-DMC review.

First interim analysis (45% planned enrollment through Protocol Amendment 4): A 
planned interim analysis for efficacy, futility and sample size reestimation was conducted 
after approximately 45% of participants completed the Day 28 assessments in the mITT 
analysis set.

Second interim analysis (80% planned enrollment through Protocol Amendment 4): At 
the request of the E-DMC, a second interim analysis was conducted on 80% of enrolled 
participants without any adjustment to the alpha.  
Details of the E-DMC are specified in the E-DMC Charter.
Statistical Methods
The primary endpoint of this study is the time (days) to sustained alleviation of all targeted 
COVID-19 signs/symptoms through Day 28. Time to sustained alleviation of all targeted 
COVID-19 signs/symptoms will be summarized graphically using Kaplan-Meier plots for 
each of the treatment group.  Log-rank test will be used to compare the difference in time 
(days) to sustained alleviation of all targeted COVID-19 signs and symptoms through Day 28 
between treatment groups. 
The initial estimate of required sample size was based on the primary endpoint, the 
difference in time to sustained alleviation of all targeted COVID-19 associated 
signs/symptoms between participants who were treated ≤3 days after COVID-19 symptom 
onset, treated with PF-07321332/ritonavir compared to placebo. The sample size was 


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calculated based on a 2-sample test-parallel design–log-rank test, assuming a 90% power, 
2-sided test at alpha=0.05, approximate accrual rate of 30 participants per day, 2 days 
difference in the median days to sustained alleviation of all targeted COVID-19-associated 
symptoms (6 days for PF-07321332/ritonavir and 8 days for placebo ie, a 25% reduction in 
time to sustained alleviation of all targeted COVID-19 signs/symptoms) based on 
Lilly-BLAZE-11 and assuming a 18% study discontinuation rate, the sample size of 
approximately 800 participants (approximately 515 events) will provide 90% power to detect 
that difference.    
Allowing for approximately 30% of participants with COVID-19 symptom onset 3 days, a 
sample size of approximately 1140 participants was to be enrolled for this study. 
After the second interim analysis (80% planned enrollment through Protocol Amendment 4), 
in order to improve estimation precision of the treatment effect in the clinically relevant key 
secondary endpoint of COVID-19-related hospitalization or death from any cause, the sample 
size was adjusted to approximately 1880 participants. This adjustment is expected to provide 
the required total number of 26 COVID-19-related hospitalizations or death from any cause, 
which will have approximately 90% conditional power (based on the second interim analysis 
data) such that the nominal 95% CI of the treatment group difference in the event rate does 
not include 0 when assuming that PF-07321332/ritonavir reduces the event rate by 70% or 
more relative to placebo.
The sample size increase of 740 participants is based on the assumption of a 1.5% event rate 
for the targeted enrollment countries. The number of participants is approximately 1880 
(1140 enrolled participants plus the increase of 740 participants). Assuming a 5% premature 
study discontinuation rate, approximately 1980 participants will be enrolled in the study.
A third interim analysis (100% planned enrollment through Protocol Amendment 4) to 
support regulatory filings was performed utilizing the dataset from 19 December 2021, which 
includes participants who had risk factors for severe COVID-19 illness and who were 
vaccinated against the SARS-CoV-2 virus as well as participants who did not have risk 
factors for severe COVID-19 illness and who were not vaccinated. This dataset was 
originally prepared to support an analysis based on all participants enrolled prior to Protocol 
Amendment 5 (21 January 2022). The data were never released nor analyzed previously 
because the protocol was amended (Protocol Amendment 5) to increase the sample size. 
Alpha was adjusted for the first interim analysis (45% planned enrollment through Protocol 
Amendment 4), no further adjustment for alpha was performed in the second interim analysis 
(80% planned enrollment through Protocol Amendment 4) and no adjustment for alpha was 
performed in the the third interim analysis (100% planned enrollment through Protocol 
Amendment 4). At the first interim analysis (45%), the IA met futility criteria and there is no 
remaining alpha for subsequent hypothesis tests.  Thus all further analysis will use nominal 
p-values for reporting.
The primary estimand is the difference between PF-07321332/ritonavir and placebo in 
median time (days) to sustained alleviation of all targeted signs and symptoms of COVID-19 
through Day 28 in nonhospitalized adult patients with COVID-19 who are at low risk of 
progression to severe disease at baseline and were treated ≤5 days after COVID-19 symptom 


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PFIZER CONFIDENTIAL
Page 15
onset. This will be estimated irrespective of adherence to randomized treatment. Because the 
study did not meet the primary endpoint based on the interim analysis at 45%, all hypothesis 
assessments are done with a nominal alpha. 
1.2. Schema


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PFIZER CONFIDENTIAL
Page 16
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 12. 
ScreeningBaseline
(Day 1)
Day 3
Day 5
Day 10  Day 14
Day
21
Day
34
LT F/U
ET 
(prior to 
Day 34) 
Notes
Week
12
Week
24
Visit Window
Day -1 to 
Day 1
0 days ±1 day ±1 day ±1 day ±2 days
±2 
days
±3 days ±7 days ±7 days ±5 days
ELIGIBILITY
Informed consent
X

See Section 10.1.3.
Verify inclusion/exclusion 
criteria
X

See Section 5.1 and Section 5.2.
Demographics and 
medical history
X

See Section 8.2.1.
COVID-19 risk factor 
assessment
X

See Appendix 9.
PHYSICAL EXAMINATION & VITAL SIGNS
Targeted physical 
examination
X
X
X
[X]
[X]
[X]

Will be completed at all in-person visits and 
on Days 14 and 34 and ET (prior to Day 34) 
if conducted in person. In the event that an in-
person visit is not feasible at the 
investigational site, targeted physical 
examinations 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 
Vital signs
X
X
[X]
X
[X]
[X]
[X]


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Visit Identifier
Abbreviations used in this 
table may be found in  
Appendix 12. 
ScreeningBaseline
(Day 1)
Day 3
Day 5
Day 10  Day 14
Day
21
Day
34
LT F/U
ET 
(prior to 
Day 34) 
Notes
Week
12
Week
24
Visit Window
Day -1 to 
Day 1
0 days ±1 day ±1 day ±1 day ±2 days
±2 
days
±3 days ±7 days ±7 days ±5 days
assessment) should be monitored to the extent 
possible if telemedicine is used.

Targeted physical examinations see 
Section 8.2.3.

Vital signs see Section 8.2.4.
Weight, height
X

Height may be self reported.

See Section 8.2.2.
LABORATORY
Hematology
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 
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.

Laboratory tests at Days 14 and 34 are 
required only if clinically relevant abnormal 
laboratory values were present from a sample 
Blood chemistry
X
X
[X]
[X]
[X]
Other laboratory 
assessments
X
X
[X]
[X]
[X]


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PFIZER CONFIDENTIAL
Page 18
Visit Identifier
Abbreviations used in this 
table may be found in  
Appendix 12. 
ScreeningBaseline
(Day 1)
Day 3
Day 5
Day 10  Day 14
Day
21
Day
34
LT F/U
ET 
(prior to 
Day 34) 
Notes
Week
12
Week
24
Visit Window
Day -1 to 
Day 1
0 days ±1 day ±1 day ±1 day ±2 days
±2 
days
±3 days ±7 days ±7 days ±5 days
drawn at the previous study visit when 
laboratory assessments were performed.  

Abnormal laboratory values related to AEs 
should be followed until resolution. See 
Section 8.2.5 and Appendix 2.
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 34 or ET visit.

See Section 8.2.6.
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 testing to be 
performed to confirm postmenopausal status.

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.
Rapid antigen testing
X

Only required if a participant does not have 
results of a positive SARS-CoV-2 test that 
was obtained within 5 days prior 
randomization.

Refer to Section 5.1.


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Final Protocol Amendment 6, 09 June 2022
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Page 19
Visit Identifier
Abbreviations used in this 
table may be found in  
Appendix 12. 
ScreeningBaseline
(Day 1)
Day 3
Day 5
Day 10  Day 14
Day
21
Day
34
LT F/U
ET 
(prior to 
Day 34) 
Notes
Week
12
Week
24
Visit Window
Day -1 to 
Day 1
0 days ±1 day ±1 day ±1 day ±2 days
±2 
days
±3 days ±7 days ±7 days ±5 days
Viral load assessment
X
X
X
X
X
•
At baseline, an NP swab will be collected by 
the investigational site staff to confirm SARS-
CoV-2 infection by RT-PCR. This test will 
not be used to determine study eligibility. 
Subsequent NP or nasal swabs will be 
collected on Days 1, 3, 5, 10, and 14.
o
NP swabs will be collected by an HCP 
during an in-person visit. Otherwise, a 
nasal swab will be self-collected by the 
participant.
•
See Section 8.6.4.
Specified protein research 
(plasma biomarkers)
X
X
[X]
•
Refer to Section 8.6.2.
 
 
 
 
 
 
 
PK
PK sample (PF-07321332)
X
X
•
On Day 1, one blood sample for PK will be 
collected 30 to 90 minutes postdose if 
feasible.
•
On Day 5, one blood sample for PK will be 
collected. The preferred time of sample 
collection is predose up to 2 hours before 
study intervention administration; if a predose 
sample collection is not possible, collect this 
sample at any time during the visit, even after 
study intervention has been administered.
•
Refer to Section 8.4.
CCI
CCI


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Page 20
Visit Identifier
Abbreviations used in this 
table may be found in  
Appendix 12. 
ScreeningBaseline
(Day 1)
Day 3
Day 5
Day 10  Day 14
Day
21
Day
34
LT F/U
ET 
(prior to 
Day 34) 
Notes
Week
12
Week
24
Visit Window
Day -1 to 
Day 1
0 days ±1 day ±1 day ±1 day ±2 days
±2 
days
±3 days ±7 days ±7 days ±5 days
Optional PK 
sampling 
([PF-07321332] 
collected via home 
health, site visit, or 
self-collected using 
Tasso; in a subset 
of participants, if 
feasible)
X

PK sample(s) will be collected either during 
in-person visit (a single blood sample 
collected at any time on either Days 2, 3, or 4) 
or self-collected by Tasso microsampling 
device (selected sites) at the following 
timepoints:
o
Day 2 before the evening dose, 
o
Day 3  after the morning dose at the 
following times: 1 sample between 30 to 
90 minutes, 1 sample between 2 to 6 
hours, and 1 sample 8 to 12 hours after 
the dose (the last sample should be 
collected before the evening dose).

Refer to Section 8.4.
RANDOMIZATION
X
STUDY INTERVENTION
Study intervention 
administration
Day 1 through Day 5 (10 
doses total)

If 1 dose was administered on Day 1, study 
intervention administration should end on 
Day 6.  

See Section 6.1
STUDY PROCEDURES & ASSESSMENTS
Collect/update secondary 
contacts
X
X
X
X
X
X
X

The investigator will capture contact 
information for at least 2 individuals who the 
site can contact if the participant is unable to 
be reached after multiple attempts.

At baseline, the investigator will also request 
contact information for any household 
members who may be eligible to participate in 
Study C4671006
Record supplemental 
oxygen requirements
X
X
X
X
X
X
X
X

See Section 8.1.4.


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Page 21
Visit Identifier
Abbreviations used in this 
table may be found in  
Appendix 12. 
ScreeningBaseline
(Day 1)
Day 3
Day 5
Day 10  Day 14
Day
21
Day
34
LT F/U
ET 
(prior to 
Day 34) 
Notes
Week
12
Week
24
Visit Window
Day -1 to 
Day 1
0 days ±1 day ±1 day ±1 day ±2 days
±2 
days
±3 days ±7 days ±7 days ±5 days
Study kit dispensed and 
participant instructed on its 
use
X
Participant-completed 
study diary (COVID-19 
signs and symptoms and 
global impression 
questions)
Every day from Day 1 through Day 28

See Section 8.1.1.and Section 8.1.5.3.

Global impression questions will be answered 
every day from Day 1 through Day 28 after 
COVID-19 signs and symptom diary is 
completed.  

Global impression questions will only be 
assessed in participants, as available.
WPAI
X
X
X
X

Will be assessed in participants, as available.

See Section 8.1.5.1.
EQ-5D-5L
X
X
X
X
X
X

Will be assessed in participants, as available.

See Section 8.1.5.2.
Exit interview
X

Exit interviews will be conducted by 
telephone and are to occur after the Day 34 
visit in a select group of US English-speaking 
participants (up to 50) at selected sites.

See Section 8.1.6.
Staff review of study diary
X
X
X
X
X
X

See Section 8.1.1.
Participant-completed 
study intervention log
Day 1 through Day 5 

Study intervention log should be completed 
daily on Days 1 through Day 6 if only 1 
dose was administered on Day 1. 

See Section 6.4.
Record COVID-19-related 
medical visits
X
X
X
X
X

COVID-19 related medical visits a participant 
has attended since the last assessment will be 
collected. See Section 8.1.2.
Retrieval of unused study 
intervention and empty 
study intervention 
containers 
X
[X]
[X]
X

If the Day 5 visit is conducted prior to last 
dose of study intervention, the study 
intervention log, empty study intervention 
containers, and unused study intervention 
should be returned at the next in-person visit.

See Section 6.4.


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Final Protocol Amendment 6, 09 June 2022
PFIZER CONFIDENTIAL
Page 22
Visit Identifier
Abbreviations used in this 
table may be found in  
Appendix 12. 
ScreeningBaseline
(Day 1)
Day 3
Day 5
Day 10  Day 14
Day
21
Day
34
LT F/U
ET 
(prior to 
Day 34) 
Notes
Week
12
Week
24
Visit Window
Day -1 to 
Day 1
0 days ±1 day ±1 day ±1 day ±2 days
±2 
days
±3 days ±7 days ±7 days ±5 days
Study intervention 
accountability
X
[X]
X
X 
[if 
needed]

Study intervention accountability is only 
performed at the Day 14 visit if the 
participant administered treatment after the 
Day 5 visit was conducted. If the Day 14 visit 
is not an in-person visit, study intervention 
accountability will then be performed during 
the Day 34 visit.

See Section 6.4.
Contraception check 
X
X
X
X
X
X
X

See Section 5.3.1.
Vital status check
X
X
X
Long-term follow-up 
telemedicine interview
X
X

Staff will ask participants if they are 
experiencing COVID-19 signs and symptoms 
and conduct a vital status check.
CONCOMITANT TREATMENT(S)
Prior/concomitant 
medications
X
X
X
X
X
X
X
X

All prescription and over-the-counter 
medications including vaccines taken by the 
participant within 30 days before study entry 
(considered prior treatment) will be recorded. 

Concomitant therapies will be collected 
through the Day 34 visit.

Refer to Section 6.8.
Adjunctive therapeutic 
procedures 
X
X
X
X
X
X
X
X

Will be collected through the Day 34 visit.
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 
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.


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Protocol C4671002
Final Protocol Amendment 6, 09 June 2022
PFIZER CONFIDENTIAL
Page 23
Visit Identifier
Abbreviations used in this 
table may be found in  
Appendix 12. 
ScreeningBaseline
(Day 1)
Day 3
Day 5
Day 10  Day 14
Day
21
Day
34
LT F/U
ET 
(prior to 
Day 34) 
Notes
Week
12
Week
24
Visit Window
Day -1 to 
Day 1
0 days ±1 day ±1 day ±1 day ±2 days
±2 
days
±3 days ±7 days ±7 days ±5 days

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 study intervention.

Day 1 is the start of dosing.

For Study Intervention Administration: Participants will receive study intervention for 5 days (10 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, 9) will be self-administered outside the study clinic (eg, at home). 

Screening, Baseline, and Day 5 visits will be conducted in person (at the investigational site approved by the investigator or a remote location, including a participant’s home).

Day 3 will only be conducted in person if a PK sample (not using Tasso) is collected by an HCP or at the discretion of the investigator.

Day 3 and Day 5 visits must be conducted on separate calendar days.

Day 10, Day 21, Week 12 and Week 24 visits will be conducted by telemedicine system. Telemedicine visits may be conducted in-person at the discretion of the investigator.

Day 14 may be conducted in person or by telemedicine system.

Day 34 will be conducted in person or by telemedicine system.

Early Termination prior to Day 34 visit will be conducted in person or by telemedicine system.


PF-07321332
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2. INTRODUCTION
PF-07321332, a potent and selective SARS-CoV-2 3CL protease inhibitor, is being 
investigated as an oral antiviral treatment of COVID-19.
2.1. Study Rationale 
The purpose of this study is to evaluate the efficacy and safety of PF-07321332/ritonavir for 
the treatment of nonhospitalized, symptomatic, adult participants with COVID-19 who are at 
low risk of progression to severe illness.
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 Concern2 on 30 January 2020 and further characterized 
the disease outbreak as a pandemic on 11 March 2020.3 As of 12 January 2022, at least 
315 million cases have been confirmed worldwide, and at least 5.5 million deaths have 
occurred.4
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,5 patients who are hospitalized with COVID-19 may have significant morbidity and 
mortality,6,7 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.8-11 Moreover, other 
comorbidities, such as hypertension, obesity, and diabetes, as well as older age and male sex 
increase the risk for worse outcomes.6
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 SoC.12-14 The FDA has approved IV 
remdesivir,15 an antiviral drug with activity against SARS-CoV-2, for hospitalized patients 
with COVID-19 and for the treatment of mild to moderate COVID-19 in high-risk 
nonhospitalized patients.16 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 viruses 20,21 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
Three IV-administered mAb based regimens have received EUA for treatment of COVID-19 
in the outpatient setting for high risk persons on the basis of observed reductions in 
hospitalizations and deaths in placebo-controlled randomized controlled trials. 22-24


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Eligibility for mAbs is limited to persons meeting EUA-defined criteria of being at high risk 
for progression to severe COVID-19 or hospitalization, may only be administered in settings 
in which health care providers have immediate access to medications to treat a severe 
infusion reaction and require patients be monitored during administration and for at least 
1 hour after infusion is complete. In addition, as the mAb based regimens primarily target the 
variable spike protein, there is ongoing risk that the continued emergence of SARS-CoV-2 
variants will negatively impact the efficacy of mAb based regimens. 
In December 2021, the FDA granted EUA for a 5 day course of treatment for 2 separate oral 
antiviral agents, PF-07321332 (nirmatrelvir)/ritonavir and molnupiravir, for the treatment of 
COVID-19 in adult and pediatric patients 12 years of age and older who weigh at least 
40 kilograms, with mild to moderate COVID-19 who are at high risk for progressing to 
severe illness. Molnupiravir is not recommended during pregnancy, as findings from animal 
reproduction studies showed that molnupiravir may cause fetal harm when administered to 
pregnant individuals. In January 2022, remdesivir received approval for this same population. 
This treatment is administered by IV infusion over 3 days for nonhospitalized patients with 
mild to moderate COVID-19 who are at high risk for progressing to severe illness.
There is thus a high unmet need for antiviral agents that could be used for the treatment of 
nonhospitalized persons with COVID-19. Such agents, particularly those that target highly 
conserved viral targets, don’t require administration in a healthcare setting, and with a 
risk/benefit profile supportive of administration to a broad patient population will 
significantly add to the treatment armamentarium for COVID-19.
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).25 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 
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 in patients with COVID-19.
In this study, PF-07321332 will be coadministered with ritonavir. Ritonavir is a strong 
CYP3A4 inhibitor, and is being coadministered with PF-07321332 to achieve exposures 
sufficient to suppress viral replication through the entire dosing interval (ie, Ctrough>EC90). 
Ritonavir is not expected to have any antiviral activity against the SARS-CoV-2 virus.
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.26


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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 indicate that 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.
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.


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Current evidence indicates that 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.
A prespecified interim analysis of Study C4671002, which included 45% of the trial's 
planned enrollment, showed that the novel primary endpoint of self-reported, sustained 
alleviation of all symptoms for 4 consecutive days, as compared to placebo, was not met. 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). 
This study, C4671002, is ongoing and participant-level treatment assignment remains 
blinded.
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 IB, which is the SRSD for this study. The 
SRSD for ritonavir is the USPI 27 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.
Hypertension
Transient increases in systolic, diastolic, and mean 
blood pressure were observed in the preclinical 
studies. In Study C4671005 (adults at high risk for 
severe disease), a small imbalance in 9 participants 
with reported events of  hypertension was reported
(1% vs <1%).
Vital signs will be monitored per SoA during the 
study during any in-clinic visits. All AEs will be 
monitored in the study. Concomitant medications 
will also be reviewed for potential new AEs and 
worsening of the condition.
Study Intervention(s): Ritonavir
Gastrointestinal disturbances (including 
diarrhea, nausea, vomiting and abdominal pain)
Frequently reported adverse reaction in HIV-positive 
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 
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 


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Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
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
PF-07321332 has been shown to have SARS-CoV-2 antiviral activity in vitro and is intended 
to reduce virus titers, thereby reducing the duration and severity of symptoms and the risk of 
mortality in SARS-CoV-2 infected patients. Efficacy, safety and tolerability of PF-07321332 
was demonstrated in the C4671005 study in adults at increased risk of progressing to severe 
COVID-19 illness. As a result, emergency use authorization has been granted for 
PF-07321332/ritonavir by the FDA for the treatment of mild to moderate COVID-19 in 
certain adults and pediatric patients (12 years of age and older) with positive results of direct 
SARS-CoV-2 testing, and who are at high risk for progression to severe COVID-19, 
including hospitalization or death. As noted in Section 2.2.2, at the 45% interim analysis for 
Study C4671002, a reduction in the number of hospitalizations or death was noted in 
participants treated with PF-07321332/ritonavir compared with placebo. On this basis, the 
potential benefit to individual study participants who receive the study intervention may 
include a shorter time to clinical recovery, prevention of hospitalization, and a lower 
probability of progressing to more severe illness or death. The potential benefit of the study 
is that it may provide a new treatment option for nonhospitalized patients with COVID-19 
who are at low risk for progression to severe disease and hospitalization. In the context of the 
global pandemic public health emergency this treatment could play an important role in 
alleviating current pressures on health care systems globally.  
2.3.3. Overall Benefit/Risk Conclusion
Taking into account the current COVID-19 global pandemic and the high burden of both 
mortality and morbidity and the potential for future epidemic outbreaks, the lack of readily 
available outpatient 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 participants with COVID-19. 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 estimation at the time of the interim analysis according to the E-DMC 
charter.


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3. OBJECTIVES, ENDPOINTS, AND ESTIMANDS
Objectives
Endpoints
Estimands
Primary: 
Primary:
Primary: 
To compare the efficacy of 
PF-07321332/ritonavir to 
placebo for the treatment of 
symptomatic COVID-19 in 
nonhospitalized adult 
participants with COVID-19 
who are at low risk of 
progression to severe disease.
Time (days) to sustained alleviation of 
all targeted COVID-19 
signs/symptoms through Day 28.
The difference in median time 
(days) to sustained alleviation 
of all targeted COVID-19 
signs and symptoms through 
Day 28 between 
PF-07321332/ritonavir and 
placebo in nonhospitalized 
adult patients with COVID-19 
who are at low risk of 
progression to severe disease 
at baseline and were treated 
≤5 days after COVID-19 
symptom onset. This will be 
estimated irrespective of 
adherence to randomized 
treatment.
Secondary: 
Secondary:
Secondary: 
To describe the safety and 
tolerability of 
PF-07321332/ritonavir relative 
to placebo in the treatment of 
nonhospitalized symptomatic 
adult participants with 
COVID-19 who are at low risk 
of progression to severe disease.
Incidence of TEAEs.
Incidence of SAEs and AEs leading to 
discontinuations.
Not Applicable.
To compare 
PF-07321332/ritonavir versus 
placebo for COVID-19-related 
hospitalization and all-cause 
mortality in nonhospitalized 
adult participants with COVID-
19 who are at low risk of 
progression to severe disease.
Proportion of participants with 
COVID-19-related hospitalization or 
death from any cause through Day 28. 
Proportion of participants with death 
(all cause) through Week 24.
The difference in proportions 
of patients experiencing 
COVID-19-related 
hospitalization or death from 
any cause through Day 28 in 
nonhospitalized adult patients 
with COVID-19 who are at 
low risk of progression to 
severe disease and were 
treated ≤5 days after 
COVID-19 symptom onset. 
This will be estimated 
without regard to adherence 
to randomized treatment.
Not Applicable
To compare 
PF-07321332/ritonavir versus 
placebo for COVID-19-related 
medical visits in nonhospitalized 
adult participants with 
COVID-19 who are at low risk 
of progression to severe disease.
Number of COVID-19-related 
medical visits through Day 28.
The difference in the 
estimated rate of the number 
of COVID-19-related medical 
visits through Day 28 in 
nonhospitalized adult patients 
with COVID-19 who are at 
low risk of progression to 
severe disease and were 
treated ≤5 days after 
COVID-19 symptom onset. 


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Objectives
Endpoints
Estimands
This will be estimated 
without regard to adherence 
to randomized treatment.
Number of days in hospital and ICU 
stay in participants with 
COVID-19-related hospitalization 
through Day 28.
The difference in the 
estimated rate of number of 
days in hospital and ICU stay 
in patients with 
COVID-19-related 
hospitalization through 
Day 28 in nonhospitalized 
adult patients with COVID-19 
who are at low risk of 
progression to severe disease 
and were treated ≤5 days after 
COVID-19 symptom onset. 
This will be estimated 
without regard to adherence 
to randomized treatment.
To compare 
PF-07321332/ritonavir to 
placebo for the duration and 
severity of signs and symptoms 
in nonhospitalized symptomatic 
adult participants with COVID-
19 who are at low risk of 
progression to severe disease.
Proportion of participants with severe 
signs/symptoms attributed to COVID-
19 through Day 28.
Time (days) to sustained resolution of 
all targeted COVID-19 
signs/symptom through Day 28.
Duration of each targeted COVID-19 
sign/symptom.
Progression to a worsening status in 
1 or more self-reported 
COVID-19-associated symptoms 
through Day 28.
Proportion of participants with a 
resting peripheral oxygen saturation 
≥95% at Days 1 and 5.
Not Applicable.
To determine the PK of 
PF-07321332 in nonhospitalized
adult participants with 
COVID-19 who are at low risk 
of progression to severe disease.
PF-07321332 PK in plasma and whole 
blood (if feasible).
Not Applicable.
To describe the viral load in 
nasal samples over time in 
nonhospitalized adult 
participants with COVID-19 
who are at low risk of 
progression to severe disease.
Viral titers measured via RT-PCR in 
NP/nasal swabs over time.
Not Applicable.
4. STUDY DESIGN
4.1. Overall Design
This Phase 2/3, randomized, double-blind, placebo-controlled study in approximately 
1980 symptomatic low risk participants with COVID-19 who are nonhospitalized will 
determine the efficacy, safety, and tolerability of PF-07321332/ritonavir compared with 
placebo. Eligible participants with a confirmed diagnosis of SARS-CoV-2 infection will be 


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randomized (1:1) to receive PF-07321332/ritonavir or placebo orally q12h for 5 days 
(10 doses total). Randomization will be stratified by geographic region, by vaccination status 
and by COVID-19 symptom onset (≤3 days vs 3 to 5 days). 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.  
The total study duration is up to 24 weeks and includes a screening period of no more than 
48 hours, administration of study intervention through Day 5 or Day 6, efficacy assessments 
through Day 28, a safety follow-up period through Day 34, and long-term follow up at 
Weeks 12 and 24. 
An independent E-DMC will review unblinded data for this Study C4671002 to ensure the 
safety of participants throughout the duration of the study.  In addition to up to weekly 
reviews of safety, the E-DMC will review the following:

Sentinel cohort safety review: The E-DMC will review unblinded safety data after 
approximately the first 100 randomized participants have completed through Day 10. 
Whether enrollment is paused for this review will depend on the successful completion of 
the Study C4671005 sentinel cohort (after approximately the first 60 randomized 
participants have completed through Day 10).  If the Study C4671005 sentinel cohort 
safety review has successfully completed and no clinically significant safety signals have 
been identified prior to enrollment of the first 100 participants in this Study C4671002, 
the study will continue without pause.  Otherwise, enrollment of Study C4671002 will be 
paused pending the E-DMC review of safety data. After review of the sentinel cohort in 
this Study C4671002, the frequency of safety reviews may be reduced subsequently 
based on E-DMC recommendations.

Proof-of-concept assessment: Viral load data when 25% (approximately 200 participants 
in the primary analysis set with evaluable data) complete the Day 5 assessments. 
Enrollment will not be paused during review of these data, but may be paused or stopped 
following E-DMC review.

First interim analysis (45% planned enrollment through Protocol Amendment 4): A 
planned interim analysis for efficacy, futility and sample size reestimation was conducted 
after approximately 45% of participants completed the Day 28 assessments in the mITT 
analysis set.

Second interim analysis (80% planned enrollment through Protocol Amendment 4): At 
the request of the E-DMC, a second interim analysis was conducted on 80% of enrolled 
participants without any adjustment to the alpha.
A third interim analysis (100% planned enrollment through Protocol Amendment 4) was 
performed on all participants enrolled through Protocol Amendment 4 and had completed the 
Day 34 visit. Data from the study are required to support regulatory submissions thereby 
necessitating this interim analysis.


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Subsequent to the interim analyses above, there will be a final analysis for reporting the 
results of this study. The final study analysis will be performed after all participants have 
completed or otherwise withdrawn from the study. 
4.2. Scientific Rationale for Study Design
This study evaluates safety and the potential effect of an investigational agent on 
alleviating/resolving COVID-19-associated symptoms, and on reducing the duration and 
severity of COVID-19-associated symptoms because participants are symptomatic upon 
entry to this study. In addition to symptoms, this study is also evaluating COVID-19-related 
hospitalization or death from any cause. Previous studies with mAbs directed against the 
SARS-CoV-2 spike (S) protein that have received an EUA from the US FDA showed 
efficacy in reducing SARS CoV-2 shedding on NP swabs and time to symptom resolution.22-
24 Efficacy assessments (including participant reported COVID-19 symptoms and severity, 
and COVID-19 related medical visits) will be collected through Day 28. The symptom 
endpoint includes those recommended by FDA and relies on targeted symptoms that have 
been associated with COVID-19, and which are expected to be dynamic and improve with 
effective anti-SARS-CoV-2 therapy. NP/nasal swabs will be collected at specified timepoints 
to assess viral load over time.
This study uses a randomized, double-blind, placebo-controlled design, which is a 
well-accepted approach for evaluating efficacy in a clinical research setting. Randomization 
will be stratified by geographic region, by vaccination status and by COVID-19 symptom 
onset (≤3 days vs 3 to 5 days). An early safety analysis will be conducted following 
enrollment of approximately 100 participants. Placebo was selected as the comparator since 
as of this date there is no globally approved SoC treatment for this patient population. 
Results from a protocol-specified 45% interim analysis of this study 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. In addition, the 45% interim analysis of the 
secondary endpoint of COVID-19-related hospitalization or death from any cause through 
Day 28 showed 0.6% of those who received PF-07321332/ritonavir were hospitalized 
following randomization (2 of 333 hospitalized with no deaths), compared with 2.4% of 
participants who received placebo and were hospitalized (8 of 329 hospitalized with no 
deaths). These secondary endpoint data demonstrate that treatment with 
PF-07321332/ritonavir may provide significant clinical benefit to patients at low risk of 
progression to severe COVID-19 as measured by the endpoint of hospitalization or death.
Furthermore, results from Study C4671005 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 are at 
increased risk of progression to severe disease when they were treated within 3 days of 
symptom onset. In a secondary endpoint, PF-07321332/ritonavir treatment also reduced the 
risk of hospitalization or death from any cause by 88% compared with placebo in participants 
treated within 5 days of symptom onset. Therefore, data from Study C4671002 will be 
analyzed irrespective of whether participants begin treatment within 3 or 5 days of symptom 
onset.  


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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).
 
4.3. Justification for Dose
A dosing regimen of 300 mg PF-07321332 coadministered with 100 mg ritonavir q12h 
administered orally for 5 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 the first dose of 300 mg of PF-07321332 coadministered with 100 mg ritonavir 
q12h, median Ctrough of unbound (free) PF-07321332 are predicted to be approximately 
289 ng/mL (equivalent to 933 ng/mL total), ie, approximately 3-fold higher than the in vitro 
EC90 of 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.
The selected duration is based on the effectiveness demonstrated following 5 day 
administration of other antiviral agents used in the treatment of acute respiratory infections, 
such as remdesivir for SARS-CoV-2 and oseltamivir for influenza.
Preliminary safety data from Study C4671001, collected up to 07 April 2021 and 14 April 
2021, 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.
In Study C4671005, a dosing regimen of 300 mg PF-07321332 coadministered with 100 mg 
ritonavir q12h administered orally for 5 days was efficacious in reducing the incidence of 
COVID-19-related hospitalization or death from any cause in nonhospitalized symptomatic 
adult participants with COVID-19 who were at increased risk of progression to severe 
disease. PF-07321332 was safe and well tolerated.
CCI


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The proposed dosing regimen of 300 mg PF-07321332 coadministered with 100 mg ritonavir 
q12h administered orally for 5 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 as shown in the SoA.
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 enrolment of a diverse participant population including, where permitted under 
local regulations, age, sex, and race, and ethnicity. The following eligibility criteria are 
designed to select participants for whom participation in the study is considered appropriate. 
All relevant medical and nonmedical conditions should be taken into consideration when 
deciding whether a particular participant is suitable for this protocol. 
Prospective approval of protocol deviations to recruitment and enrollment criteria, also 
known as protocol waivers or exemptions, is not permitted.
5.1. Inclusion Criteria
Participants are eligible to be included in the study only if all of the following criteria apply:
Age and Sex:
1. Participants ≥18 years of age (or the minimum country-specific age of consent if >18) at 
the time of 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. Confirmed SARS-CoV-2 infection as determined by RT-PCR in any specimen collected 
within 5 days prior to randomization. 
Note: RT-PCR is the preferred method; however, with evolving approaches to 
confirmation of SARS-CoV-2 infection, other molecular or antigen tests that detect viral 
RNA or protein are allowed. The test result must be available to confirm eligibility. 


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Participants may be enrolled based on positive results of a rapid SARS-CoV-2 antigen 
test performed at screening.
3. Initial onset of signs/symptoms attributable to COVID-19 within 5 days prior to the day 
of randomization and at least 1 of the specified signs/symptoms attributable to COVID-
19 present on the day of randomization (see Appendix 9 for criteria).
4. Participants who are willing and able to comply with all scheduled visits, treatment plan, 
laboratory tests, lifestyle considerations, and other study procedures.
Informed Consent:
5. 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. Has at least 1 characteristic or underlying medical condition (self-report is acceptable) 
associated with an increased risk of developing severe illness from COVID-19, including:

≥65 years of age;

BMI≥30 kg/m2;

Current smoker (cigarette smoking within the past 30 days) and history of at least 100 
lifetime cigarettes;

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 
(including palliative treatment), as long as the treatment is not among the prohibited 
medications that must be administered/continued during the trial period;


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
Medical-related technological dependence (eg, CPAP [not related to COVID-19]).  
2. 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, etc.), 
immunomodulators (eg, methotrexate, 6MP, azathioprine, etc), or cancer 
chemotherapy within 90 days prior to study entry’;

HIV infection with CD4+ cell count <200/mm3. 
3. History of hospitalization for the medical treatment of COVID-19.  
4. Current need for hospitalization or anticipated need for hospitalization within 48 hours 
after randomization in the clinical opinion of the site investigator (see Section 8.1.2).
5. Prior to current disease episode, any confirmed SARS-CoV-2 infection, as determined by 
a molecular test (antigen or nucleic acid) from any specimen collection.
6. Known medical history of active liver disease (other than nonalcoholic hepatic steatosis), 
including chronic or active hepatitis B or C infection, primary biliary cirrhosis, Child-
Pugh Class B or C or acute liver failure.
7. Receiving dialysis or have known renal impairment.
8. Known HIV infection with viral load >400 copies/mL or taking prohibited medications 
for HIV treatment (from known medical history within past 6 months of the screening 
visit) (Appendix 8).  
9. Suspected or confirmed concurrent active systemic infection other than COVID-19 that 
may interfere with the evaluation of response to the study intervention.
10. 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.
11. History of hypersensitivity or other contraindication to any of the components of the 
study intervention, as determined by the investigator.
12. 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:
13. 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 


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with serious and/or life-threatening events during treatment and for 4 days after the last 
dose of PF-07321332/ritonavir (see Appendix 8).
14. 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).
15. Has received or is expected to receive monoclonal antibody treatment, antiviral treatment 
(eg, molnupiravir), or convalescent COVID-19 plasma. 
16. Has received any SARS-CoV-2 vaccination within 12 months of screening.  
Note: Participants entering the study must not receive any dose of a SARS-CoV-2 
vaccine prior to Day 34.
Prior/Concurrent Clinical Study Experience:
17. 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 long-term follow-up visit. Previous administration with any investigational drug or 
vaccine within 30 days (or as determined by the local requirement) or 5 halflives 
preceding the first dose of study intervention used in this study (whichever is longer).
18. Known prior participation in this trial or other trial involving PF-07321332.
Diagnostic Assessments:
19. Known history of any of the following abnormalities in clinical laboratory tests (within 
past 6 months of the screening visit): 

AST or ALT level ≥2.5 X ULN;

Total bilirubin ≥2 X ULN (≥3 X 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 formula;28

Absolute neutrophil count <1000/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. 
20. Oxygen saturation of < 92% on room air obtained at rest within 24 hours prior to 
randomization.


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NOTE: For a potential participant who regularly receives chronic supplementary oxygen 
for an underlying lung condition, oxygen saturation should be measured while on their 
standard home oxygen supplementation.
Other Exclusions:
21. Females who are pregnant or breastfeeding.
22. 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 
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.  
5.5. Criteria for Temporarily Delaying Enrollment/Randomization/Administration of 
Study Intervention 
Not applicable.


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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 q12h for 
5 days
0 mg q12h for 
5 days
100 mg q12h for 
5 days
0 mg q12h for 
5 days
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 
required per country 
requirement. Products 
will be provided with 
blinded labels.
Study 
intervention 
will be 
provided in 
blister wallets. 
Each wallet 
will be labeled 
as required per 
Study intervention 
will be provided in 
HDPE bottles. Each 
bottle will be labeled 
as required per 
country requirement.
Study 
intervention 
will be 
provided in 
HDPE bottles. 
Each bottle 
will be labeled 
as required 


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Study Interventions(s)
country 
requirement.
per country 
requirement.
Current/Former 
Name(s) or Alias(es)
PF-07321332
N/A
ritonavir
N/A
Study Arm(s)
Arm Title
PF-07321332/ritonavir
Placebo
Arm Type
experimental 
placebo
Arm Description
Participants will receive 
PF-07321332/ritonavir
300 mg/100 mg every 12 hours 
for 5 days.
Participants will receive 0 mg every 
12 hours for 5 days
Associated Intervention Labels
PF-07321332/ritonavir
Placebo
6.1.1. Administration
PF-07321332 150 mg tablets or placebo for PF-07321332, will be administered for 5 days 
with ritonavir 100 mg or placebo for ritonavir capsules. Participants will be dispensed 1 
blister wallet of PF-07321332 150 mg or placebo for PF-07321332 tablets and 1 bottle of 
ritonavir or placebo for ritonavir capsules. Participants will be given clear dosing instruction 
to take:

2 tablets of PF-07321332 150 mg or placebo for PF-07321332 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 or the 2 tablets of placebo for PF-07321332 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 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 drug in 


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order to “make up” what had been missed. Dosing should be stopped at the end of the 
treatment period (10 doses total). Any remaining tablets and/or capsules at the end of 5 days 
(or 6 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.
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 


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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.
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 
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 visits summarized in the SoA. 
Returned study intervention must not be redispensed to the study 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.


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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 a clinician, statistician and programmer(s) and 
will be separate from the blinded members of the study team.  

An unblinded submissions team will be responsible for preparing unblinded analyses 
and documents to support regulatory activities that may be required while the study is 
ongoing. 
The study will be unblinded after all participants complete the Day 34 visit (or ET prior to 
Day 34 visit), and analyses through Day 34, including the primary efficacy endpoint 
analyses, will be conducted. 
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) and will be educated to record the date and time of their study 
intervention dosing, preferably at the time of first dose.
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.


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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 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).
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).


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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 may receive SoC therapy for COVID-19, in addition to study intervention, 
unless listed as prohibited medication (see Appendix 8) or as defined in Section 5.2. 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. Investigator 
should ensure that any recommended SoC therapy is not a strong inducer of CYP3A4 or 
highly dependent on CYP3A4 for clearance.
Prohibited During the Study
Participants should not receive monoclonal antibody treatment, antiviral treatment (eg, 
molnupiravir), or convalescent COVID-19 plasma treatment for COVID-19 during the study 
period. COVID-19 vaccinations are permitted after the Day 34 visit.
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, 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 of PF-07321332. 
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 before the first 
dose of study intervention is administered 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. 


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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 or legally authorized representative

Hospitalization during the active treatment period;

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 postscreening eGFR is <45 ml/min/1.73 m2 the participant will be instructed to discontinue 
any remaining study intervention doses as soon as study staff become aware of laboratory 
results. 


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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 Section7.2.1) for 
disclosure of future information, no further evaluations should be performed and no 
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.


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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.
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.


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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 
150 mL. An additional optional blood sample of up to 4 mL will be collected for a subset of 
participants who agree to collect an optional PK sample. 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 will use their own device to 
record: daily COVID-19 signs and symptoms, study intervention and administration, and 
other PRO assessments in the study diary. 
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, 24 hours), 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. 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 ≤24 hours, 


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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. 
Hospitalization is defined as >24 hours 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 purposes of public health and/or clinical trial 
execution.
8.1.3. 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 described in Section 8.1.1.
COVID-19-related symptoms will be evaluated in accordance with FDA guidelines 
(Appendix 9).29 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. 
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. 
Targeted COVID-19-associated symptoms are a subset of these symptoms (Appendix 9). 
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. PRO Assessments
8.1.5.1. WPAI Questionnaire
COVID-19 impacts manual and office-based work, and results in missed work due to illness 
or quarantine and loss of productivity.30  The Work Productivity and Activity Impairment 
Questionnaire:  General Health (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.31
The WPAI-COVID-19 consists of 6 questions that refer to the following assessments for 
work productivity: 1 = currently employed, 2 = hours missed due to health problems, 3 = 


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hours missed other reasons, 4 = hours actually worked, 5 = degree health affected 
productivity while working (using a 0 to 10 VAS), and 6 = degree health affected 
productivity in regular unpaid activities. The recall period for questions 2 through 6 is 7 days. 
Four main outcomes will be generated from the WPAI-COVID-19 and reported as: 1) 
percent work time missed due to COVID-19 for those who are currently employed, 2) 
percent impairment while working due to COVID-19 for those who are currently employed 
and actually worked in the past 7 days, 3) percent overall work impairment due to COVID-19 
for those who are currently employed, and 4) percent activity impairment due to COVID-19 
for all respondents.31 The WPAI-COVID-19 should be completed as specified in the SoA.
8.1.5.2. 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.32-34 Recently, a version 
was developed called EQ-5D-5L with 5 response levels on each dimension compared to the 3 
response levels in the EuroQol Quality of Life 5-Dimension 3-Level Scale (EQ-5D-3L).32-38
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.32,34,36,37 Both the EuroQol 
EQ-5D-3L and EQ-5D-5L versions are well established instruments used to measure health 
states and utilities in various diseases areas and assess mobility, self-care, usual activities, 
pain/discomfort, anxiety/depression and health status using a VAS.35,39 The EQ-5D-5L
should be completed as described in the SoA.
8.1.5.3. Global Impression Questions
Three 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:29  
8.1.6. Exit Interview
Qualitative exit interviews with a select group of US English-speaking participants (up to 50) 
at selected sites will be conducted by telephone, as indicated in the SoA. Interviews will be 
conducted by trained moderators, that are not part of study site staff, and are anticipated to be 
approximately 60 minutes in duration. Participant understanding of daily diary signs and 
symptoms questions and global impression questions will be evaluated based on transcripts 
and interviewer field notes. 
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 in addition to COVID-19 disease history and demographics will be collected 
at screening. Smoking status will be collected. Complete medication history of all 


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prescription or nonprescription drugs (including vaccinations), and dietary and herbal 
supplements taken within 30 days prior to the planned first dose will be collected.
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, oxygen saturation level, and blood pressure will be 
assessed as specified in the SoA.
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).
Vital signs are to be taken before blood collection for laboratory tests.
Each participant will also be supplied with a pulse oximeter to be used based on the 
instruction and medical judgment of the site investigator.
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 DAIDS Table for Grading the 
Severity of Adult and Pediatric Adverse Events40, version 2.1. The investigator must review 


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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.
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.
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). 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 


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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.
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.
After the defined active collection period, participants are contacted by phone for a vital 
status check at Week 12 and Week 24 (long-term follow-up period). Any SAE identified 
during this follow-up period and determined to be related to PF-07321332/ritonavir is 
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. Investigators 
are not otherwise obligated to report AEs after the defined active collection period.
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.


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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.
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 


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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 
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). 


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
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.
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: 


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
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.  
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
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.
AESIs include hemodynamic events, inflammatory events, and thyroid-related events.


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All AESIs must be reported as an AE or SAE following the procedures described in 
Section 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.  
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.


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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 
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 1.5 mL plasma, will be 
collected for measurement of plasma concentrations of PF-07321332 as specified in the SoA. 
In a subset of participants, additional optional PK samples may be collected via home health 
visit, in-clinic visits, or self-collected whole blood microsample (Tasso device) 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 does not apply to samples that are 
specified to be collected “at any time”.
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 concentration of ritonavir.
Genetic analyses will not be performed on these plasma samples unless consent for this was 
included in the informed consent. Participant confidentiality will be maintained.
Samples collected for measurement of plasma concentrations of study intervention will be 
analyzed using a validated analytical method in compliance with applicable SOPs. Potential 
metabolites may be analyzed with either validated or exploratory methods.
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. 


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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.
Any changes in the timing or addition of time points for any planned study assessments must 
be documented and approved by the relevant study team member and then archived in the 
sponsor and site study files, but will not constitute a protocol amendment. The IRB/EC will 
be informed of any safety issues that require alteration of the safety monitoring scheme or 
amendment of the ICD.
8.5. Genetics
8.5.1. Specified Genetics
Genetics (specified analyses) are not evaluated in this study.
 
 
 
 
 
 
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:
•
NP/nasal swab will be collected to measure SARS CoV-2 viral load by RT-PCR. 
•
Residual NP/nasal viral load samples may be used for SARS CoV-2 viral sequencing.
•
Residual NP/nasal viral load samples may be used for SARS CoV-2 infectivity assays 
and phenotypic analyses. 
 
8.6.1. Specified Gene Expression (RNA) Research 
Specified gene expression (RNA) research is not included in this study.
CCI
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8.6.3. Specified Metabolomic Research 
Specified metabolomic research is not included in this study.
8.6.4. Viral Load Assessments
An NP/nasal swab will be collected per the SoA, and may be analyzed to measure SARS-
CoV-2 RNA by RT-PCR. Residual viral load samples may be utilized for viral sequencing to 
assess for signs of viral evolution and evaluation of potential genetic viral variants (eg, 3CL 
gene) or immune responses, SARS CoV-2 infectivity assays, and additional molecular 
analysis.
Residuals of all samples may be banked for future research. Storage and shipping instructions 
will be in accordance with 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 
are outlined here and further detailed in a SAP, which will be maintained by the sponsor. The 
CCI
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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 to be tested is whether or not there is a difference in median time 
(days) to sustained alleviation of all targeted COVID-19 signs and symptoms through Day 28 
between PF-07321332/ritonavir and placebo. The statistical hypothesis is as follows:

The null hypothesis (H0) is that there is no difference in median time to sustained 
alleviation of targeted symptoms of COVID-19 between PF-07321332/ritonavir and 
placebo; 

The alternative hypothesis (H1) is that there is a difference in median time to sustained 
alleviation of targeted symptoms of COVID-19 between PF-07321332/ritonavir and 
placebo.
Because the prespecified 45% interim analysis of the primary endpoint was not met, the 
following secondary endpoints will be analyzed to provide a point estimate and 95% CI to 
measure associated variability. The analysis will be performed with a nominal alpha: 
1) Proportion of participants with COVID-19-related hospitalization or death from 
any cause through Day 28.
2) Number of COVID-19-related medical visits through Day 28.
In support of the COVID-19 related medical visits endpoint, the number of days in hospital 
and ICU stay in patients with COVID-19-related hospitalization through Day 28 will be 
summarized. 
Other secondary endpoints, which will be identified in the SAP, will be subsequently tested 
following the Hochberg procedure.41
Imputation of missing data within other specific efficacy variables and endpoints will be 
computed according to the rules specified in the SAP.
9.1.1. Estimands
9.1.1.1. Primary Estimand/Co-Primary Estimands
The primary estimand is the difference in median time (days) to sustained alleviation of all 
targeted COVID-19 signs and symptoms through Day 28 between PF-07321332/ritonavir
and placebo in nonhospitalized adult patients with COVID-19 who are at low risk of 
progression to severe disease at baseline and were treated ≤5 days after COVID-19 symptom 
onset. This will be estimated irrespective of adherence to randomized treatment. Because the 
study did not meet the primary endpoint based on the interim analysis at 45%, all hypothesis 
assessments are done with a nominal alpha.


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9.1.1.2. Secondary Estimands
The estimands associated with the secondary objectives are as follows:

The difference in proportions of patients experiencing COVID-19 related hospitalization 
or death from any cause through Day 28 in nonhospitalized adult patients with 
COVID-19 who are at low risk of progression to severe disease and were treated ≤5 days 
after COVID-19 symptom onset. This will be estimated without regard to adherence to 
randomized treatment.

The difference in the estimated rate of the number of COVID-19-related medical visits 
through Day 28 in nonhospitalized adult patients with COVID-19 who are at low risk of 
progression to severe disease and were treated ≤5 days after COVID-19 symptom onset. 
This will be estimated without regard to adherence to randomized treatment.

The difference in the estimated rate of number of days in hospital and ICU stay in 
patients with COVID-19 related hospitalization through Day 28 in nonhospitalized adult 
patients with COVID-19 who are at low risk of progression to severe disease and were 
treated ≤5 days after COVID-19 symptom onset. This will be estimated without regard to 
adherence to randomized treatment.
Estimands for the other outcome measures are not presented.


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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 
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 study intervention they 
received. A randomized but not treated participant will be 
excluded from the safety analyses.
Modified Intent -To-Treat 
(mITT)
All participants randomly assigned to study intervention who 
take at least 1 dose of study intervention and with at least 1 
postbaseline visit through Day 28 who were treated ≤3 days 
after COVID-19 symptom onset. Participants will be 
analyzed according to the study intervention to which they 
were randomized.
Modified Intent -To-Treat 
1 (mITT1)
All participants randomly assigned to study intervention, who 
take at least 1 dose of study intervention. Participants will be 
analyzed according to the study intervention to which they 
were randomized.
Per-Protocol (PP)
All participants in the mITT1 set without major protocol 
violations 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.
Both the mITT1 and PP analysis sets will be used in the analyses of the primary efficacy 
endpoint, with the mITT1 being primary. For proportion of COVID-19-related 
hospitalization or death from any cause endpoint, mITT1 will be used. For all other efficacy 
analysis, the  mITT1 analysis set will be used, as defined in the SAP. The Safety Analysis Set 
will be used in the analyses of the safety data.  
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.


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9.3.1. General Considerations
Descriptive statistics for all efficacy endpoints by treatment group and visit will be provided. 
The number of participants screened will be reported.  The number of participants 
randomized to the double-blind treatment phase, completing the study drug administration, 
completing the study, and discontinued the study will be summarized from the FAS analysis 
set for each treatment group. 
Baseline demographic and other characteristics will be tabulated for the FAS analysis set 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).
For continuous endpoints, MMRM analysis of covariance model will be used to analyze 
change from baseline over time. Estimated mean differences between treatments and their 
respective 95% CI and p‑values will be calculated.
Binary endpoints will be summarized with the number and percent of participants satisfying 
the endpoint.  Comparisons between groups will be presented as odds ratios with 95% 
confidence intervals based on logistic regression analysis with terms for treatment.
For categorical endpoints, proportion of participant 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 endpoints will be summarized with Kaplan-Meier curves. Log-rank test will 
be used to compare the median time-to-event between the treatment group. Rate ratios or 
hazard ratios and the associated 95% 2-sided CIs will be estimated by Cox proportional 
hazards models, including treatment and the strata as covariate.
9.3.2. Primary Endpoint(s)/Estimand(s) Analysis
The primary efficacy analysis will be conducted using the mITT1 population.  
The primary endpoint, time to sustained alleviation of all targeted COVID-19 
signs/symptoms through Day 28, is defined as time (days) from start of study intervention or 
placebo (Day 1) until sustained alleviation of all targeted COVID-19 associated 
signs/symptoms.
Sustained alleviation of all targeted COVID-19 signs/symptoms is defined as the event 
occurring on the first of 4 consecutive days when all symptoms scored as moderate or severe 
at study entry are scored as mild or absent AND all symptoms scored mild or absent at study 
entry are scored as absent. Missing severity at baseline will be treated as mild.  


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Participants who are hospitalized/dead due to COVID-19 will be considered to have 1 or 
more targeted symptoms not absent for the duration of the hospitalization.
The time to sustained symptom alleviation for the purpose of this study is defined as: 
•
For a participant with sustained symptom alleviation (event), time-to-event will be 
calculated as (First Event Date) – (First Dose Date) +1.
•
For a participant that either completes Day 28 of the study or discontinues from the 
study before Day 28 without sustained symptom alleviation/resolution (censored), 
censoring date will be at the last date on which symptom alleviation/resolution is 
assessed, and time will be calculated as (Censoring Date) – (First Dose Date) +1 or 
Day 25 whichever occurs first
•
The primary estimand is the difference in median time (days) to sustained alleviation 
of all targeted COVID-19 signs and symptoms through Day 28 between 
PF-07321332/ritonavir and placebo in nonhospitalized adult patients with COVID-19 
who are at low risk of progression to severe disease at baseline and were treated ≤3 
days after COVID-19 symptom onset. This will be estimated irrespective of 
adherence to randomized treatment.
Time to sustained alleviation of all targeted COVID-19 signs/symptoms will be summarized 
with Kaplan-Meier curves. Log-rank test will be used to compare the difference in time 
(days) to sustained alleviation of all targeted COVID-19 signs and symptoms through Day 28 
between treatment groups. 
9.3.2.1. Supplemental Analyses
•
The primary efficacy analyses will also be conducted using the PP population as 
supplemental analysis;
•
The primary endpoint will also be analyzed in which participants who discontinued 
the study before Day 28 without event will be censored at Day 25.   
•
To support the analysis of primary endpoint, Cox proportion hazard models with 
terms including treatment and treatment strata as factor will be used to estimate the 
hazard ratio (the ratio of alleviation of all targeted signs and symptoms) and its 
95% CI. Analyses will be fitted to proportion of participants who achieved sustained 
alleviation of all targeted COVID-19 signs/symptoms (proportion of events) and will 
include treatment and effect based on investigator site as independent variables 
(p-values will be reported from main model). Additional analyses may be performed 
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adjusting for baseline covariates (such as age, gender, vaccination status, etc) as 
additive terms to the primary model, if necessary.  
9.3.3. Secondary Endpoint(s)/Estimand(s) Analysis
Proportion of participants with COVID-19 related hospitalization or death from any 
cause through Day 28
The estimand for proportion of participants experiencing COVID 19 related hospitalization 
or death from any cause through Day 28 is the difference in proportions of patients 
experiencing COVID-19-related hospitalization or death from any cause through Day 28 in 
nonhospitalized adult patients with COVID-19 who are at low risk of progression to severe 
disease and were treated ≤5 days after COVID-19 symptom onset. This will be estimated 
irrespective of adherence to randomized treatment.
The statistical methodology for proportion of participants with COVID-19 related 
hospitalization or death from any cause through Day 28 will be as follows:
The cumulative proportion of participants hospitalized for the treatment of COVID-19 or 
death during the first 28 days of the study will be estimated for each treatment group using 
the Kaplan-Meier method to include all participants and summarized graphically for each 
treatment group. The estimand is the difference of the proportions in the 2 groups. The 95% 
CI will be presented together with the associated Wald Test results. For the 95% CI, the 
corresponding estimate of the standard error is computed using Greenwood’s formula.42 The 
Greenwood’s formula to estimate the variance of the difference of proportions at Day 28 is 
[Var(SPF(28)) + Var(SPlacebo(28))]. Instead of dealing with S(ti) the log-log approach to CI 
will be used. The 95% CI will be computed for the estimate of L(t)= log(log(S(t))), the log 
hazard function. 
The CI will be in the right range when transformed back to S(t) = exp (-exp (L(t)). 
Antilogging this CI will give a 95% confidence interval for the difference itself.
For participants with missing data due to lost to follow up, for COVID-19-related 
hospitalization or death from any cause, a sensitivity analysis will implement the following 
event imputation methodology for those with missing data:

If the participant’s last observed data is prior to Day 21, then impute as an event 
with event day as day of last observed data +1.

If the participant’s last observed data is on or after Day 21, then no imputation for 
an event will be done and participant remains censored at day of last observed 
data.
Number of COVID-19-related medical visits through Day 28
The estimand for the number of COVID-19-related medical visits through Day 28 is the 
difference in estimated rate of number of COVID-19 related medical visits through Day 28 in 
nonhospitalized adult patients with COVID-19 who are at low risk of progression to severe 


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disease and were treated ≤5 days after COVID-19 symptom onset. This will be estimated 
without regard to adherence to randomized treatment. 
The statistical methodology for this endpoint will be as follows:
The number of COVID-19 related medical visits will be analyzed with a negative-binomial 
regression model, using the log-total number of days of data collection as the participant 
offset variable. The resulting analysis will provide the estimated difference in rate of medical 
visits between treatment groups and the associated 95% CI.
Number of days in hospital and ICU stay in participants with COVID-19-related 
hospitalization through Day 28
Summary statistics for this endpoint will be provided in support of the number of 
COVID-19-related medical visits through Day 28.
Details on the definitions and analyses of the following secondary endpoints will be 
described in the SAP.
•
Time (days) to sustained resolution of all targeted COVID-19 signs/symptoms 
through Day 28.
•
Proportion of participants with severe signs/symptoms attributed to COVID-19 
through Day 28.
•
Duration of each targeted COVID-19 sign/symptom.
•
Progression to a worsening status in 1 or more self-reported COVID-19 associated 
symptoms through Day 28.
•
Proportion of participants with a resting peripheral oxygen saturation ≥95% at Days 1 
and 5.
•
Proportion of participants with death (all cause) through Week 24.
•
PF-07321332 PK in plasma and whole blood (if feasible).
•
Viral titers measured via RT-PCR in nasal swabs over time.
9.3.5. Other Safety Analyses
Safety analyses will be carried out for the Safety population.  
CCI


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The safety assessments include AEs, laboratory assessments, physical examinations, vital 
signs and persistent symptoms of COVID-19.
No formal statistical analysis will be conducted on any of the other safety data listed above.
9.3.5.1. Laboratory Test Results  
All clinical laboratory data will be subjected to clinical review, summarized by frequency of 
events and mean changes from baseline.
9.3.5.2. Physical Examination and Vital Signs
All physical examination and vitals will be descriptively summarized by treatment group.  
9.3.5.3. Persistent Symptoms of COVID-19 
The proportion of participants with persistent symptoms of COVID-19 will be summarized at 
Week 12 and Week 24 in participants who had at least 1 symptom present on the last day the 
symptom diary was completed (eg, Day 28).
 
 
 
 
 
 
9.3.6.1. PK Analyses 
PK samples will be collected on Days 1 and 5, per SoA. Additional PK sampling may be 
collected in a subset of participants via home health, site visit, or self-collected using Tasso, 
if feasible. Descriptive statistics and graphical summaries of PF-07321332 concentrations 
will be generated. 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.
9.4. Interim Analyses
There will be 3 interim analyses as follows:
First interim analysis (45% planned enrollment through Protocol Amendment 4): An interim 
analysis was conducted for efficacy, futility and sample size re-estimation, and reviewed by 
an independent E-DMC after a prespecified accrual of participants (ie, approximately 45% 
overall participants of the initial projected enrollment of 1140 participants completed Day 28 
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efficacy assessment in the mITT analysis set), according to the SAP and E-DMC charter. The 
sample size can be increased one time and the increase is limited to 30 to 35%. A well-
established method described by Cui, Hung, and Wang (1999) (implemented in EAST 6.5) 
will be used to control the Type I error probability. 43,44 Details will be pre-specified in the 
interim analysis plan and/or E-DMC charter. 
The nominal significance level for the interim and final time to sustained alleviation of all 
targeted COVID-19 signs/symptoms analyses is determined by means of the Lan-DeMets 
procedure with an O’Brien-Fleming stopping boundary, with an overall 2-sided type I error 
rate of 5%. 
O’Brien-Fleming approach will be used for decision making, ie, reject H0 with 2-sided 
p-value ≤0.002, or reject H1 with 2-sided p-value >0.924 at the interim analysis. At the final 
analysis, the p-value for rejecting H0 will be ≤0.049 (2-sided) or reject H1 with 2-sided p-
value >0.049 will be considered. The actual stopping boundaries will depend on the exact 
timing of the interim analysis. 
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 an E-DMC charter. In addition, the analysis details will be 
documented and approved in the SAP.
The first interim analysis (45% planned enrollment through Protocol Amendment 4) 
summarized above was performed as described.
Second interim analysis (80% planned enrollment through Protocol Amendment 4): Upon 
review of the 45% analysis, the E-DMC requested the Sponsor to consider appropriate course 
of action for the ongoing trial to assess the clinical benefit. In order to respond properly to 
fulfill the E-DMC recommendation, the RRP decided that a second interim analysis should 
be conducted to address the E-DMC’s request. This resulted in the analysis of 80% of 
enrolled participants through protocol amendment 4, without any adjustment to the alpha.
Third interim analysis (100% planned enrollment through Protocol Amendment 4): A third 
interim analysis was completed on enrolled participants who had risk factors for severe 
COVID-19 illness (ie, vaccinated against the SARS-CoV-2 virus) as well as participants who 
did not have risk factors for severe COVID-19 illness (ie, not vaccinated). Data from the 
study are required to support regulatory submissions thereby necessitating an interim analysis 
utilizing the 19 December 2021 dataset. This dataset had not been analyzed previously
because the protocol was amended to increase the sample size and extend enrollment to 
assess the potential benefit of participants at low risk of progression to severe COVID-19 in 
the clinically relevant endpoint of hospitalization or death (Protocol Amendment 5, 
21 January 2022). The participants who were vaccinated are considered the high risk 
population and the unvaccinated participants are considered standard risk in the statistical 
analysis.


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There was no adjustment for alpha for this third interim analysis. Nominal p-values will be 
reported. This third interim analysis did not include any data from participants who entered 
the study under Protocol Amendment 5.
Before the third interim analysis was performed, the details of the objectives, dissemination 
plan, method of maintaining the study blind, and the analysis details as per Pfizer’s SOPs 
will be documented and approved in the interim CSR analysis plan. 
9.5. Sample Size Determination
The initial estimate of required sample size was based on the primary endpoint, the 
difference in time to sustained alleviation of all targeted COVID-19 associated 
signs/symptoms between participants who were treated ≤3 days after COVID-19 symptom 
onset, treated with PF-07321332/ritonavir compared to placebo. The sample size was 
calculated based on a 2-sample test-parallel design–log-rank test, assuming a 90% power, 
2-sided test at alpha = 0.05, approximate accrual rate of 30 participants per day, 2 days 
difference in the median days to sustained alleviation of all targeted COVID-19-associated 
symptoms (6 days for PF-07321332/ritonavir and 8 days for placebo ie, a 25% reduction in 
time to sustained alleviation of all targeted COVID-19 signs/symptoms) based on the 
Lilly-BLAZE-11 and assuming a 18% study discontinuation rate, the sample size of 
approximately 800 participants (approximately 515 events) will provide 90% power to detect 
that difference. Allowing for approximately 30% of participants with COVID-19 symptom 
onset 3 days, a sample size of approximately 1140 participants were to be enrolled for this 
study.  
After the second interim analysis (80% planned enrollment through Protocol Amendment 4), 
in order to improve estimation precision of the treatment effect in the clinically relevant key 
secondary endpoint of COVID-19-related hospitalization or death from any cause, the sample 
size  was adjusted to approximately 1880 participants. This adjustment is expected to provide 
the required total number of 26 COVID-19-related hospitalizations or death from any cause, 
which will have approximately 90% conditional power (based on the second interim analysis 
data) such that the nominal 95% CI of the treatment group difference in the event rate does 
not include 0 when assuming that PF-07321332/ritonavir reduces the event rate by 70% or 
more relative to placebo.
The sample size increase of 740 participants is based on the assumption of a 1.5% event rate 
for the targeted enrollment countries. The number of participants is approximately 1880 
(1140 enrolled participants plus the increase of 740 participants). Assuming a 5% premature 
study discontinuation rate, approximately 1980 participants will be enrolled in the study.


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10. SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS
10.1. Appendix 1: Regulatory, Ethical, and Study Oversight Considerations
10.1.1. Regulatory and Ethical Considerations
This study will be conducted in accordance with the protocol and with the following:

Consensus ethical principles derived from international guidelines, including the 
Declaration of Helsinki and CIOMS International Ethical Guidelines;

Applicable ICH GCP guidelines;

Applicable laws and regulations, including applicable privacy laws.
The protocol, protocol amendments, ICD, SRSD(s), and other relevant documents (eg, 
advertisements) must be reviewed and approved by the sponsor, submitted to an IRB/EC by 
the investigator, and reviewed and approved by the IRB/EC before the study is initiated.
Any amendments to the protocol will require IRB/EC approval before implementation of 
changes made to the study design, except for changes necessary to eliminate an immediate 
hazard to study participants.
Protocols and any substantial amendments to the protocol will require health authority 
approval prior to initiation except for changes necessary to eliminate an immediate hazard to 
study participants.
The investigator will be responsible for the following:

Providing written summaries of the status of the study to the IRB/EC annually or 
more frequently in accordance with the requirements, policies, and procedures 
established by the IRB/EC;

Notifying the IRB/EC of SAEs or other significant safety findings as required by 
IRB/EC procedures;

Providing oversight of the conduct of the study at the site and adherence to 
requirements of 21 CFR, ICH GCP guidelines, the IRB/EC, European regulation 
536/2014 for clinical studies (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 sub-investigators 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.
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.


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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 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 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. 
The E-DMC will review unblinded data to ensure the safety of participants throughout the 
duration of the study.  In addition to up to weekly reviews of safety, the E-DMC will review 
the following:

Sentinel cohort safety review: The E-DMC will review unblinded safety data after 
approximately the first 100 randomized participants have completed through Day 10.  
Whether enrollment is paused for this review will depend on the successful completion of 


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the Study C4671005 sentinel cohort (after approximately the first 60 randomized 
participants have completed through Day 10). If the Study C4671005 sentinel cohort 
safety review has successfully completed and no clinically significant safety signals have 
been identified prior to enrollment of the first 100 participants in this Study C4671002, 
the study will continue without pause.  Otherwise, enrollment of Study C4671002 will be 
paused pending the E-DMC review of safety data. After review of the sentinel cohort in 
this Study C4671002, the frequency of safety reviews may be reduced subsequently 
based on E-DMC recommendations.

Proof-of-concept assessment: Viral load data when 25% (approximately 200 participants 
in the primary analysis set with evaluable data) complete the Day 5 assessments. 
Enrollment will not be paused during review of these data, but may be paused or stopped 
following E-DMC review.

First interim analysis (45% planned enrollment through Protocol Amendment 4): A 
planned interim analysis for efficacy, futility and sample size reestimation was conducted 
after approximately 45% of participants completed the Day 28 assessments in the mITT 
analysis set.

Second interim analysis (80% planned enrollment through Protocol Amendment 4): At 
the request of the E-DMC, a second interim analysis was conducted on 80% of enrolled 
participants without any adjustment to the alpha.
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.
Details of the E-DMC are specified in the E-DMC Charter.
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, 


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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 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 “bonafide 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.


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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 
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 onsite 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.


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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.
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;


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
Inadequate recruitment of participants by the investigator; 

Discontinuation of further study intervention development.
If the study is prematurely terminated or suspended, the sponsor shall promptly inform the 
investigators, the ECs/IRBs, the regulatory authorities, and any CRO(s) used in the study of 
the reason for termination or suspension, as specified by the applicable regulatory 
requirements. The investigator shall promptly inform the participant and should assure 
appropriate participant therapy and/or follow-up.
Study termination is also provided for in the clinical study agreement. If there is any conflict 
between the contract and this protocol, the contract will control as to termination rights.
10.1.10. 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.


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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 
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
Creatininea
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)
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. 28
b.
FSH testing is performed locally 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.
Hospitalization for elective treatment of a preexisting condition that did not worsen 
from baseline is not considered an AE.


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d. Results in persistent or significant disability/incapacity

The 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.  
The event may be suspected from clinical symptoms or laboratory findings indicating 
an infection in a participant exposed to a Pfizer product. The terms “suspected 
transmission” and “transmission” are considered synonymous. These cases are 
considered unexpected and handled as serious expedited cases by pharmacovigilance 
personnel. Such cases are also considered for reporting as product defects, if 
appropriate.
g. Other situations:

Medical or scientific judgment should be exercised by the investigator in deciding 
whether SAE reporting is appropriate in other situations, such as significant 
medical events that may jeopardize the participant or may require medical or 
surgical intervention to prevent one of the other outcomes listed in the above 
definition. These events should usually be considered serious.

Examples of such events include invasive or malignant cancers, intensive treatment 
in an emergency room or at home for allergic bronchospasm, blood dyscrasias or 
convulsions that do not result in hospitalization, or development of drug 
dependency or drug abuse.
10.3.3. Recording/Reporting and Follow-Up of AEs and/or SAEs During the Active 
Collection Period 
AE and SAE Recording/Reporting
The table below summarizes the requirements for recording AEs on the CRF and for 
reporting SAEs on the CT SAE Report Form to Pfizer Safety throughout the active 
collection period. These requirements are delineated for 3 types of events: (1) SAEs; (2) 


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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.

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.


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
It is not acceptable for the investigator to send photocopies of the participant’s 
medical records to Pfizer Safety in lieu of completion of the CT SAE Report 
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)40 Table for Grading the Severity of Adult and Pediatric 
Adverse Events, 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.

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.


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
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.

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.


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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 non-estrogen hormonal highly effective contraception methods 
if they wish to continue their HRT during the study. Otherwise, they must


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discontinue HRT to allow confirmation of postmenopausal status before study 
enrollment.
10.4.4. Contraception Methods
Contraceptive use by men or women should be consistent with local availability/regulations 
regarding the use of contraceptive methods for those participating in clinical trials.
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 
evaluated in relation to the duration of the study and the preferred and usual 
lifestyle of the participant.


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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 co-administered, a barrier method or other nonhormonal method of contraception must 
also be used if the participant is using estradiol-containing contraceptives.


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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 3A4 a
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-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
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-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 
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-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 
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-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 
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, Predisone, 
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. 


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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-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 
Hepatitis C direct acting 
antivirals (DAAs) 
Elbasvir/Grazoprevir,
Glecaprevir/Pibrentasvir
Ombitasvir/Paritaprevir/Ritonavir 
and Dasabuvir
Sofosbuvir/Velpatasvir/Voxilaprevir
Increased Grazoprevir 
concentrations can result in ALT 
elevations.
It is not recommended to 
co-administer Ritonavir with 
Glecaprevir/Pibrentasvir. 
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.


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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-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 
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 
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 (>5 mg 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
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 Attributable to COVID-19
Table 2.
Signs and Symptoms Attributable to COVID-19
Daily Sign and Symptom Collection29
Entry 
Criterion#3 
Targeted 
(used for 
study entry)
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
Chills or shivering
X
X
X
Fatigue (low energy or tiredness)
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
Loss of taste
X


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10.10. Appendix 10: Country-Specific Requirements
10.10.1. France 
Contrat Unique
1. GCP Training 
Before enrolling any participants, the investigator and any subinvestigators will 
complete the Pfizer-provided Good Clinical Practice training course (“Pfizer GCP 
Training”) or training deemed equivalent by Pfizer. Any investigators who later join 
the study will do the same before performing study-related duties. For studies of 
applicable duration, the investigator and subinvestigators will complete Pfizer GCP 
Training or equivalent every 3 years during the term of the study, or more often if 
there are significant changes to the ICH GCP guidelines or course materials. 
2. Study Intervention 
No participants or third-party payers will be charged for study intervention.
3. Urgent Safety Measures 
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 ICH GCP that 
the investigator becomes aware of.
4. Termination Rights 
Pfizer retains the right to discontinue development of PF-07321332 at any time.
10.10.2. Japan
A Protocol Administrative Change Letter was issued on 22 July 2021 to provide Japan 
country specific guidance regarding Exclusion Criterion #8.  
Exclusion Criterion #8: Known HIV infection with 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.


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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.


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10.11. Appendix 11: Protocol Amendment History
The Protocol Amendment Summary of Changes Table for the current amendment is located 
directly before the TOC. The protocol amendment summary of changes tables for past 
amendment(s) can be found below:
Amendment 1 (02-July-2021)
Overall Rationale for the Amendment: The protocol was amended to incorporate feedback 
from the FDA.
Section # and Name
Description of Change
Brief Rationale
1.1. Synopsis
1.3. Schedule of Activities
4.1. Overall Design
10.1.5.1. Data Monitoring 
Committee
Changed sentinel cohort safety 
review to allow for either the 
sentinel cohort from the 
C4671005 study or the data from 
the ACTIV-2b study to allow for 
continued enrollment into 
C4671002.
FDA allowed for continued enrollment 
(no pause) after completion of either 
the sentinel cohort from C4671005 or 
ACTIV-2b.
1.1. Synopsis
3. OBJECTIVES, 
ENDPOINTS, AND 
ESTIMANDS
9.3.3. Secondary 
Endpoint(s)/Estimand(s) 
Analysis
Removed the following secondary
endpoint: COVID-19 severity 
ranking based on symptom 
severity scores through Day 28.
FDA requested removal of this 
endpoint due to Agency guidance on 
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
1.1. Synopsis
3. OBJECTIVES, 
ENDPOINTS, AND 
ESTIMANDS
9.3.3. Secondary 
Endpoint(s)/Estimand(s) 
Analysis
Changed endpoint to include, 
instead of exclude hospitalization: 
Number of COVID-19 related 
medical visits including 
hospitalization through Day 28.
FDA requested updating of this 
endpoint due to Agency guidance on 
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
1.1. Synopsis
4.1. Overall Design
4.2. Scientific Rationale for 
Study Design 
Added that randomization will be 
stratified by geographic region, by 
vaccination status and by 
COVID-19 symptom onset (< 3 
days vs. 3 to 5 days).
FDA recommendations on stratification 
were implemented.
1.2 Schema
Schema footnote was updated.
For clarification.


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Section # and Name
Description of Change
Brief Rationale
1.3. Schedule of Activities
Flexible language added to PROs 
rollout.
Availability of some translations may 
be forthcoming, so allowances were 
made. 
1.3 Schedule of Activities
5.1. Inclusion Criteria
5.2. Exclusion Criteria
Confirmed SARS-CoV-2 
infection requirement updated 
from 72 hours to 5 days.
Timing window was updated in 
response to questions on feasibility.
1.3. Schedule of Activities
8.1.5.3. Global Impression 
Questions
9.3.6. Other Analyse(s)
Added in the Global impression 
questions from Days 1-28 after 
the sentinel cohort.
FDA recommendation on the inclusion 
of patient-reported global impression 
items were implemented.
5.2. Exclusion Criteria
Changed exclusion criteria to 
allow both partially and fully 
vaccinated participants with or 
without COVID-19 risk factors, 
with the exception of those with 
immunosuppressive disease.
FDA request to include fully vaccinated 
immunocompetent subjects, regardless 
of risk factors.
9.3.2. Primary 
Endpoint(s)/Estimand(s) 
Analysis
Updated definition of sustained 
alleviation by changing “any” to 
“all”.
FDA recommendations on update to the 
definition of sustained alleviation were 
implemented.
Throughout
Other typographical or 
administrative edits.
Updated to improve readability and 
consistency.
Amendment 2 (19-July-2021)
Overall Rationale for the Amendment: The protocol was amended to incorporate 
additional feedback from the FDA.
Section # and Name
Description of Change
Brief Rationale
1.1. Synopsis
1.3. Schedule of Activities
4.1. Overall Design
10.1.5.1. Data Monitoring 
Committee
Changed C4671002 sentinel 
cohort safety review to reference 
the sentinel cohort review from 
the C4671005 study to allow for 
continued enrollment into 
C4671002.
No longer participating in the ACTIV-
2b study.
1.1. Synopsis
Statistical clarifications made to 
time to event analyses and sample 
size section and corrections were 
The rationale for changing the 
statistical sections are as follows:


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Section # and Name
Description of Change
Brief Rationale
3. OBJECTIVES, 
ENDPOINTS, AND 
ESTIMANDS
9.1. Statistical Hypotheses
9.1.1.1. Primary 
Estimand/Co-Primary 
Estimands
9.1.1.2. Secondary 
Estimands
9.3.1. General 
Considerations
9.3.2. Primary 
Endpoint(s)/Estimand(s) 
Analysis
9.3.2.1. Sensitivity Analyses
9.4. Interim Analyses
9.5. Sample Size 
Determination
made in the interim analysis and 
final analysis stopping rules.  
a) To provide clarification in the 
primary endpoint analysis and to clarify 
how the sample size is estimated based 
on the primary analysis. 
b) To correct the interim analysis and 
final analysis stopping rules.
1.3. Schedule of Activities
8.1.6 Exit Interview
9.3.6 Other Analyse(s)
Exit interviews have been added 
to the protocol.
Added to confirm content validity of 
COVID-19 signs and symptoms daily 
diary, to describe participant’s 
treatment experience and the 
importance and meaningfulness of any 
improvements reported.
5.1. Inclusion Criteria
Upper age limit of 59 years was 
removed from Inclusion criteria.
Participants aged greater than or equal 
to 60 years of age are at increased risk 
for COVID-19, but will be allowed if 
they are fully vaccinated, and fulfill 
other entry criteria.
5.2. Exclusion Criteria
Vaccination criteria was updated 
from partially to fully vaccinated 
and the risk factor of ≥60 years of 
age was added.  
FDA request to include fully vaccinated 
immunocompetent participants, 
regardless of risk factors, and to 
exclude partial vaccination as it does 
not have the same protective effect as 
full vaccination.
6.3.2. Blinding of the 
Sponsor
Added Section to reference the 
Unblinding Plan. 
To provide additional information and 
clarification in the process of 
unblinding.


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Section # and Name
Description of Change
Brief Rationale
8. STUDY ASSESSMENTS 
AND PROCEDURES
Updated total blood volume 
projection.  
Final blood volumes from the central 
lab became available and were different 
than original estimates. 
Throughout
Other typographical or 
administrative edits.
Updated to improve readability and 
consistency.
Amendment 3 (03-August-2021)
Overall Rationale for the Amendment: 
The primary analysis set (mITT) has been refined to include just those participants who were 
randomized within 3 days of COVID-19 symptom onset. There is precedent for early 
treatment of acute respiratory illnesses being critical for successful antiviral intervention. 
This change allows for optimization of the primary analysis set by further reducing the 
symptom onset window from 5 days to ≤3 days.
Section # and Name
Description of Change
Brief Rationale
1.1. Synopsis
4.1. Overall Design
9.4. Interim Analyses
10.1.5.1. Data Monitoring 
Committee
Added the mITT analysis set detail to 
the interim analysis.
Added clarification to the analysis set for 
the interim analysis.
1.1. Synopsis
3. OBJECTIVES, 
ENDPOINTS, AND 
ESTIMANDS
4.1. Overall Design
4.2. Scientific Rationale for 
Study Design
9.1. Statistical Hypotheses
9.1.1.1. Primary Estimand/Co-
Primary Estimands
9.1.1.2. Secondary Estimands
9.2. Analysis Sets
9.3.2. Primary 
Endpoint(s)/Estimand(s) 
Analysis
Primary estimand changed to specify 
inclusion of participants who were 
randomized ≤3 days after symptom 
onset. 
Stratification was updated 
accordingly and so was sample size. 
Sample size increased from 800 to 
1140.
Added in a new mITT analysis set 
restricted to participants with 
COVID-19 symptom onset ≤3 days.
Due to uncertainty on the effect of time 
from symptom onset relative to initiation of 
treatment on the effectiveness of an 
antiviral, a change has been made to the 
primary analysis set. Primary analysis is 
now based upon the mITT, which includes 
those participants randomized within 3 days 
of symptom onset.
Other changes are a consequence of the 
change in primary efficacy analysis.  
Sample size has been adjusted, and the key 
secondary endpoint analyses will include 
participants regardless of their symptom 
onset.


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Section # and Name
Description of Change
Brief Rationale
9.3.2.1. Supplemental Analyses
9.3.3 Secondary 
Endpoint(s)/Estimand(s) 
Analysis
9.5. Sample Size Determination
1.3. Schedule of Activities
Minor edits to footnotes.
To clarify use of brackets and procedure 
requirements associated with the location 
for expected visits.
5.2. Exclusion Criteria #16
Vaccination criteria was updated to 
clarify that participants without 
underlying medical conditions 
associated with an increased risk of 
developing severe illness from 
COVID-19 are not eligible if they 
have been vaccinated.  It is only fully 
vaccinated participants with 
underlying medical conditions that 
are eligible.  
Provide clarification around vaccination 
status in participants without underlying 
medical conditions associated with an 
increased risk of developing severe illness 
from COVID-19.
6.2. Preparation, Handling, 
Storage, and Accountability
Guidance added regarding shipping 
study intervention by courier and 
temperature monitoring for ground 
transportation.
Stability data demonstrate that if the total 
duration of transit is less than 24 hours, 
temperature monitoring is not required.
6.3.2. Blinding of the Sponsor
Modified language to specify that the 
study will be completely unblinded 
after the last data has been collected 
for the PCD.
At Day 34, all of the study endpoints 
(except mortality through Week 24) will be 
assessed, including the primary endpoint. 
There is limited data collected at the 
Week 12 and Week 24 visits and thus 
having an unblinded team completing the 
study poses little risk.
9.3.6. Other Analyse(s)
Updated Exit Interview analysis 
language.
Updated per the Exit Interview final 
proposal from vendor. 
10.10.2. Japan
Added Japan country-specific 
guidance regarding Exclusion 
Criterion #8.
To incorporate country-specific changes 
into the global protocol.
10.11 Appendix 11
Modified with Amendment 2 
changes.
Per Pfizer protocol template.
Throughout
Other administrative edits.
Updated to provide clarity.
Amendment 4 (23 November 2021)
Overall Rationale for the Amendment: 
Approximately 60% of enrolled participants in C4671002 have risk factors for severe 
COVID-19 but have been vaccinated against COVID-19. The secondary endpoint of 
COVID-19 related hospitalization or death from any cause through Day 28 is therefore of 


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greater relevance, and the hierarchal order of the secondary endpoints has been revised 
accordingly.
Section # and Name
Description of Change
Brief Rationale
Section 1.1. Synopsis
Section 3. OBJECTIVES, 
ENDPOINTS, AND 
ESTIMANDS
Section 9.1. Statistical 
Hypotheses
Section 9.1.1.2. Secondary 
Estimands
Section 9.3.3. Secondary 
Endpoint(s)/Estimand(s) 
Analysis
Secondary endpoints and estimands 
updated to reflect new hypothesis 
testing hierarchy
Secondary endpoint of COVID-19 related 
hospitalization or death from any cause 
through Day 28 is of greater relevance in the 
population enrolled and has been revised 
accordingly.
Section 1.2. Schema
Schema updated to remove the need 
for Day 3 in-person visits for ECG 
monitoring per PACL dated 
31Aug21.
Updated to reflect changes from PACL.
Section 1.3. Schedule of 
Activities
Schedule of Activities updated to 
reflect updates PACL dated 13Aug21.
Updated to reflect changes from PACL.
Section 2.3.3. Overall 
Benefit/Risk Conclusion
Corrected to be consistent with 
Section 9.4.
Correct inconsistency.
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.
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 8.2.5. 
Electrocardiograms
Section 10.7. Appendix 7: ECG 
Findings of Potential Clinical 
Concern
Section removed, as ECGs are no 
longer required, per PACL dated 
31Aug21.
Updated to reflect changes from PACL.
Section 9.2. Analysis Sets
Analysis set wording aligned with 
C4671005.
To promote consistency in wording of 
analysis sets across the C4671002 and 
C4671005 protocols.
Section 9.3.2.1. Supplemental 
Analyses
Added a supplemental analysis for 
censoring of the primary endpoint for 
discontinued participants. 
Section updated per regulatory request  to 
include an additional sensitivity analysis 
that considers all participants in the mITT 


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Section # and Name
Description of Change
Brief Rationale
population with missing data for the primary 
endpoint by Day 28 as censored.
Section 9.3.6. Other Analyse(s)
Added wording for how the long-term 
COVID-19 symptoms will be 
analyzed.
Section updated, as there was no mention of 
the analysis of this data in prior protocol 
versions.
Section 10.8. Appendix 8: 
Prohibited Concomitant 
Medications That May Result in 
DDI
Corrections and updates to the list of 
precautionary and prohibited 
medications as in PACL dated 
27Sep21.
Updated to reflect changes from PACL.
Throughout
Other administrative edits.
Updated to provide clarity.
Amendment 5 (21 January 2022)
Overall Rationale for the Amendment:
Results from a protocol-specified interim analysis of this study, 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).
Furthermore, results from Study C4671005 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. In a secondary endpoint, PF-07321332/ritonavir treatment also reduced the 
risk of hospitalization or death from any cause by 88% compared with placebo in participants 
treated within 5 days of symptom onset.
This protocol amendment, while acknowledging the lack of stringency of statistical type I 
error control, is primarily intended to extend study enrollment to assess potential benefit to 
participants at low risk of progression to severe COVID-19 in the clinically relevant endpoint 
of hospitalization or death. The rationale is based on the outcome from the interim analysis 
from this study and the final results of Study C4671005.
Section # and Name
Description of Change
Brief Rationale
Section 1.1. Synopsis
The secondary endpoint of incidence 
of COVID-19-associated 
hospitalizations or death from any 
cause will be analyzed to provide a 
point estimate and 95% CI to measure 
Despite no demonstration of treatment 
benefit in the primary endpoint of 
alleviation of symptoms at the 45% IA, the 
potential benefit in the clinically relevant 
secondary endpoint of hospitalization or 


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Section # and Name
Description of Change
Brief Rationale
Section 3. OBJECTIVES, 
ENDPOINTS, AND 
ESTIMANDS
Section 9.1. Statistical 
Hypotheses
Section 9.1.1.2. Secondary 
Estimands
Section 9.3.3. Secondary 
Endpoint(s)/Estimand(s) 
Analysis
associated variability. Other clinically 
relevant secondary endpoints 
(COVID-19 related medical visits) 
will also be analyzed.
death will be explored with this amendment. 
Other clinically relevant secondary 
endpoints (COVID-19 related medical 
visits) will also be analyzed. 
Based on outcomes in Study C4671005, in 
which PF-07321332/ritonavir treatment 
reduced the risk of hospitalization or death 
from any cause in participants treated within 
3 or 5 days of symptom onset, results will 
be analyzed regardless of whether 
participants begin study treatment within 
3 or 5 days of symptom onset, and 
estimands have been updated accordingly.
Section 2.2.2. Clinical 
Overview
Results from Study C4671005 and 
interim analysis of C4671002 are 
presented.
Provide support for further evaluation of 
COVID-19-related hospitalizations and all 
cause death in the study population at low 
risk for progression to severe disease.
Section 2.3.2. Benefit 
Assessment
Results from Study C4671005 and the 
45% interim analysis for Study 
C4671002 added.
To support the potential benefit of 
reductions in COVID-19 hospitalizations 
and all cause deaths for participants at 
standard risk of progression to severe 
disease. 
Section 4.1. Overall Design
Updated sample size.
Per sample size re-estimation in Section 9.5.
Section 4.2. Scientific Rationale 
for Study Design
Added rationale for extending study 
enrollment based on Study C4671005 
results and the interim analysis results 
for Study C4671002.
To allow a more complete assessment of the 
efficacy of PF-07321332/ritonavir in 
reducing the incidence of 
COVID-19-associated hospitalization or 
death from any cause in standard risk 
participants.
Section 4.3. Justification for 
Dose
Brief statement of C4671005 results 
added
To further support dose and length of 
treatment in this study.
Section 5.2. Exclusion Criteria
Exclusion Criteria #1 and #16 
updated.
#1: All participants with positive results of 
direct SARS-CoV-2 testing and who are at 
high risk for progression to severe 
COVID-19, including hospitalization or 
death are eligible to receive PaxlovidTM
regardless of vaccination status, and so are 
excluded from this placebo-controlled 
study; age and BMI risk factors have been 
updated based on the Paxlovid Fact Sheet 
for Healthcare Providers.
#16: Participants at low risk for serious 
complications who have received a 
SARS-CoV-2 vaccination ≥12 months prior 
to screening will be eligible, based on 
emerging data for the omicron variant 
showing substantially reduced vaccine 
efficacy against symptomatic SARS-CoV-2 
infection and waning efficacy over time 


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Section # and Name
Description of Change
Brief Rationale
against severe disease requiring 
hospitalization.
Section 6.8. Concomitant 
Therapy
Added antiviral treatment for 
COVID-19 to prohibited medications 
during the study.
Based on the availability of authorized 
antiviral treatment for COVID-19. 
Section 9.2. Analysis Sets
Analysis set wording aligned with 
C4671005.
To promote consistency in wording of 
analysis sets across the C4671002 and 
C4671005 protocols.
Section 9.4 Interim Analyses
Indicated no further interim analyses
are planned.
No further interim analysis is needed given 
information provided from the previous 
45% interim analysis and other data that 
have informed the new sample size 
estimate.
Section 9.5. Sample Size 
Determination
Increase in sample size
To power the study for an assessment of the 
efficacy of PF-07321332/ritonavir in 
reducing the incidence of 
COVID-19-associated hospitalization or 
death from any cause in standard risk 
participants.
Section 10.8: Appendix 8: 
Prohibited Concomitant 
Medications That May Result in 
DDI
Updated table.
To align with the Emergency Use 
Authorization Fact Sheet for PaxlovidTM.
Throughout
Other administrative edits.
Updated to provide clarity.


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10.12. Appendix 12: Abbreviations
The following is a list of abbreviations that may be used in the protocol.
Abbreviation
Term
3CL
3C-like protein
6MP
mercaptopurine
Abs
absolute
AE
adverse event
AESI
adverse events of special interest
ALT
alanine aminotransferase
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
bpm
beats per minute
BMI
body mass index
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
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
the maximum concentration recorded
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
CYP
cytochrome P450
CYP3A4
cytochrome P450 3A4
DAA
direct acting antivirals


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Abbreviation
Term
DAIDS
Division of AIDS
DDI
drug-drug interaction 
DILI
drug-induced liver injury
DNA
deoxyribonucleic acid
dNHBE
differentiated normal human bronchial epithelial cells
DU
dispensable unit
EC
ethics committee
EC90
concentration required for 50% 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
estimated glomerular filtration rate
EMA
European Medicines Agency
ePRO
electronic patient reported outcome
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
follow up
fu
fraction of unbound drug in serum or plasma
GCP
Good Clinical Practice
GFR
glomerular filtration rate
GGT
gamma-glutamyl transferase
GH
good health
GLP
Good Laboratory Practice
HCP
health care professional; health care provider
HCV
hepatitis C virus
HCoV
human coronavirus
HDPE
high-density polyethylene
HF
heart failure
HIV
human immunodeficiency virus


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Abbreviation
Term
HMG-CoA
3-hydroxy-3-methylglutaryl co-enzyme
HR
heart rate
HRT
hormone replacement therapy
hsCRP
high-sensitivity C-reactive protein
HTA
health technologies assessment
IA
interim analysis
IB
investigator’s brochure
ICD
informed consent document
ICH
International Council for Harmonisation
ICU
intensive care unit
ID
identification
Ig
immunoglobulin
IMP
investigational medicinal product
IND
investigational new drug
INR
international normalized ratio
IP
investigational product
IP manual
investigational product manual
IPAL
Investigational Product Accountability Log
IRB
institutional review board
IRT
interactive response technology
ITT
intent-to-treat 
IV
intravenous(ly)
IWR
interactive Web-based response
LDH
lactate dehydrogenase
LFT
liver function test
LT
long-term
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
mRNA
messenger ribonucleic acid
msec
millisecond
N/A
not applicable
NHP
non-human primate
NIAID
National Institute of Allergy and Infectious Diseases
NIH
National Institutes of Health
NIMP
noninvestigational medicinal product
NP
nasopharyngeal
PCD
primary completion date
PCI
percutaneous coronary intervention
PDE-5
Phosphodiesterase 5
PK
pharmacokinetic(s)


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Abbreviation
Term
PP
per-protocol
PRO
patient reported outcomes
PT
prothrombin time
PTT
partial thromboplastin time
PVC
premature ventricular contraction/complex
q12h
every 12 hours
QTc
corrected QT
QTcF
corrected QT (Fridericia method)
QTL
quality tolerance limit
RBC
red blood cell
RNA
ribonucleic acid
RRP
Recommendation Review Panel
RT-PCR
reverse transcription polymerase chain reaction
SAD
single ascending dose
SAE
serious adverse event
SAP
statistical analysis plan
SARS-CoV2
severe acute respiratory syndrome coronavirus 2
SAS
safety analysis set
SCr
serum creatinine
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
TOC
table of contents
TSH
thyroid-stimulating hormone
ULN
upper limit of normal
US
United States of America
USPI
United States Prescribing Information; United States Package Insert
VAS
visual analogue scale
WBC
white blood cell
WHO
World Health Organization
WOCBP
women of child bearing potential
WPAI
Work Productivity and Impairment


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11. REFERENCES
1.
Gottlieb RL, Nirula A, Chen P, et al. Effect of bamlanivimab as monotherapy or in 
combination with etesevimab on viral load in patients with mild to moderate COVID-
19: A randomized clinical trial. JAMA. 2021;325(7):632-44.
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.
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Final Protocol Amendment 6, 09 June 2022
PFIZER CONFIDENTIAL
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SAP_001.pdf: 
Protocol C4671002 (PF-07321332) Statistical Analysis Plan 
 
 
PFIZER CONFIDENTIAL  
Page 1 
  
 
 
 
 
Protocol C4671002 
 
 
AN INTERVENTIONAL EFFICACY AND SAFETY, PHASE 2/3, DOUBLE-BLIND, 
2-ARM STUDY TO INVESTIGATE ORALLY ADMINISTERED 
PF-07321332/RITONAVIR COMPARED WITH PLACEBO IN NONHOSPITALIZED 
SYMPTOMATIC ADULT PARTICIPANTS WITH COVID-19 WHO ARE AT LOW 
RISK OF PROGRESSING TO SEVERE ILLNESS 
 
 
Statistical Analysis Plan 
(SAP) 
 
Version: 
1 
Date:  
18 AUG 2021  
Version: 
2 
Date:  
01 DEC 2021 
Version:  
3 
Date:   
16 DEC 2021 
Version 
4 
Date:  
14 JUL 2022 


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Protocol C4671002 (PF-07321332) Statistical Analysis Plan 
 
 
PFIZER CONFIDENTIAL  
Page 4 
6.5.1. Baseline Summaries ....................................................................................29 
6.5.2. Study Conduct and Participant Disposition ................................................29 
6.5.3. Study Treatment Exposure .........................................................................29 
6.5.4. Prior and Concomitant Medications ...........................................................30 
6.6. Safety Summaries and Analyses .............................................................................30 
6.6.1. Adverse Events ...........................................................................................30 
6.6.2. Subgroup Analysis of Adverse Events and Serious Adverse Events .........30 
6.6.3. Laboratory Data ..........................................................................................30 
6.6.4. Vital Signs ..................................................................................................30 
7. INTERIM ANALYSES .......................................................................................................31 
7.1. Interim Analyses and Summaries ............................................................................31 
7.2. Data Monitoring Committee ...................................................................................32 
7.3. Blinding of the Sponsor ...........................................................................................32 
8. REFERENCES ....................................................................................................................33 
9. APPENDICES .....................................................................................................................34 
 
LIST OF TABLES 
Table 1  Summary of Changes ...................................................................................................5 
 
LIST OF FIGURES 
Figure 1.  Schema ……………………………………………………………………12 
 
APPENDICES 
Appendix 1. Summary of Efficacy Analyses ...........................................................................34 
Appendix 2. Data Derivation Details .......................................................................................38 
Appendix 2.1. Definition and Use of Visit Windows in Reporting .........................................38 
Appendix 3. List of Abbreviations...........................................................................................39 
Appendix 4. Signs and Symptoms Attributable to COVID-19................................................40 
Appendix 5. List of Pre-Specified AESIs ................................................................................41 
 
 
 


Protocol C4671002 (PF-07321332) Statistical Analysis Plan 
 
 
PFIZER CONFIDENTIAL  
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1. VERSION HISTORY 
Table 1  Summary of Changes 
 
Version/ 
Date 
Rationale 
Specific Changes 
V1/ 
18AUG2021 
Original SAP 
No changes 
V2/ 
18OCT2021 
 
Protocol Amendment 4 
and other clarification 
• 
Updated Section 2.1.2 to include estimand for COVID-19 
related hospitalization or death from any cause.  
• 
Updated Section 3.2 to reorder secondary endpoints; moving 
COVID-19 related hospitalization or death from any cause up 
to second secondary endpoint. 
• 
Updated Section 3.4 with definition of baseline visit and 
baseline derived variables.  
• 
Added to Section 3.5 the definition of stratification variable 
geographical region and clarified stratification variables for 
mITT & mITT1 populations. 
• 
Updated Section 4 to clarify analyses population sets. 
• 
Updated Section 5.1 to include Covid-19 related 
hospitalization and death of any cause in the sequential testing. 
• 
Section 5.2.2 updated to clarify strata by analyses population 
sets. 
• 
Section 5.2.2 has been updated to add ANCOVA model for 
change from baseline to Day 5 of viral load data in addition to 
the MMRM model and added baseline serology as covariate in 
the model. 
• 
Section 5.1 has been updated to include the Covid 19 related 
hospitalization or death due to any cause as the second 
secondary endpoint in sequential testing. Furthermore, the 
following endpoints, proportion of subject with severe signs 
and symptoms and medical visits were removed from the 
sequential testing. 
• 
Section 6.1.1.2 has been updated to include a new sensitivity 
analysis. based on FDA request, a sensitivity analysis exclude 
participants from site 1488. 
• 
Section 6.1.1.2 updated to add sensitivity analysis for primary 
endpoint for participants who discontinued the study before 
Day 28 with events to be censored at Day 25. 
• 
Section 6.1.1.2 updated to add factors such as region, 
vaccination, baseline serology in the analysis model. 
• 
Added changes to Section 6.2.4 – added KM for proportions of 
hospitalizations/deaths. 
• 
Section 6.2.6 updated to add the plot of proportions for each 
targeted signs and symptom with severe category and 


Protocol C4671002 (PF-07321332) Statistical Analysis Plan 
 
 
PFIZER CONFIDENTIAL  
Page 6 
Version/ 
Date 
Rationale 
Specific Changes 
additional analysis of proportion of severe signs/symptoms in 
order to understand the severe signs/symptoms data. 
• 
Section 6.2.12 updated to clarify ANCOVA model for viral 
titer endpoint.  
• 
Section 6.2.12 updated to add the analysis for association 
between baseline viral load and primary endpoint based on the 
viral strains identified at baseline.  
• 
Section 6.2.14 updated to add “through Day 28” and removed 
the following text “if data permit, negative binomial model 
analysis”. 
• 
Section 6.4 subset analysis section has been updated to include 
a subset analysis for viral load categories defined in section 
3.4. 
• 
Section 6.4 updated to add subgroup analyses of first and 
second secondary endpoint by vaccination status. 
• 
Section 6.6 has been updated to add a subgroup analysis of AE 
and SAE by vaccination status (new Section 6.6.2). 
• 
Updated Appendix 1 to change the logistic regression to 
Kaplan-Meier method. 
• 
Updated visit window for efficacy endpoints to Appendix 2.  
• 
Added Appendix 5 with list of adverse events of special 
interest. 
• 
Section 8 updated to add Greenwood Formula reference. 
V3/ 
16DEC2021 
 
According to FDA 
request 
• 
Section 4 has been modified to update the mITT, mITT1 and 
mITT2 populations requested by FDA. 
• 
Section 6.2.12 has been updated to include nasopharyngeal 
(Y/N) in the model.  
• 
Section 6.2.12 has been updated to remove analysis of 
association between baseline viral variants and primary 
endpoint (as per virology meeting of 12/13/2021 this 
assessment was nor needed).  
• 
Section 3.5 updated to add Brazil to the rest of the world 
region. 
• 
Section 3.4, 6.6.5, Appendix 2. Appendix 3 has been updated 
to remove ECG. 
• 
General clarification in section 6.2.6, 6.2.12. 
• 
Section 6.2.8 updated to add the following: 
• 
Proportion of participants with any progression to worsening 
of targeted symptoms attributed to COVID 19 Day 2 to Day 6 
(during treatment). Proportion of participants with any 
progression to worsening of targeted symptoms attributed to 
COVID 19 Day 7 to Day 28 (post treatment). 


Protocol C4671002 (PF-07321332) Statistical Analysis Plan 
 
 
PFIZER CONFIDENTIAL  
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Version/ 
Date 
Rationale 
Specific Changes 
• 
Section 6.2.13 & 6.2.14 removed “through day 28” for the 
endpoint. 
• 
Appendix 1: Added change from baseline to day 5 ANCOVA 
model for viral titer.  
V4/ 
11JUL2022 
 
 
Protocol Amendment 5 • 
Section 2.2, the total number of participant update from 1140 
to 1980 and the section cleaned up to align with Protocol 
Amendment #5. 
• 
Section 2.2 , the following (Aside from ongoing E-DMC 
review of safety data mentioned above, the aforementioned 
reviews and formal interim analysis were performed as 
specified above.) was added to align with Protocol 
Amendment #5 and to indicate that IA, Proof-of-concept and 
sentinel cohort analysis has been already performed.  
• 
Section 2.3, sample size update to align with protocol 
amendment #5  
• 
Section 3.3 updated to add persistent signs and symptoms of 
COVID-19 endpoint and long COVID-19 endpoint  
• 
Section 3.5 updated to add Russia, Slovakia, and Romania to 
EU region 
• 
Section 3.5 was updated to provide definition of vaccination 
subgroup/strata 
• 
Section 4 updated to specify mITT1 as the main population 
• 
Section 5.1 updated to remove the sequential testing as it is no 
longer applicable to Protocol Amendment #5. 
• 
Section 5.1 updated to specify COVID-19 related 
hospitalization and death to any cause, number of medical 
visits, number of days in ICU. 
• 
Section 5.2.1 updated to clarify binary endpoints 
• 
Section 5.2.2 updated to remove use of mITT population 
• 
Section 5.3 updated to remove the (BOCF) form imputation of 
missing value. 
• 
Section 6 update to re-arrange the secondary endpoint to align 
with Protocol Amendment #5 endpoints and removed use of 
mITT population 
• 
Section 6.2.7 updated to include additional analysis of severity 
of signs and symptoms of COVID-19 for individual targeted 
symptoms 
• 
Section 6.2.7 updated to include an expanded definition and 
analysis of severity of signs and symptoms  


Protocol C4671002 (PF-07321332) Statistical Analysis Plan 
 
 
PFIZER CONFIDENTIAL  
Page 8 
Version/ 
Date 
Rationale 
Specific Changes 
• 
Section 6.2.10 updated to include expanded definition and 
analysis of worsening of signs and symptoms 
• 
Section 6.3.1 added to include proportion of participants with 
persistent symptoms of COVID-19 at Week 12, Week 24 
• 
Section 6.3.2 added to include long-term COVID-19 
symptoms collected by telephone interviews at Week 12 and 
Week 24 
 
V4 
11JUL2022 
 
Protocol Amendment 6 
• At the first interim analysis, the IA did not meet primary 
endpoint objective and there is no remaining alpha for 
subsequent hypothesis tests. Thus, all further analysis will use 
nominal p-values for reporting. 
 
• The total study duration is up to 24 weeks, with study 
intervention through Day 5 or Day 6, efficacy assessments 
through Day 28, a safety follow-up period through Day 34, and 
long-term follow-up at Weeks 12 and 24. 
 
• Proportion of participants with death (all cause) through Week 
24 and final visit. 
• Update sections 2.1, 2.1.1 and 2.1.2 to align with the Protocol 
Amendment 6 
• Section 2.1.2, rearrange the order of the secondary estimands to 
align with secondary objectives. 
• Section 3.2 updated to re-arrange the secondary endpoints to be 
aligned with objective of the protocol amendment #6 
• Section 3.5 updated to stratification of symptom onset. 
• Section 4 update mITT definition 
• Section 6 update to re-arrange the secondary endpoint to align 
with protocol amendment #6 endpoints and removed use of 
mITT population 
• Section 6.4 updated to change subset analysis criteria to align 
with PAS #6  
• 
Appendix 1 updated to use mITT1 population set and added 
relevant analyses per plan. 
 
For the entire document, text in Italic format will represent language copied directly from 
protocol. 


Protocol C4671002 (PF-07321332) Statistical Analysis Plan 
 
 
PFIZER CONFIDENTIAL  
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2. INTRODUCTION 
PF-07321332, a potent and selective SARS-CoV-2 3CL protease inhibitor, is being 
investigated as an oral antiviral treatment of COVID-19.  
The purpose of this study is to evaluate the efficacy and safety of PF-07321332/ritonavir for 
the treatment of nonhospitalized, symptomatic adult participants with COVID-19 who are at 
low risk of progressing to severe illness. 
The first interim analysis (IA) did not meet the primary endpoint objectives and there is no 
remaining alpha for subsequent hypothesis tests. Thus, all further analysis will use nominal 
p-values for reporting. 
 
 
All data entered in the eCRF will be analyzed and additional subgroup analyses will be 
included in the final CSR. 
2.1. Study Objectives, Endpoints, and Estimands 
Primary Efficacy Objective:  
To compare the efficacy of PF-07321332/ritonavir to placebo for the treatment of 
symptomatic COVID-19 in nonhospitalized adult participants with COVID-19 who are at 
low risk of progression to severe disease. 
Secondary Efficacy Objective:  
To compare PF-07321332/ritonavir versus placebo for COVID-19-related hospitalization 
and all-cause mortality in nonhospitalized adult participants with COVID-19 who are at low 
risk of progression to severe disease. 
To compare PF-07321332/ritonavir versus placebo for COVID-19-related medical visits in 
nonhospitalized adult participants with COVID-19 who are at low risk of progression to 
severe disease 
To compare PF-07321332/ritonavir to placebo for the duration and severity of signs and 
symptoms in nonhospitalized symptomatic adult participants with COVID-19 who are at low 
risk of progression to severe disease. 
Secondary Safety Objective:  
To describe the safety and tolerability of PF-07321332/ritonavir relative to placebo in the 
treatment of nonhospitalized symptomatic adult participants with COVID-19 who are at low 
risk of progression to severe disease. 
Other Secondary Objectives: 


Protocol C4671002 (PF-07321332) Statistical Analysis Plan 
 
 
PFIZER CONFIDENTIAL  
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To determine the PK of PF-07321332 in nonhospitalized adult participants with COVID-19 
who are at low risk of progression to severe disease. 
 
To describe the viral load in nasal samples over time in nonhospitalized adult participants 
with COVID-19 who are at low risk of progression to severe disease. 
 
2.1.1. Primary Estimand 
The difference in median time (days) to sustained alleviation of all targeted COVID-19 signs 
and symptoms through Day 28 between PF-07321332/ritonavir and placebo in 
nonhospitalized adult patients with COVID-19 who are at low risk of progression to severe 
disease at baseline and were treated ≤5 days after COVID-19 symptom onset. This will be 
estimated irrespective of adherence to randomized treatment.   
Because the study did not meet the primary endpoint based on the interim analysis at 45%, 
all hypothesis assessments are done with a nominal alpha. 
2.1.2. Secondary Estimands 
The estimands associated with the secondary objectives are as follows: 
• The difference in proportions of patients experiencing COVID-19-related 
hospitalization or death from any cause through Day 28 in nonhospitalized adult 
patients with COVID-19 who are at low risk of progression to severe disease and 
were treated ≤5 days after COVID-19 symptom onset. This will be estimated without 
regard to adherence to randomized treatment. 
• The difference in estimated rate of number of COVID-19-related medical visits 
through Day 28 in nonhospitalized adult patients with COVID--19 who are at low 
risk of progression to severe disease at baseline. This will be estimated irrespective of 
adherence to randomized treatment 
• The difference in the estimated rate of number of days in hospital and ICU stay in 
patients with COVID-19-related hospitalization through Day 28 in nonhospitalized 
adult patients with COVID-19 who are at low risk of progression to severe disease 
and were treated ≤5 days after COVID-19 symptom onset. This will be estimated 
without regard to adherence to randomized treatment. 
 
Estimands for the other outcome measures are not presented. 
2.2. Study Design 
This Phase 2/3, randomized, double-blind, placebo-controlled study in approximately 
1980 symptomatic adult participants with COVID-19 who are at low risk of progressing to 
severe illness will determine the efficacy, safety, and tolerability of PF-07321332/ritonavir 
compared with placebo. Eligible participants with a confirmed diagnosis of SARS-CoV-2 
infection will be randomized (1:1) to receive PF-07321332/ritonavir or placebo orally q12h 


Protocol C4671002 (PF-07321332) Statistical Analysis Plan 
 
 
PFIZER CONFIDENTIAL  
Page 11 
for 5 days (10 doses total). Randomization will be stratified by geographic region, by 
vaccination status and by COVID-19 symptom onset (≤3 days vs >3 to 5 days).  
The total study duration is up to 24 weeks and includes a screening period of no more than 
48 hours, administration of study intervention through Day 5 or Day 6, efficacy assessments 
through Day 28, a safety follow-up period through Day 34, and long-term follow up at 
Weeks 12 and 24. 
An independent E-DMC will review unblinded data for this Study C4671002 to ensure the 
safety of participants throughout the duration of the study. In addition to up to weekly 
reviews of safety, the E-DMC will review the following: 
• Sentinel cohort safety review: The E-DMC will review unblinded safety data after 
approximately the first 100 randomized participants have completed through Day 10. 
Whether enrollment is paused for this review will depend on the successful 
completion of the Study C4671005 sentinel cohort (after approximately the first 
60 randomized participants have completed through Day 10). If the C4671005 
sentinel cohort safety review has successfully completed and no clinically significant 
safety signals have been identified prior to enrollment of the first 100 participants in 
this Study C4671002, the study will continue without pause. Otherwise, enrollment of 
Study C4671002 will be paused pending the E-DMC review of safety data. After 
review of the sentinel cohort in this Study C4671002, the frequency of safety reviews 
may be reduced subsequently based on E-DMC recommendations. 
• Proof-of-concept assessment: Viral load data when 25% (approximately 200 
participants in the primary analysis set who were treated ≤3 days following COVID-
19 symptoms onset) complete the Day 5 assessments. Enrollment will not be paused 
during review of these data but may be paused or stopped following E-DMC review. 
• First interim analysis (45% planned enrollment through Protocol Amendment 4): A 
planned interim analysis for efficacy, futility and sample size reestimation was 
conducted after approximately 45% of participants completed the Day 28 
assessments in the mITT analysis set. 
 
• Second interim analysis (80% planned enrollment through Protocol Amendment 4): 
At the request of the E-DMC, a second interim analysis was conducted on 80% of 
enrolled participants without any adjustment to the alpha. 
• Third Interim analysis (100% planned enrollment through Protocol Amendment 4): A 
third interim analysis was completed on enrolled participants who had risk factors for 
severe COVID-19 illness (ie, vaccinated against the SARS-CoV-2 virus) as well as 
participants who did not have risk factors for severe COVID-19 illness (ie, not 
vaccinated). Data from the study were required to support regulatory submissions 
thereby necessitating an interim analysis utilizing the 19 December 2021 dataset. This 
dataset had not been analyzed previously because the protocol was amended to 
increase the sample size and extend enrollment to assess the potential benefit of 


Protocol C4671002 (PF-07321332) Statistical Analysis Plan 
 
 
PFIZER CONFIDENTIAL  
Page 12 
participants at low risk of progression to severe COVID-19 in the clinically relevant 
endpoint of hospitalization or death (Protocol Amendment 5, 21 January 2022). The 
participants who were vaccinated were considered the high risk population and the 
unvaccinated participants were considered standard risk in the statistical analysis.  
This interim analysis was without any adjustment to the alpha. 
 
Subsequent to the interim analyses above, there will be a final analysis for reporting the 
results of this study. The final study analysis will be performed after all participants 
have completed or otherwise withdrawn from the study. The study schematic is provided 
in Figure 1. 
 
Figure 1.  Schema 
  


Protocol C4671002 (PF-07321332) Statistical Analysis Plan 
 
 
PFIZER CONFIDENTIAL  
Page 13 
2.3. Sample Size Determination 
The initial estimate of required sample size was based on the primary endpoint, the 
difference in time to sustained alleviation of all targeted COVID-19 associated 
signs/symptoms between participants who were treated ≤3 days after COVID-19 symptom 
onset with PF-07321332/ritonavir compared to placebo. The sample size is calculated 
based on a 2-sample test - parallel design – log-rank test, assuming a 90% power, 2-sided 
test at alpha = 0.05, approximate accrual rate of 30 participants per day, 2 days difference 
in the median days to sustained alleviation of all targeted COVID-19-associated symptoms 
(6 days for PF-07321332/ritonavir and 8 days for placebo ie, a 25% reduction in time to 
sustained alleviation of all targeted COVID-19 signs/symptoms) based on the Lilly - 
BLAZE-11 and assuming a 18% study discontinuation rate, the sample size of approximately 
800 participants (approximately 515 events) will provide 90% power to detect that 
difference. 
Allowing for approximately 30% of participants with COVID-19 symptom onset >3 days, a 
sample size of approximately 1140 participants will be enrolled for this study.   
After the second interim analysis (80% planned enrollment through Protocol Amendment 4), 
in order to improve estimation precision of the treatment effect in the clinically relevant key 
secondary endpoint of COVID-19-related hospitalization or death from any cause, the 
sample size has been adjusted to approximately 1880 participants. This adjustment will 
provide the required total number of 26 COVID-19-related hospitalizations or death from 
any cause, which will have approximately 90% conditional power (based on the interim 
data) such that the nominal 95% CI of the treatment group difference in the event rate does 
not include 0 when assuming that PF-7321332/ritonavir reduces the event rate by 70% or 
more relative to placebo. 
The sample size increase of 740 participants is based on the assumption of a 1.5% event 
rate for the targeted enrollment countries. The number of participants is approximately 
1880 (1140 enrolled participants plus the 740 participants). Assuming a 5% premature 
study discontinuation rate, approximately 1980 participants will be enrolled in the study. 
 
3. ENDPOINTS AND BASELINE VARIABLES:  DEFINITIONS AND 
CONVENTIONS 
3.1. Primary Endpoint 
• Time (days) to sustained alleviation of all targeted COVID-19 signs/symptoms 
through Day 28. 
3.2. Secondary Endpoint(s) 
• Incidence of treatment emergent adverse events (TEAEs).  
• Incidence of SAEs and AEs leading to discontinuations. 


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Protocol C4671002 (PF-07321332) Statistical Analysis Plan 
 
 
PFIZER CONFIDENTIAL  
Page 15 
• Baseline Viral Load defined as: <104 copies/mL vs ≥104 copies/mL.  
• Baseline Viral Load defined as: <107 copies/mL vs ≥107 copies/mL. 
• Nasopharyngeal (Y/N). 
3.5. Stratification Variables 
Randomization was stratified by geographic region, by vaccination status and by COVID-19 
symptom onset (<3 days vs >3 to 5 days).  
Vaccination status is defined as completely vaccinated (high risk) and not vaccinated 
(standard risk).  
 
Geographical region is defined as follows: 
• US region: country of the United States, including Puerto Rico.  
• Europe region: countries of Bulgaria, Czech Republic, Hungary, Poland, Spain, 
Ukraine, Slovakia and Romania. 
• Rest of the World region: countries of Argentina, Brazil, Colombia, Japan, Malaysia, 
Mexico, South Africa, Republic of Korea, Taiwan, Thailand, and Turkey.  
Baseline and stratification variables defined above will be applied to the analyses depending 
on the analysis population used: 
• mITT1 analysis will include: Baseline viral load, baseline serology status, 
geographic region, vaccination status and symptom onset days to first dose date 
(≤3 days, >3 days).  Detail will be described in each endpoint if applied. 
3.6. Safety Endpoints 
The safety endpoints of this study are:  
• Incidence of treatment emergent adverse events (TEAEs) 
• Incidence of SAEs and AEs leading to discontinuation. 
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 adverse event (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 


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Treatment-Emergent Adverse Event (TEAE) if the event started on or after the study 
medication start date and time.  
3.6.2. Medical History 
Medical history in addition to COVID-19 disease history and demographics will be 
collected at screening. Smoking status was collected for participants who enrolled under the 
original protocol (18 June 2021) or any of the first 4 amendments (02 July 2021; 19 July 
2021; 03 August 2021; and 23 November 2021, respectively). Participants who enrolled 
under Protocol Amendment 5 (21 January 2022) were not eligible to participate in the study 
if they were smokers. 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. General medical history will combine data collected 
before and after Protocol Amendment 5 (21 January 2022). Significant medical history 
collected under the original protocol and the first 4 amendments (ie, before Protocol 
Amendment 5, 21 Jan 2022) will be reported separately for the CSR.   
3.6.3. Height and Weight 
Height and weight will be measured and recorded at screening. 
3.6.4. Laboratory Data 
To determine if there are any clinically significant laboratory abnormalities, the 
hematological and clinical biochemistry 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. 
3.6.5. Vital Signs 
Vital signs measure include temperature, pulse rate, respiratory rate, oxygen saturation 
level, and blood pressure. 
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 who receive 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 with at least 1 
postbaseline visit through Day 28 who were treated ≤3 days 
after COVID symptoms onset. Participants will be analyzed 
according to the study intervention to which they were 
randomized. 
Modified Intent-To-Treat 
(mITT1) 
All participants randomly assigned to study intervention, who 
take at least 1 dose of study intervention. Participants will be 
analyzed according to the study intervention they were 
randomized. 
Per-Protocol (PP) 
All participants in the mITT1 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. 
Both the mITT1 and PP analysis sets will be used in the analyses of the primary efficacy 
endpoint, with the mITT1 being primary. For proportion of COVID-19 related 
hospitalization or death from any cause and all other efficacy endpoints, mITT1 will be 
used. The Safety Analysis Set will be used in the analyses of the safety data.   
Multiple Enrollers: 
If a participant enters/is randomized into Study C4671002 more than once or is enrolled in 
Study C4671002 and in 1 or 2 other Phase 2/3 nirmatrelvir/ritonavir studies:    
(1) The primary and key secondary efficacy analyses will be performed by considering 
all enrolled participants (subject IDs) as independent participants. 
 
(2) Sensitivity analyses for both the primary and key secondary endpoints will be 
performed using only data from a duplicate participant’s first enrollment within this 
study and excluding data from a duplicate participant’s subsequent enrollments.   
 
 
5. GENERAL METHODOLOGY AND CONVENTIONS 
The final analysis will be performed after dataset release. 
5.1. Hypotheses and Decision Rules 
The primary hypothesis to be tested is whether or not there is a difference in median time 
(days) to sustained alleviation of all targeted COVID-19 signs and symptoms through Day 
28 between PF-07321332/ritonavir and placebo. The statistical hypothesis is as follows: 


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• The null hypothesis (H0) is that there is no difference in median time to sustained 
alleviation of targeted symptoms of COVID-19 between PF-07321332/ritonavir and 
placebo. 
• The alternative hypothesis (H1) is that there is a difference in median time to 
sustained alleviation of targeted symptoms of COVID-19 between 
PF-07321332/ritonavir and placebo. 
Because the prespecified 45% interim analysis of the primary endpoint was not met, the 
following secondary endpoints will be analyzed to provide a point estimate and 95% CI to 
measure associated variability. The analysis will be performed with a nominal alpha: 
1) Proportion of participants with COVID-19-related hospitalization or death from any 
cause through Day 28. 
2) Number of COVID-19-related medical visits through Day 28. 
In support of the COVID-19 related medical visits endpoint, the number of days in hospital 
and ICU stay in patients with COVID-19-related hospitalization through Day 28 will be 
summarized. 
Other secondary endpoints listed below will be subsequently tested following the Hochberg 
procedure. 
• Time (days) to sustained resolution of all targeted signs/symptoms through Day 28 
mITT1 population. 
• Proportion of participants with a resting peripheral oxygen saturation ≥95% at 
Days 1 and 5 mITT1 population. 
• Proportion of participants with severe signs/symptoms attributed to COVID 19 
through Day 28. 
 
5.2. General Methods 
All data will be presented by treatment groups. Descriptive statistics will be provided for 
efficacy endpoints. The following listing of individual participants data will also be 
produced: (Disposition Events, Potentially Important Protocol Deviations, Subject 
Evaluation Groups, Demographic Information, Primary Diagnosis, Concomitant 
Medications, Compliance with Study Intervention, primary efficacy endpoint [time to 
sustained alleviation of all targeted signs and symptoms through Day 28], and the two key 
secondary endpoints [proportion of participants with COVID-19-related hospitalization or 
death from any cause through Day 28; number of COVID-19-related medical visits through 
Day 28], Adverse Events, Laboratory Data – Standardized (all the variables that are listed in 
the SAP Section 6.4 plus visit ID, participant ID, treatment). 


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The number of participants screened will be reported. The number of participants 
randomized to the double-blind treatment phase, completing the study drug administration, 
completing the study, completing the follow-up phase (through Day 34 visit) and 
discontinued the study will be summarized from the FAS analysis set for each 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, median minimum, and maximum), and 
qualitative variables will be summarized by frequency tables with number and proportion in 
each category (with the corresponding sample sizes). 
For mITT1 population, strata will be region, vaccination subgroup/strata, onset of signs and 
symptoms of COVID-19 (≤3 days, >3-5 days), nasopharyngeal (Y/N), and baseline viral 
load. 
5.2.1. Analyses for Binary Endpoints 
Binary endpoints other than COVID-19 related hospitalization and death due to any cause 
(ie, proportion of participants with severe signs/symptoms attributed to COVID-19 through 
Day 28, worsening status in 1 or more self-reported COVID-19 associated symptoms 
through Day 28 and proportion of participants with death [all cause] through Week 24) will 
be summarized with the number and percent of participants satisfying the endpoint. 
Treatment comparisons between groups will be presented as odds ratios with 95% 
confidence intervals and P-value based on logistic regression model (if data permits). 
5.2.2. Analyses for Continuous Endpoints 
For continuous endpoints (ie, viral titers measured via RT-PCR in nasal swabs over time), 
an MMRM analysis of covariance model will be used to analyze change from baseline over 
time. Estimated mean differences between treatments and their respective 95% CI and 
P-values will be calculated. In addition, an ANCOVA model will be used to analyze change 
from baseline (Day 1) to Day 5 in viral titers. 
For mITT1 population, the strata will be region, vaccination subgroup/strata, baseline 
serology (positive or negative), and baseline viral load (<104 copies/mL, ≥104 copies/mL). 
5.2.3. Analyses for Categorical Endpoints 
For categorical endpoints, (ie, proportion of participants with a resting peripheral oxygen 
saturation ≥95% at Days 1 and 5), proportion of participants for each category will be 
summarized for each group and a test for homogeneity of odds ratio using Breslow-Day test 
will be summarized. 
5.2.4. Analyses for Count Endpoints 
For count endpoints (ie, number of COVID-19 related medical visits through Day 28 and 
number of days of hospitalizations/ICU stay in participant with COVID-19-related 
hospitalization through Day 28), a negative binomial regression model analysis, using the 


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log total number of days of data collection as the participant offset variable, will be 
conducted and the difference in estimated rate will be provided. 
5.2.5. Analyses for Time-to-Event Endpoints 
Time-to-event endpoints (ie, Time (days) to sustained resolution of all targeted 
signs/symptoms through Day 28) will be summarized with Kaplan-Meier curves. Log-rank 
test will be used to compare the time-to-event between the treatment group.  
5.3. Methods to Manage Missing Data 
For missing efficacy data other than time to event endpoints, last observation carried 
forward (LOCF) approach will be used.  For efficacy endpoints related to COVID-19 
sign/symptoms, missing data at baseline will be treated as mild.  
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 time (days) to sustained alleviation of all targeted COVID-19 
signs/symptoms through Day 28 in the mITT1 population. 
Sustained alleviation of all targeted COVID-19 signs/symptoms is defined as the event 
occurring on the first of 4 consecutive days when all symptoms scored as moderate or 
severe at study entry are scored as mild or absent AND all symptoms scored mild or absent 
at study entry are scored as absent. The first day of the 4 consecutive-day period will be 
considered the First Event Date.  
For symptoms with no reported severity in baseline, the symptom will have to be absent in 
order to be counted as sustained alleviated/resolved (missing severity at baseline will be 
treated as mild). 
Day 25 is the last possible day the symptom alleviation and resolution endpoints can be 
achieved (definition includes data from the subsequent three days) and Day 28 is the last 
day participants report their daily signs and symptoms. 
The time to sustained symptom alleviation/resolution for the purpose of this study is defined 
as: 
• For a participant with sustained symptom alleviation/resolution (event), time to 
event will be calculated as (First Event Date) – (First Dose Date) +1. 


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• For a participant that either completes Day 28 of the study or discontinues from the 
study before Day 28 without sustained symptom alleviation/resolution (censored), 
censoring date will be at the last date on which symptom alleviation/resolution is 
assessed, and time will be calculated as (Censoring Date) – (First Dose Date) +1 or 
Day 25 whichever occurs first. 
The decision to require 4 consecutive days of all targeted symptoms alleviation/resolution 
was based on exploratory analyses of data from the ACTIV-2/A5401 study, which 
suggested that this choice (rather than requiring fewer consecutive days) better captured 
sustained symptom resolution with low probability of subsequent relapse. 
Participants who are hospitalized for the treatment of COVID-19 or death from any cause 
during the 28-day period will be classified as not achieving sustained symptom alleviation 
and will be censored at Day 25. 
Time to sustained alleviation of all targeted COVID-19 signs/symptoms will be summarized 
with Kaplan-Meier curves. Log-rank test will be used to compare the difference in time 
(days) to sustained alleviation of all targeted COVID-19 signs and symptoms through 
Day 28 between treatment groups. 
6.1.1.2. Sensitivity and Supplemental Analyses 
Sensitivity analyses will be performed to the primary efficacy endpoint: 
The primary efficacy analyses will also be conducted using the PP population as 
supplemental analyses. 
The primary endpoint will also be analyzed in which participants who discontinued the 
study before Day 28 without event will be censored at Day 25.   
For sensitivity analysis of primary endpoint, Cox proportion hazard models with terms 
including treatment and treatment strata (ie, region, vaccination, baseline serology, 
baseline viral load <104 copies/mL vs ≥104 copies/mL). These factors will be used to 
estimate the hazard ratio (the ratio of alleviation of all targeted signs and symptoms) and 
its 95% CI. Additional analyses may be performed adjusting for baseline covariates 
(such as age, gender, etc) as additive terms to the primary model, if necessary.  
Based on FDA request, a sensitivity analysis excluding participants only from Site 1488 
will be conducted as well. 
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.   


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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 COVID-19 Related Hospitalization or Death 
From Any Cause Through Day 28 
The estimand for proportion of participants experiencing COVID-19 related hospitalization 
or death from any cause through Day 28 is the difference in proportions of participants 
experiencing COVID-19 related hospitalization or death from any cause through Day 28 in 
nonhospitalized adult patients with COVID-19 who are at low risk of progression to severe 
disease and were treated ≤5 days after COVID-19 symptom onset. This will be estimated 
irrespective of adherence to randomized treatment. 
The statistical methodology for proportion of participants with COVID-19 related 
hospitalization or death from any cause through Day 28 will be as follows: 
The cumulative proportion of participants hospitalized for the treatment of COVID-19 or 
death during the first 28 days of the study will be estimated for each treatment group using 
the Kaplan-Meier method to take account of lost to follow-up and summarized graphically 
for each treatment group. The estimand is the difference of the proportions in the 2 groups 
and its 95% CI will be presented, as well as, the associated two sample proportion test 
(Wald test results). For the 95% CI, the corresponding estimate of the standard error is 
computed using Greenwood’s formula4. The Greenwood’s formula to estimate the variance 
of the difference of proportions at Day 28 is [Var(SPF(28)) + Var(SPlacebo(28))]. Instead of 
dealing with S(ti) the log-log approach to CI will be used. The 95% CI will be computed for 
the estimate of L(t)= log( log(S(t)), the log hazard function.  
The CI will be in the right range when transformed back to S(t) = exp (-exp (L(t)). 
Antilogging this CI will give a 95% confidence interval for the difference itself. 
A sensitivity analysis for proportion of participants with COVID-19 related hospitalization 
or death from any cause through Day 28 will be provided using mITT1 as follows:  
For participants with missing data due to lost to follow up for COVID-19 related 
hospitalization or death from any cause, the sensitivity analysis will implement the 
following event imputation methodology for those with missing data: 
• If the participant’s last observed data is prior to Day 21, then impute as an event with 
event day as day of last observed data +1. 
• If the participant’s last observed data is on or after Day 21, then no imputation for 
event will be done and   participant remains censored at day of last observed data. 


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6.2.4. Proportion of Participants with Death (all cause) through Week 24 
Descriptive statistics will be used to summarize proportion of death through Week 24 by 
treatment group using mITT1 populations. Treatment comparisons between groups will be 
presented as odds ratios with 95% confidence intervals and P-value based on logistic 
regression model (if data permit).  
If zero counts are observed in either treatment group, the Fishers Exact test will be 
performed (instead of logistic regression) and p-value provided. 
 
The participants enrolled under or after protocol amendment 6 will not include this 
summary. 
 
6.2.5. Number of COVID-19 Related Medical Visits through Day 28  
The number of COVID-19 related medical visits will 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). The resulting analysis will evaluate the difference in 
estimated rate of number of medical visits between treatment groups and the associated 95% 
CI. The analyses will be done using mITT1 populations. 
6.2.6. Number of Days of Hospital and ICU Stay in Participants with COVID-19 
Related Hospitalization  
Health resource utilization data will be summarized by treatment group for each treatment. 
The analyses will be done using mITT1 populations. Descriptive statistics (ie, mean, 
median, range) will be used to summarize this endpoint. 
The resulting analysis will provide the estimated difference in the average of number of 
days stayed in the hospital between treatment groups, with p-value and 95% confidence 
interval. The analyses will be done using the mITT1 population. 
6.2.7. Proportion of Participants with Severe Signs/symptoms Attributed to COVID19 
through Day 28  
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. A participant with severe score for any targeted 
symptoms post-baseline will be counted as 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. 


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The proportion of participants with any severe targeted signs/symptoms attributed to 
COVID-19 through Day 28 will be summarized by treatment group. Observed proportions 
for each targeted signs and symptom with severe category only will be plotted over time 
through Day 28. Additionally, observed proportion of participants reporting the presence of 
each targeted sign and symptom that is mild, moderate or severe categories will also be 
presented. 
Treatment comparisons between groups will be presented as odds ratios with 95% CI and p-
value based on logistic regression model and using the mITT1 population.  
To evaluate the severity of signs/symptoms attributed to COVID-19, the following analysis 
will be performed and treatment comparison between groups will be done using the same 
statistical method as mentioned above:  
• Proportion of participants with any severe (ie, any targeted symptoms with severe 
baseline score) targeted signs/symptoms attributed to COVID-19 at Day 1 (baseline). 
• Proportion of participants with any severe targeted signs/symptoms attributed to 
COVID-19 Day 2 to Day 6 (during treatment). 
• Proportion of participants with any severe targeted signs/symptoms attributed to 
COVID-19 Day 7 to Day 28 (post treatment). 
The above severity endpoint is based on participant daily diary data only. To align the 
severity of signs and symptoms with the primary and key secondary endpoints, an expanded 
evaluation of severity of will be assessed to include hospitalization due to COVID-19 and 
death of any cause in the severity assessment based on CRF data.   
An expanded definition severity of signs and symptoms that will include CRF data 
(hospitalization due to COVID-19 and death of any cause) is defined as follows: Participant 
with hospitalization due COVID-19 or death of any cause will be considered as having 
severe signs and symptoms, this definition overrides the observed severity of signs and 
symptoms from participant diary. To incorporate hospitalization and death in the severity of 
signs and symptoms, the date of hospitalization and date of discharged will be used. 
Treatment comparisons between groups for expanded severity will be presented as odds 
ratios with 95% CI and p-value based on logistic regression model and using the mITT1 
population  
This analysis will be performed for overall, baseline (Day 1), Day 2 to Day 6 (during 
treatment) and Day 7 to Day 28 (post treatment).  
6.2.8.  Time (days) to Sustained Resolution of All Targeted COVID-19 Signs/symptoms 
through Day 28 
The secondary endpoint of time (days) from start of study intervention or placebo (Day 1) 
until sustained resolution of all targeted COVID-19 associated signs/symptoms will be 
based on self-assessment. 


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Sustained resolution is defined as when all targeted symptoms are scored as absent for 
4 consecutive days. The first day of the 4 consecutive-day period will be considered the 
First Event Date.  
The censoring method and analysis of time (days) to sustained resolution of all targeted 
COVID-19 signs/symptoms will be similar to the censoring method and analysis of the 
primary endpoint. The analysis will be done using mITT1 population. 
6.2.9.  Duration of Each Targeted COVID-19 Sign/symptom  
Duration of each targeted COVID-19 signs/symptoms is defined as (First Date when the 
symptom alleviated/resolved) – (First Dose Date) +1 for each participant with baseline 
severity of mild, moderate, or severe.  
For duration of each targeted COVID-19 sign/symptom, a Kaplan-Meier analysis providing 
the median and quartiles will be provided for each treatment group for mITT1 population 
set. Two additional figures (Number of Participants and Median Time to Sustained 
Alleviation of Each Targeted Sign/Symptom by Treatment Group [mITT1]) will be included 
for the endpoint of Duration of Each Targeted COVID-19 Sign/Symptom. 
6.2.10.  Progression to a Worsening Status in 1 or More Self-reported COVID-19 
Associated Symptoms through Day 28  
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 (mild) for 1 to 2 times, 2 (moderate) for 3 to 4 times, and 3 (severe) for 
5 or greater. 
Progression to a worsening status for any targeted symptom will be derived 
programmatically based upon increasing severity (ie, the first time any targeted symptom 
worsens after treatment relative to baseline):  
Progression to worsening (Yes/No) 
 
Increasing severity 
Yes 
Not increasing severity 
No 
The proportion of participants with progression (increasing severity for any targeted 
symptom) will be summarized by treatment group. Treatment comparison between groups 
will be presented as odds ratios with 95% CIs and p-value based on logistic regression 
model. The analyses will be done using mITT1 population. Missing severity at baseline will 
be treated as mild. 
The above definition of worsening was derived only from participant diary data, to align the 
worsening with the primary and keys secondary endpoint, an expanded evaluation of 


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worsening will be assessed to include hospitalization due to COVID-19 and death of any 
cause. An expanded definition of worsening of signs and symptoms that will include CRF 
data (hospitalization due to COVID-19 and death of any cause) is defined as follows: 
Participant with hospitalization due COVID-19 or death of any cause will be considered as 
having worse signs and symptoms, this definition overrides the observed worsening of signs 
and symptoms from participant diary data. To incorporate hospitalization and death in the 
expanded worsening of signs and symptoms, date of hospitalization and date of discharge 
will be used. 
To evaluate the progression to worsening of symptoms attributed to COVID-19, the 
following analysis will be performed for both worsening and expanded worsening and 
treatment comparison between groups will be done using the same statistical method as 
mentioned above:  
• Proportion of participants with any progression to worsening of targeted symptoms 
attributed to COVID-19 Day 2 to Day 6 (during treatment). 
• Proportion of participants with any progression to worsening of targeted symptoms 
attributed to COVID-19 Day 7 to Day 28 (post treatment). 
6.2.11. Proportion of Participants with a Resting Peripheral Oxygen Saturation ≥ 95% 
at Days 1 and 5  
The oxygen saturation level will be measured for each participant. A resting peripheral 
oxygen saturation will be derived programmatically based on following table:  
Oxygen saturation (Yes/No) 
 
≥95% 
Yes 
<95% 
No 
The count and proportion of participants with a resting peripheral oxygen saturation 
≥95% will be summarized by treatment group and by visits (Days 1 and 5). A cross 
tabulation will be presented for both Day 1 and Day 5, ie, for each proportion presented at 
Day 1, both proportions at Day 5 will be summarized. Treatment comparison between group 
for the odds ratio (baseline (Day 1) ≥95% vs <95%) of comparing oxygen saturation ≥95% 
at Day 5 will be analyzed with a Breslow-Day test for homogeneity of the odds ratios. The 
analyses will be done using mITT1 populations. Missing data at Day 1 or Day 5 will be 
excluded from the analysis.  
6.2.12.  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.  


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Protocol C4671002 (PF-07321332) Statistical Analysis Plan 
 
 
PFIZER CONFIDENTIAL  
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• Chronic lung disease requiring medication; 
• Hypertension (taking medications for hypertension); 
• Cardiovascular disorders; 
• Diabetes (taking medications for diabetes) for safety reporting; 
• Chronic kidney disease; 
• Sickle cell disease; 
• Neurodevelopmental disorders; 
• Cancer other than localized skin cancer; 
• Medical-related technological dependence.  
 
6.5. Baseline and Other Summaries and Analyses 
6.5.1.  Baseline Summaries 
The demographic characteristics will be summarized by treatment group within the FAS. 
This will include age, gender, race, ethnicity baseline height, and baseline weight. All 
baseline disease characteristics will be summarized by treatment group within the FAS.  
6.5.2.  Study Conduct and Participant Disposition 
Participant evaluation groups will be presented for all screened participants, and participant 
disposition will be summarized within the FAS population. The number of participants 
screened and randomized will be presented. The number of participants treated, completing 
and discontinuing by study phase, 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, the number of participants who were excluded from the PP analysis set will be 
summarized by reasons for the exclusion.  
6.5.3.  Study Treatment Exposure 
Duration of treatment 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. 


Protocol C4671002 (PF-07321332) Statistical Analysis Plan 
 
 
PFIZER CONFIDENTIAL  
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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 Clinical 
Data Interchange Standards Consortium (CDISC) and Pfizer Standards (CaPS). 
6.6. Safety Summaries and Analyses 
Standard summary tables and listings will be generated in accordance with Clinical Data 
Interchange Standards Consortium (CDISC) and Pfizer Standards (CaPS) for safety 
reporting for the following parameters: adverse events, lab parameters, vital signs, 
discontinuations from study, discontinuations from treatment, and treatment duration. 
6.6.1. Adverse Events 
All adverse events will be coded according to the Medical Dictionary for Regulatory 
Activities (MedDRA) and will be summarized by treatment group within SAS population. 
Only TEAE summaries to AEs that started on or prior to Day 34 will be summarized. A list 
of pre-specified AESIs is provided in Appendix 5.   
6.6.2. Subgroup Analysis of Adverse Events and Serious Adverse Events  
A subgroup analysis of treatment emergent AEs and SAEs will be provided by vaccination 
status. 
6.6.3. Laboratory Data 
Descriptive statistics will be summarized by treatment group as well as mean change from 
baseline for laboratory parameters within SAS population. 
Laboratory shift tables from baseline will be presented for the following laboratory 
abnormalities at baseline: D-dimer levels, Liver function tests (ALT/AST), Creatinine 
Clearance (derived using Cockcroft-Gault Equation), TSH, T4 (free), fibrinogen, platelets, 
PT, aPTT, albumin, and total proteins. 
All laboratory data will be reported in accordance with Clinical Data Interchange Standards 
Consortium (CDISC) and Pfizer Standards (CaPS) for safety reporting. 
6.6.4. Vital Signs 
The measurement taken immediately prior to start of study drug will be used as the baseline 
for calculating change from baseline.  
All vital signs data will be descriptively summarized by treatment group within SAS 
population and reported in accordance with Pfizer data standard for safety reporting. 
 


Protocol C4671002 (PF-07321332) Statistical Analysis Plan 
 
 
PFIZER CONFIDENTIAL  
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7. INTERIM ANALYSES 
7.1. Interim Analyses and Summaries 
There were 3 interim analyses as follows: 
First interim analysis (45% planned enrollment through Protocol Amendment 4): An interim 
analysis was conducted for efficacy, futility and sample size re-estimation, and reviewed by 
an independent E-DMC after a prespecified accrual of participants (ie, approximately 45% 
overall participants have completed Day 28 efficacy assessment in the mITT population), 
according to the SAP and E-DMC charter. The sample size could be increased one time and 
the increase is limited to 30 to 35%. A well-established method described by Cui, Hung, and 
Wang (1999)2 (implemented in EAST 6.5) would be used to control the Type I error 
probability.3  
The nominal significance level for the interim and final time to sustained alleviation of all 
targeted COVID-19 signs/symptoms analyses was determined by means of the Lan-DeMets 
procedure with an O’Brien-Fleming stopping boundary, with an overall 2-sided type I error 
rate of 5%.  
O’Brien-Fleming approach was used for decision making, ie, reject H0 with 2-sided p-value 
≤0.002, or reject H1 with 2-sided p-value >0.924 at the formal interim analysis. At the final 
analysis, the p-value for rejecting H0 will be ≤0.049 (2-sided) or reject H1 with 2-sided p-
value >0.049 will be considered.  
Before any interim analysis was performed, the details of the objectives, decision criteria, 
dissemination plan, and method of maintaining the study blind as per Pfizer’s SOPs was 
documented and approved in an E-DMC charter. 
The first interim analysis (45% planned enrollment through Protocol Amendment 4) 
summarized above was performed as described. 
Second interim analysis (80% planned enrollment through Protocol Amendment 4): Upon 
review of the 45% analysis, the E-DMC requested the Sponsor to consider appropriate 
course of action for the ongoing trial to assess the clinical benefit. In order to respond 
properly to fulfill the E-DMC recommendation, the RRP decided that a second interim 
analysis should be conducted to address the E-DMC’s request. This resulted in the analysis 
of 80% of enrolled participants through Protocol Amendment 4, without any adjustment to 
the alpha.  
Third interim analysis (100% planned enrollment through Protocol Amendment 4): A third 
interim analysis was completed on enrolled participants who had risk factors for severe 
COVID-19 illness (ie, vaccinated against the SARS-CoV-2 virus) as well as participants 
who did not have risk factors for severe COVID-19 illness (ie, not vaccinated). Data from 
the study are required to support regulatory submissions thereby necessitating an interim 
analysis utilizing the 19 December 2021 dataset. This dataset had not been analyzed 
previously because the protocol was amended to increase the sample size and extend 
enrollment to assess the potential benefit of participants at low risk of progression to severe 


Protocol C4671002 (PF-07321332) Statistical Analysis Plan 
 
 
PFIZER CONFIDENTIAL  
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COVID-19 in the clinically relevant endpoint of hospitalization or death (Protocol 
Amendment 5, 21 January 2022). The participants who were vaccinated are considered the 
high risk population and the unvaccinated participants are considered standard risk in the 
statistical analysis. 
7.2. 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 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.  
7.3. 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 medical monitor/clinicians, reporting 
statistician and reporting programmer(s) and will be separate from the direct members of the 
study team. The reporting team may include designated ad hoc member(s). 
After all participants complete the Day 34 visit (or Early Termination (ET) prior to Day 34 
visit), the study will be unblinded and analyses through Day 34, including the primary 
efficacy endpoint analyses, will be conducted. A blinded team will remain in place to 
monitor and manage the study until primary completion date is attained (all participants 
have reached Day 34 visit or discontinued prior to Day 34 visit). 
Details of the unblinded sponsor staff supporting the E-DMC and the timing of unblinding 
will be outlined in the Unblinding Plan. 


Protocol C4671002 (PF-07321332) Statistical Analysis Plan 
 
 
PFIZER CONFIDENTIAL  
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8. REFERENCES 
1. 
Gottlieb RL, Nirula A, Chen P, et al. Effect of bamlanivimab as monotherapy or in 
combination with etesevimab on viral load in patients with mild to moderate 
COVID-19: A randomized clinical trial. JAMA. 2021;325(7):632-44. 
2. 
Cui L, Hung HM, Wang SJ. Modification of sample size in group sequential 
clinicaltrials. Biometrics. 1999;55(3):853-7. 
3. 
FDA. Food and Drug Administration Guidance for Industry: Adaptive Design Clinical 
Trials for Drugs and Biologics November 2019. Available from: 
https://www.fda.gov/media/78495/download. Available from: 
https://www.fda.gov/regulatory-information/search-fda-guidancedocuments/assessing-
covid-19-related-symptoms- outpatient-adult-and-adolescent subjects-clinical-trials-
drugs. Accessed on: 16 June 2021. 
4. 
Kalbfleisch JD, Prentice RL. In The statistical analysis of failure time data. Edited by: 
John Wiley & Sons, Inc; 1980. 
 


Protocol C4671002 (PF-07321332) Statistical Analysis Plan 
 
 
PFIZER CONFIDENTIAL  
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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 
Time (days) to 
sustained alleviation of 
all targeted COVID-19 
signs/symptoms 
through Day 28. 
Primary efficacy 
Analysis 
mITT1  
All data collected will be 
included. Missing severity at 
baseline will be treated as mild. 
Other missing data will be 
estimated with KM (lifetest) 
procedure 
Kaplan-Meier & 
Log rank test  
Time (days) to 
sustained alleviation of 
all targeted COVID-19 
signs/symptoms 
through Day 28. 
Sensitivity analysis 
for primary 
endpoint 
mITT1  
All data collected will be 
included. Missing severity at 
baseline will be treated as mild. 
Cox 
proportional 
hazard model 
Time (days) to 
sustained alleviation of 
all targeted COVID-19 
signs/symptoms 
through Day 28. 
Sensitivity analysis 
for primary 
endpoint 
mITT1  
exclude site 
1488 
All data collected will be 
included. Missing severity at 
baseline will be treated as mild. 
Cox 
proportional 
hazard model 
Time (days) to 
sustained alleviation of 
all targeted COVID-19 
signs/symptoms 
through Day 28. 
Supplemental 
analysis for primary 
endpoint 
PP  
Participants who discontinued the 
study before Day 28 without 
event will be censored at Day 25. 
Kaplan-Meier & 
Log rank test 
Time (days) to 
sustained alleviation of 
all targeted COVID-19 
signs/symptoms 
through Day 28. 
Sensitivity 
analysis for 
Primary Efficacy 
analysis for 
multiple enrollers 
mITT1 
including  
only data 
with first 
randomizatio
n within the 
study  
All data collected will be 
included regardless of 
intercurrent events. Kaplan-
Meier method to take account 
of losses to follow-up.  
Kaplan-Meier 
method 
Time (days) to 
sustained alleviation of 
all targeted COVID-19 
signs/symptoms 
through Day 28 
by vaccination status 
Subgroup analysis 
for primary 
endpoint 
mITT1 
Use baseline variables as 
described in Section 6.4. 
 
Cox 
proportional 
hazard model 
Proportion of 
participants with 
COVID-19 related 
hospitalization or death 
from any cause through 
Day 28 
Key secondary 
analysis 
mITT1 
All data collected will be 
included regardless of 
intercurrent events. 
Kaplan-Meier method to take 
account of losses to follow-up. 
Kaplan-Meier 
method 
Proportion of 
participants with 
COVID-19 related 
hospitalization or death 
from any cause through 
Day 28 
Sensitivity analysis 
for key secondary 
endpoint   
 mITT1 
If the participant’s last 
observed data is prior to Day 21, 
then impute as an event with 
event day as day of last observed 
data +1. 
If the participant’s last 
observed data is on or after Day 
21, do not impute an event and 
Kaplan-Meier 
method 


Protocol C4671002 (PF-07321332) Statistical Analysis Plan 
 
 
PFIZER CONFIDENTIAL  
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Endpoint 
Analysis Type 
Population 
Data Inclusion and Rules for 
Handling Intercurrent Events 
and Missing Data  
Analysis Model 
participant remains censored at 
day of last observed data. 
Proportion of 
participants with 
COVID-19 related 
hospitalization or death 
from any cause through 
Day 28 
Sensitivity 
analysis for key 
secondary 
efficacy analysis 
for multiple 
enrollers 
mITT1 
including  
only data 
with first 
randomizatio
n within the 
study  
All data collected will be 
included regardless of 
intercurrent events. Kaplan-
Meier method to take account 
of losses to follow-up.  
Kaplan-Meier 
method 
Proportion of 
participants with 
COVID-19 related 
hospitalization or death 
from any cause through 
Day 28 
by vaccination status 
Subgroup analysis 
for key secondary 
endpoint 
mITT1 
Subset analysis identified in 
Section 6.4. 
Kaplan-Meier 
method 
Proportion of 
participants with 
COVID-19 related 
hospitalization or death 
from any cause through 
Day 28 
Supplemental 
analysis for key 
secondary efficacy 
endpoint 
PP  
Participants who discontinued the 
study before Day 28 without 
event will be censored at Day 25. 
Kaplan-Meier & 
Log rank test 
Proportion of 
participants with death 
(all cause) through 
Week 24. 
Secondary analysis 
 mITT1 
 
All data collected will be included 
regardless of intercurrent events 
exclude participants enrolled 
under PA6 
Logistic 
Regression  
Number of COVID-19 
related medical visits 
through Day 28. 
Secondary analysis  
mITT1  
All data collected will be included 
regardless of intercurrent events. 
Missing data will not be imputed. 
Descriptive 
statistics  (based 
on negative 
Binomial 
Model) 
Number of days in 
hospital and ICU stay in 
participants with 
COVID-19 related 
hospitalization through 
Day 28. 
Secondary analysis  
mITT1 
All data collected will be included 
regardless of intercurrent events. 
Missing data will not be imputed. 
Descriptive 
statistics  
Proportion of 
participants with 
severe signs/symptoms 
attributed to 
COVID-19 through 
Day 28. 
Secondary Efficacy 
Analysis 
mITT1 
All data collected will be included 
regardless of intercurrent events, 
LOCF for missing data. 
  
Logistic 
regression 
model  
Proportion of 
participants with any 
severe targeted 
signs/symptoms 
attributed to COVID 
19 at Day 1(baseline). 
Supplemental 
analysis for 
secondary endpoint 
mITT1 
Any severe (ie, any targeted 
symptoms with severe baseline 
score) LOCF for missing data. 
 
 
Logistic 
regression 
model 
Proportion of 
participants with any 
severe targeted 
signs/symptoms 
Supplemental 
analysis for 
secondary endpoint  
 mITT1 
Any severe (ie, any targeted 
symptoms with severe baseline 
score) LOCF for missing data. 
 
 Logistic 
regression 
model 


Protocol C4671002 (PF-07321332) Statistical Analysis Plan 
 
 
PFIZER CONFIDENTIAL  
Page 36 
Endpoint 
Analysis Type 
Population 
Data Inclusion and Rules for 
Handling Intercurrent Events 
and Missing Data  
Analysis Model 
attributed to COVID 
19 from Day 2 to Day 
6 (during treatment) 
 
Proportion of 
participants with any 
severe targeted 
signs/symptoms 
attributed to COVID 
19 from Day 7 to Day 
28 (post treatment) 
Supplemental 
analysis for 
secondary endpoint  
mITT1 
Any severe (ie, any targeted 
symptoms with severe baseline 
score) LOCF for missing data. 
 
 
Logistic 
regression 
model  
Proportion of 
participants with 
severe signs/symptoms 
attributed to COVID 
19 through Day 28. 
 
Supplemental 
analysis for 
secondary endpoint 
mITT1 
Observed proportions for each 
targeted signs and symptom with 
severe category only will be 
plotted over time through Day 28. 
Additionally, observed proportion 
of participants reporting the 
presence of each targeted sign and 
symptom that is mild, moderate or 
severe categories will also be 
presented 
Plot/Figure 
Time (days) to 
sustained resolution of 
all targeted COVID-19 
signs/symptom through 
Day 28. 
Secondary analysis 
  mITT1 
All data collected will be 
included. Missing severity at 
baseline will be treated as mild. 
Other missing data will be 
estimated with KM (lifetest) 
procedure  
Kaplan-Meier  
& Log rank test 
Duration of each 
targeted COVID-19 
sign/symptom. 
Secondary analysis 
 mITT1 
All data collected will be included 
regardless of intercurrent events. 
Missing data will not be imputed. 
Kaplan-Meier  
estimate, 
Descriptive 
statistics 
(median, 
quartiles) 
Progression to a 
worsening status in 1 
or more self-reported 
COVID19 associated 
symptoms through Day 
28. 
Secondary analysis 
 mITT1 
All data collected will be included 
regardless of intercurrent events. 
Missing severity at baseline will 
be treated as mild. 
Logistic 
regression 
model 
Progression to a 
expanded worsening 
status in 1 or more 
self-reported 
COVID19 associated 
symptoms through Day 
28. 
Secondary analysis 
mITT1 
All data collected will be included 
regardless of intercurrent events. 
Missing severity at baseline will 
be treated as mild. 
Logistic 
regression 
model 
Proportion of 
participants with a 
resting peripheral 
oxygen saturation 
≥95% at Days 1 and 5. 
Secondary analysis 
mITT1 
All data collected will be included 
regardless of intercurrent events. 
Missing data will not be imputed. 
Breslow-Day 
test for 
Homogeneity of 
the Odds Ratios 
Viral titers measured 
via RT-PCR in nasal 
swabs over time. 
Secondary analysis 
mITT1 
All data collected will be included 
regardless of intercurrent events. 
If visit data in viral load is 
missing, the earliest measurement 
MMRM 
analysis  


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Protocol C4671002 (PF-07321332) Statistical Analysis Plan 
 
 
PFIZER CONFIDENTIAL  
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Appendix 2. Data Derivation Details 
Appendix 2.1. Definition and Use of Visit Windows in Reporting 
The following table defines the visit windows and labels to be used for reporting: 
Visit Number 
Visit Label  Definition [Day window] 
2 
Baseline 
= Day -2 to Day 1 
3 
Day 3 
= Day 3, with a window of ±1 Day, (ie, Days 2 to 4) 
4 
Day 5 
= Day 5, with a window of ±1 Day, (ie, Days 4 to 6) 
5 
Day 10 
= Day 10, with a window from Days 7 to 11 
6 
Day 14 
= Day 14, with a window from Days 12 to 17 
7 
Day 21 
= Day 21, with a window from 18 to 24 
8 
Day 34 
= Day 34, with a window from days 25 to 37 
9 
Week 12 
= Day 84, with a window of ±7 Days, (ie, Days 77 to 91) 
10 
Week 24 
= day 168 with a window of ±7 days, (ie, Days 161 to 175) 
• Viral Load: Baseline visit is set up according to study days of Day -2 to Day 1. The 
only viral load results collected after the start of dosing during the Baseline visit that 
are treated as Baseline data are those that were collected within 1 hour post start of 
dosing. 
• Labs, COVID-19 Signs and Symptoms, Vital Signs: Baseline window will be Day -2 
to Day 1, without any consideration to the time factor. 
• When data from study Day 4 has an overlap between Day 3 and Day 5 windows, 
decision made is to assign the window according to the nominal visit. The rule will 
not be applicable to other study days 2 and 3 for Day 3 window, and days 5 and 6 for 
Day 5 window. 
• If multiple readings fall into the same window, choose the one closer to the target 
day. If equidistant, then select the later one after the target day. If multiple 
observations fall on the same day after the windowing logic has been applied, average 
observations. 
 


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Appendix 3. List of Abbreviations 
Abbreviation 
Term 
AE 
adverse event 
ANCOVA 
analysis of covariance 
BOCF 
baseline observation carried forward 
CDARS 
Clinical Data Analysis and Reporting System  
CI 
confidence interval 
E-DMC 
external data monitoring committee  
FAS 
full analysis set 
FDA 
Food and Drug Administration (United States) 
LOCF 
last observation carried forward 
MedDRA 
Medical Dictionary for Regulatory Activities 
mITT 
modified intent-to-treat 
MMRM 
mixed-effects model with repeated measures 
PD 
pharmacodynamic(s) 
PK 
pharmacokinetic(s) 
PP 
per-protocol 
POC 
Proof-of-concept 
RRP 
Recommendation Review Panel 
PT 
preferred term 
QTc 
corrected QT 
QTcF 
corrected QT (Fridericia method) 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SAS 
Safety Analysis Set 
SD 
standard deviation 
SOC 
Schedule of Activities 
SOP 
standard operating procedure 
WHO  
World Health Organization 
 


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Appendix 4. Signs and Symptoms Attributable to COVID-19 
 
 
Daily Sign and Symptom Collection28 
Entry 
Criterion#3 
Targeted 
(used for 
study entry) 
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 
Chills or shivering 
X 
X 
X 
Fatigue (low energy or tiredness) 
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 
 
Loss of taste 
 
X 
 
 


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Appendix 5. List of Pre-Specified AESIs