Conditions: COVID-19
Keywords: severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 2091
Healthy volunteers: no

Brief summary:
The purpose of this study is to determine whether PF-07321332/ritonavir is safe and effective for the treatment of adults who are ill with COVID-19 and do not need to be in the hospital, but are at an increased risk of developing severe illness. Throughout the study period, provision will be made to allow study visits to be conducted at a participant's home or another non-clinic location if available. The total study duration is up to 24 weeks.

Detailed description:

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 descriptions: intervention 1: PF-07321332 (tablet) intervention 2: Ritonavir (capsule) intervention 3: Placebo (tablet or capsule)

Protocol document:
Prot_000.pdf: 
PF-07321332
Protocol C4671005
Final Protocol Amendment 4, 20 November 2021
PFIZER CONFIDENTIAL
Page 1
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 
INCREASED RISK OF PROGRESSING TO SEVERE ILLNESS
Study Intervention Number:
PF-07321332
Study Intervention Name:
N/A
US IND Number:
153517
EudraCT Number:
2021-002895-38
ClinicalTrials.gov ID:
NCT04960202
Protocol Number:
C4671005
Phase:
2/3
Brief Title: A Phase 2/3 Efficacy and Safety Study of PF-07321332/Ritonavir in 
Nonhospitalized High 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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Final Protocol Amendment 4, 20 November 2021
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Document History
Document 
Version Date
Amendment 4
20 November 2021
Amendment 3
26 October 2021
Amendment 2
02 August 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.
Protocol Amendment Summary of Changes Table
Amendment 4 (20 November 2021)
Overall Rationale for the Amendment: To remove the second interim analysis (70% 
interim analysis that was added under Amendment 3) from the protocol because the objective 
of the planned 45% interim analysis was met.
Section # and Name
Description of Change
Brief Rationale
Section 1.1
Synopsis
Second interim analysis at 70% 
has been removed, and sample 
size updated to lower it from 
3100 to approximately 3000 
participants due to removal of 
second interim analysis.
Study enrollment will be 
stopped after approximately 
1717 participants are available 
for the primary analysis.
The 70% interim analysis has been 
removed because the planned interim 
analysis objective was achieved.
Section 2.3.3 
Overall Benefit/Risk 
Conclusion
Text updated to clarify that the 
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
and futility at the time of the 
interim analysis.
To be consistent with the rest of the 
document.
Section 4.1
Overall Design
Sample size updated to lower it 
from 3100 to approximately 
3000 participants due to 
To provide a more comprehensive 
description of the overall study design
and specifically to reduce the sample size 


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Section # and Name
Description of Change
Brief Rationale
removal of second interim 
analysis.
Removed second interim 
analysis. 
in response to the interim analysis 
outcome.
Section 9 
Statistical Considerations

9.3.2 Primary 
Endpoint(s)/Estimand(s) 
Analysis: updated to remove 
primary analysis being
conducted for 2 planned 
interim analyses.

9.4. Interim Analyses: Second 
interim analysis removed. The 
45% interim analysis
boundary was updated as a 
result, and a sentence added 
regarding boundaries at end of 
trial.

9.5 Sample Size 
Determination: text updated
due to removal of second 
interim analysis: Study
enrollment will be stopped 
after approximately 1717 
participants are available for 
the primary analysis.

Total sample size changed 
from 3100 to 3000 
participants.
The second interim analysis has been 
removed and as a result the sample size 
has been modified back to the number of 
participants in the original design. 
Section 10 
Supporting documentation 
and Operational 
considerations
Second interim analysis removed.
The second interim analysis has been 
removed from the Data Monitoring 
Committee description under Committee 
Structure.
Throughout the protocol
Typographical errors were 
corrected and minor edits were 
made.
For clarification and to ensure 
consistency.


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TABLE OF CONTENTS
LIST OF TABLES.....................................................................................................................9
1. PROTOCOL SUMMARY...................................................................................................10
1.1. Synopsis ..................................................................................................................10
1.2. Schema ....................................................................................................................14
1.3. Schedule of Activities .............................................................................................15
2. INTRODUCTION ...............................................................................................................22
2.1. Study Rationale .......................................................................................................22
2.2. Background .............................................................................................................22
2.2.1. Nonclinical Studies of PF-07321332..........................................................23
2.2.2. Clinical Overview.......................................................................................24
2.3. Benefit/Risk Assessment.........................................................................................24
2.3.1. Risk Assessment.........................................................................................25
2.3.2. Benefit Assessment.....................................................................................27
2.3.3. Overall Benefit/Risk Conclusion................................................................27
3. OBJECTIVES, ENDPOINTS, AND ESTIMANDS ...........................................................27
4. STUDY DESIGN.................................................................................................................29
4.1. Overall Design.........................................................................................................29
4.2. Scientific Rationale for Study Design.....................................................................30
4.2.1. Diversity of Study Population ....................................................................31
4.2.2. Choice of Contraception/Barrier Requirements .........................................31
4.2.3. Collection of Retained Research Samples..................................................31
4.3. Justification for Dose ..............................................................................................31
4.4. End of Study Definition ..........................................................................................32
5. STUDY POPULATION......................................................................................................32
5.1. Inclusion Criteria.....................................................................................................32
5.2. Exclusion Criteria....................................................................................................34
5.3. Lifestyle Considerations..........................................................................................36
5.3.1. Contraception..............................................................................................36
5.4. Screen Failures ........................................................................................................37
5.5. Criteria for Temporarily Delaying 
Enrollment/Randomization/Administration of Study Intervention...........................37


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6. STUDY INTERVENTION(S) AND CONCOMITANT THERAPY.................................37
6.1. Study Intervention(s) Administered........................................................................37
6.1.1. Administration............................................................................................38
6.2. Preparation, Handling, Storage, and Accountability...............................................39
6.2.1. Preparation and Dispensing........................................................................41
6.3. Measures to Minimize Bias: Randomization and Blinding.....................................41
6.3.1. Allocation to Study Intervention ................................................................41
6.3.2. Blinding of the Sponsor..............................................................................41
6.3.3. Breaking the Blind......................................................................................42
6.4. Study Intervention Compliance...............................................................................42
6.5. Dose Modification...................................................................................................43
6.6. Continued Access to Study Intervention After the End of the Study......................43
6.7. Treatment of Overdose............................................................................................43
6.8. Concomitant Therapy..............................................................................................43
6.8.1. Rescue Medicine.........................................................................................44
7. DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL...........................................................................45
7.1. Discontinuation of Study Intervention ....................................................................45
7.1.1. Potential Cases of Decreased eGFR ...........................................................45
7.2. Participant Discontinuation/Withdrawal From the Study.......................................46
7.2.1. Withdrawal of Consent...............................................................................46
7.3. Lost to Follow Up ...................................................................................................47
8. STUDY ASSESSMENTS AND PROCEDURES...............................................................47
8.1. Efficacy Assessments..............................................................................................48
8.1.1. Participant Diary.........................................................................................48
8.1.2. COVID-19-Related Medical Visit Details..................................................48
8.1.3. Daily Signs and Symptoms of COVID-19 .................................................49
8.1.4. Oxygen Support Details..............................................................................49
8.1.5. PRO Assessments.......................................................................................49
8.1.5.1. Global Impression Questions ....................................................49
8.1.5.2. WPAI.........................................................................................49
8.1.5.3. EQ-5D-5L Scale........................................................................50


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8.2. Safety Assessments .................................................................................................50
8.2.1. Medical History ..........................................................................................50
8.2.2. Height and Weight......................................................................................50
8.2.3. Targeted Physical Examinations.................................................................51
8.2.4. Vital Signs ..................................................................................................51
8.2.5. Electrocardiograms.....................................................................................51
8.2.6. Clinical Safety Laboratory Assessments ....................................................52
8.2.7. Pregnancy Testing ......................................................................................52
8.3. Adverse Events, Serious Adverse Events, and Other Safety Reporting .................53
8.3.1. Time Period and Frequency for Collecting AE and SAE Information.......53
8.3.1.1. Reporting SAEs to Pfizer Safety...............................................54
8.3.1.2. Recording Nonserious AEs and SAEs on the CRF...................54
8.3.2. Method of Detecting AEs and SAEs ..........................................................54
8.3.3. Follow Up of AEs and SAEs......................................................................54
8.3.4. Regulatory Reporting Requirements for SAEs...........................................55
8.3.5. Environmental Exposure, Exposure During Pregnancy or 
Breastfeeding, and Occupational Exposure.....................................................55
8.3.5.1. Exposure During Pregnancy......................................................56
8.3.5.2. Exposure During Breastfeeding ................................................57
8.3.5.3. Occupational Exposure .............................................................58
8.3.6. Cardiovascular and Death Events...............................................................58
8.3.7. Disease-Related Events and/or Disease-Related Outcomes Not 
Qualifying as AEs or SAEs..............................................................................58
8.3.8. Adverse Events of Special Interest.............................................................58
8.3.8.1. Lack of Efficacy........................................................................58
8.3.9. Medical Device Deficiencies......................................................................58
8.3.10. Medication Errors.....................................................................................58
8.4. Pharmacokinetics ....................................................................................................59
8.5. Genetics...................................................................................................................60
8.5.1. Specified Genetics ......................................................................................60
8.6. Biomarkers ..............................................................................................................61
8.6.1. Specified Gene Expression (RNA) Research .............................................61
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8.6.3. Specified Metabolomic Research ...............................................................61
8.6.4. Viral Load Assessments .............................................................................61
8.7. Immunogenicity Assessments.................................................................................62
8.8. Health Economics ...................................................................................................62
9. STATISTICAL CONSIDERATIONS ................................................................................62
9.1. Statistical Hypotheses .............................................................................................63
9.1.1. Estimands....................................................................................................63
9.1.1.1. Primary Estimand/Co-Primary Estimands ................................63
9.1.1.2. Secondary Estimands ................................................................63
9.2. Analysis Sets ...........................................................................................................64
9.3. Statistical Analyses .................................................................................................65
9.3.1. General Considerations...............................................................................65
9.3.2. Primary Endpoint(s)/Estimand(s) Analysis ................................................66
9.3.3. Key Secondary Efficacy Endpoint(s)/Estimand(s) Analysis......................67
9.3.4. Secondary Endpoint(s)/Estimand(s) Analyses ...........................................68
9.3.6. Other Safety Analyses ................................................................................69
9.3.6.1. Laboratory.................................................................................69
9.3.6.2. Physical Examination and Vital Signs ......................................69
9.4. Interim Analyses .....................................................................................................70
9.5. Sample Size Determination.....................................................................................70
10. SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS..........................................................................................................72
10.1. Appendix 1: Regulatory, Ethical, and Study Oversight Considerations...............72
10.1.1. Regulatory and Ethical Considerations ....................................................72
10.1.1.1. Reporting of Safety Issues and Serious Breaches of the 
Protocol or ICH GCP.........................................................................72
10.1.2. Financial Disclosure .................................................................................73
10.1.3. Informed Consent Process ........................................................................73
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10.1.4. Data Protection .........................................................................................74
10.1.5. Committees Structure ...............................................................................74
10.1.5.1. Data Monitoring Committee ...................................................74
10.1.6. Dissemination of Clinical Study Data ......................................................75
10.1.7. Data Quality Assurance ............................................................................76
10.1.8. Source Documents....................................................................................78
10.1.9. Study and Site Start and Closure ..............................................................78
10.1.10. Publication Policy...................................................................................79
10.1.11. Sponsor’s Qualified Medical Personnel .................................................80
10.2. Appendix 2: Clinical Laboratory Tests .................................................................81
10.3. Appendix 3: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-Up, and Reporting .....................................................................82
10.3.1. Definition of AE .......................................................................................82
10.3.2. Definition of an SAE ................................................................................83
10.3.3. Recording/Reporting and Follow-Up of AEs and/or SAEs During 
the Active Collection Period............................................................................85
10.3.4. Reporting of SAEs....................................................................................88
10.4. Appendix 4: Contraceptive and Barrier Guidance ................................................90
10.4.1. Male Participant Reproductive Inclusion Criteria....................................90
10.4.2. Female Participant Reproductive Inclusion Criteria.................................90
10.4.3. Woman of Childbearing Potential ............................................................91
10.4.4. Contraception Methods.............................................................................92
10.5. Appendix 5: Genetics............................................................................................94
10.6. Appendix 6: Liver Safety: Suggested Actions and Follow-Up Assessments 
and Study Intervention Rechallenge Guidelines .......................................................95
10.7. Appendix 7: ECG Findings of Potential Clinical Concern ...................................97
10.8. Appendix 8: Prohibited Concomitant Medications That May Result in DDI.......99
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
10.11. Appendix 11: Protocol Amendment History.....................................................112
10.12. Appendix 12: Abbreviations .............................................................................119


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11. REFERENCES ................................................................................................................123
LIST OF TABLES
Table 1.
Protocol-Required Safety Laboratory Assessments .................................81
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 Increased Risk 
Of Progressing To Severe Illness.
Brief Title: A Phase 2/3 Efficacy and Safety Study of PF-07321332/Ritonavir in 
Nonhospitalized High 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 
increased risk of progressing 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 COVID-19 in 
nonhospitalized symptomatic 
adult participants with COVID-19 
who are at increased 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 
symptomatic COVID-19 who are at 
increased risk of progression to severe 
disease, who did not receive 
COVID-19 therapeutic mAb 
treatment and were treated ≤3 days 
after COVID-19 symptom onset. This
will be estimated without regard to
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 increased risk of 
progression to severe disease.
Incidence of TEAEs.
Incidence of SAEs and AEs leading 
to discontinuations.
Not applicable. 

To compare the efficacy of 
PF-07321332/ritonavir to placebo 
for the treatment of COVID-19 in 
nonhospitalized symptomatic 
adult participants with COVID-19 
who are at increased 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 
symptomatic COVID-19 who are at 
increased risk of progression to severe 


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Objectives
Endpoints
Estimands
disease and who did not receive 
COVID-19 therapeutic mAb 
treatment. 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 increased risk of 
progression to severe disease.
Time (days) to sustained alleviation 
of all targeted signs/symptoms 
through Day 28.
Proportion of participants with 
severe signs/symptoms attributed to 
COVID-19 through Day 28.
Time (days) to sustained resolution 
of all targeted signs/symptoms 
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.
The absolute difference in median 
time to sustained alleviation or 
resolution of symptoms for all 
nonhospitalized adult patients with 
COVID-19 who are at increased risk 
of progression to severe disease. This 
will be estimated irrespective of 
adherence to randomized treatment.

To compare 
PF-07321332/ritonavir to placebo 
for all-cause mortality in 
nonhospitalized symptomatic 
adult participants with COVID-19 
who are at increased risk of 
progression to severe disease.
Proportion of participants with death 
(all cause) through Week 24.

Not applicable.

To determine the PK of 
PF-07321332 in nonhospitalized 
symptomatic adult participants 
with COVID-19 who are at 
increased 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 symptomatic 
adult participants with COVID-19 
who are at increased risk of 
progression to severe disease.
Viral titers measured via RT-PCR in 
nasal swabs over time.

Not applicable.

To compare 
PF-07321332/ritonavir to placebo 
for COVID-19-related medical 
visits in nonhospitalized 
symptomatic adult participants 
with COVID-19 who are at 
increased risk of progression to 
severe disease.
Number of COVID-19 related 
medical visits through Day 28.

Not applicable

To compare 
PF-07321332/ritonavir to placebo 
for COVID-19-related 
hospitalizations in 
Number of days in hospital and ICU 
stay in participants with COVID-19 
related hospitalization.

Not applicable.


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Objectives
Endpoints
Estimands
nonhospitalized symptomatic 
adult participants with COVID-19 
who are at increased risk of 
progression to severe disease.
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 increased 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 and 
whether participants have received/are expected to receive COVID-19 therapeutic mAb 
treatment (yes/no) based on the site investigator’s assessment at the time of randomization.
Enrollment of participants who have received/are expected to receive COVID-19 therapeutic 
mAb treatment is expected to be approximately 20% and will be limited to approximately 
25% of participants. Enrollment of participants that had COVID-19 symptom onset >3 days 
prior to randomization is expected to be approximately 25% and will be limited to a total of 
approximately 1000 participants.
Number of Participants
Approximately 3000 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 of 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, 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 on an 
ongoing basis 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 60 participants have completed Day 10 of the study, at which 
point enrollment will be paused pending E-DMC review of the safety data. After 
review of the sentinel cohort, the frequency of safety reviews may be reduced 
subsequently based on E-DMC recommendations.

Proof-of-concept assessment: The E-DMC will review viral load data when 
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.

Interim analysis: A planned interim analysis for efficacy and futility will be done 
after approximately 45% of participants in the mITT analysis set complete the Day 28 
assessments (ie, 28 days after randomization). 
Statistical Methods
The cumulative proportion of participants hospitalized for the treatment of COVID-19 or 
dying during the first 28 days of the study will be estimated for each treatment group using 
the Kaplan-Meier method to take account of losses to follow-up and summarized graphically 
for each treatment group. The estimand is then the difference of the proportions in the 2 
groups and its 95% CI will be presented as well as the associated Wald test. For the 95% CI, 
the corresponding estimate of the standard error is computed using Greenwood’s formula.1
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 above primary analysis will also be conducted for the planned interim analysis. 
Two-sided 95% CI (adjusted for the planned interim analysis) and associated p-value for the 
null hypothesis of no difference between treatment groups will be presented. Significance 
level will be determined using the O’Brien-Fleming approach at the interim analysis and the 
final analysis. The overall significance level is set at 5% (2 sided).
The estimate of required sample size is based on data from the BLAZE-1 Phase 2/3 trial 
among participants with mild to moderate COVID-19 who were at high risk for progressing 
to severe COVID-19 and/or hospitalization at enrollment.2 During the 29-day period 
following enrollment, the proportion of placebo-treated participants with a 
COVID-19-related hospitalization/emergency department visit was 7% in the Phase 3 portion 
of the trial.3


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This study is designed to have 90% statistical power to show a difference of 3.5% in the 
proportion of participants hospitalized/dying that did not receive COVID-19 therapeutic mAb 
between the treatment arms (PF-07321332/ritonavir versus placebo), using a 2-sided Type I 
error rate of 5%. Based on the above study2, the proportion of hospitalization/death in the 
placebo arm is assumed to be 7%.
For a 2-sample proportion test, the sample size needed to detect this difference with 90% 
power at a 2-sided significance level of 5% was determined to be 1717 randomized 
participants.
Enrollment of participants that have received/are expected to received COVID-19 therapeutic 
mAb treatment is expected to be approximately 20% of participants and will be limited to 
approximately 25% of participants. Enrollment of participants that had COVID-19 symptom 
onset >3 days prior to randomization is expected to be approximately 25%, and will be 
limited to a total of approximately 1000 participants. Assuming a 5% dropout rate, the total 
sample size for this study will be approximately 3000 participants.
Study enrollment will be stopped after approximately 1717 participants are available for the 
primary analysis.
The primary estimand is the difference in proportions of patients experiencing COVID-19 
related hospitalization or death from any cause through Day 28 in nonhospitalized adult 
participants with COVID-19 who are at increased risk of progression to severe disease, who 
did not receive COVID-19 therapeutic mAb treatment and were treated ≤3 days after 
COVID-19 symptom onset. This will be estimated without regard to adherence to 
randomized treatment. 
1.2. Schema


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1.3. Schedule of Activities
The SoA table provides an overview of the protocol visits and procedures. Refer to the STUDY ASSESSMENTS AND 
PROCEDURES section of the protocol for detailed 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.
Screening Baseline
(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]

Targeted physical examinations 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 via an in-person 
visit.

Previously identified AEs (either by interview, 
physical exam, or other assessment) should be 
monitored to the extent possible if telemedicine is 
used. 

See Section 8.2.3 and Section 8.2.4.
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.
Screening Baseline
(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
Weight, height
X

Height may be self reported.

See Section 8.2.2.
ECG
X
X
X
X

Will be assessed for the first 60 participants 
(sentinel cohort). Further ECG monitoring may 
occur pursuant to E-DMC or FDA 
recommendation after the sentinel cohort safety 
review (Section 10.1.5.1).

See Section 8.2.5.
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 drawn at the 
previous study visit when laboratory assessments 
were performed. 
Blood chemistry
X
X
[X]
[X]
[X]
Other laboratory 
assessments
X
X
[X]
[X]
[X]


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Visit Identifier
Abbreviations used in this table 
may be found in Appendix 12.
Screening Baseline
(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

Abnormal laboratory values related to AEs should 
be followed until resolution. See Section 8.2.6 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 8.2.7.
FSH
X

FSH is to be performed 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 age 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 to randomization.

Refer to Section 5.1.
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 


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Visit Identifier
Abbreviations used in this table 
may be found in Appendix 12.
Screening Baseline
(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
swab will be self collected by the 
participant.
•
See Section 8.6.4.
 
 
 
 
 
 
 
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 for 
the participant to remain at the site.
•
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 anytime during 
the visit, even after study intervention has been 
administered.
•
Refer to Section 8.4.
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 
CCI
CCI
CCI


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Visit Identifier
Abbreviations used in this table 
may be found in Appendix 12.
Screening Baseline
(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
(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 as applicable.
Record supplemental oxygen 
requirements
X
X
X
X
X
X
X
X

See Section 8.1.4.
Study kit dispensed and 
participant instructed on its 
use
X
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 8.1.5.1.

Global impression questions will be answered 
every day from Day 1 through Day 28 after 
COVID-19 signs and symptom diary is completed. 

These additional questions will only be assessed in 
participants who enroll after the sentinel cohort 
(ie, the first 60 participants) as available.
WPAI
X
X
X
X

Will only be assessed in participants who enroll 
after the sentinel cohort (ie, the first 60 
participants) as available.

See Section 8.1.5.2.


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Visit Identifier
Abbreviations used in this table 
may be found in Appendix 12.
Screening Baseline
(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
EQ-5D-5L
X
X
X
X
X
X

Will only be assessed in participants who enroll 
after the sentinel cohort (ie, the first 60 
participants) as available.

See Section 8.1.5.3. 
Staff review of study diary
X
X
X
X
X
X
X
X

See Section 8.1.1.
Participant-completed study 
intervention log
Day 1 through Day 5/6 

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.
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 


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Visit Identifier
Abbreviations used in this table 
may be found in Appendix 12.
Screening Baseline
(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
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.

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 must be conducted in-person for the first 60 participants (sentinel cohort) and thereafter only if a PK sample (not using Tasso) is collected by an HCP or if ECG is 
required.

Day 3 and Day 5 visits should 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 converted to an in-person visit at the discretion of the 
investigator.

Day 14 visit must be conducted in-person for the first 60 participants (sentinel cohort). Thereafter the visit may be conducted in-person or by telemedicine. After the sentinel 
cohort the visit must be conducted in person only if ECG is required.

Day 34 visit 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.


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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 
increased risk of progressing 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 Concern4 on 30 January 2020 and further characterized 
the disease outbreak as a pandemic on 11 March 2020.5 As of June 2021, at least 171,776,210 
cases have been confirmed worldwide, and at least 3,693,623 deaths have occurred.6
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,7 patients who are hospitalized with COVID-19 may have significant morbidity and 
mortality,8,9 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.10-13 Moreover, 
other comorbidities, such as hypertension, obesity, and diabetes, as well as older age and 
male sex increase the risk for worse outcomes.14
Although there are symptomatic and/or supportive treatments for COVID-19, few antiviral 
drugs are available or in late-stage development to help treat COVID-19 in patients with mild 
to moderate COVID-19. Existing compounds, such as hydroxychloroquine and 
lopinavir/ritonavir, have been evaluated as potential treatment options for COVID-19, but 
have not demonstrated benefit or efficacy beyond the SOC.15-17 The FDA has approved IV 
remdesivir,18 an antiviral drug with activity against SARS-CoV-2, for hospitalized patients 
with COVID-19. However, remdesivir monotherapy may not be sufficient in all subsets of 
patients19 across the COVID-19 spectrum or has shown modest effects.20,21 Favipiravir is 
currently under investigation for its activity against SARS-CoV-2 due to its broad-spectrum 
activity against various RNA viruses22,23 and has been approved in India and Russia to treat 
mild to moderate COVID-19.24 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.22
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.3,25,26


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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.
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).27 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.28
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 


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Page 24
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.
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.
2.3. Benefit/Risk Assessment
More detailed information about the known and expected benefits and risks and reasonably 
expected AEs of PF-07321332 may be found in the investigator’s brochure, which is the 
SRSD for this study. The SRSD for ritonavir is the USPI for NORVIR.


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Page 25
2.3.1. Risk Assessment
Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
Study Intervention(s) PF-07321332
Emesis
Sporadic emesis was observed at ≥100 mg/kg/day of 
PF-07321332 in the 15-day NHP toxicology study.
AEs will be monitored and participants may 
receive antiemetics.
Hemodynamic and inflammatory effects
Low level inflammation (increase in fibrinogen) in 
15-day NHP toxicology study and changes in 
platelets, globulin and albumin/globulin ratio and 
coagulation system (increase in PT and aPTT) in 
14-day rat toxicology study.
In addition to vital signs and close observation for 
AEs, fibrinogen, platelets, D-dimer, PT and aPTT, 
albumin, and total protein will also be monitored.
Refer to Section 8.3.8.
TSH elevations
TSH changes observed with the administration of 
PF-07321332 during study C4671001
TSH and T4 (free) will be monitored.
Refer to Section 8.3.8.
Study Intervention(s): Ritonavir
Gastrointestinal disturbances (including 
diarrhea, nausea, vomiting and abdominal pain)
Frequently reported adverse reaction in 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.


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


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2.3.2. Benefit Assessment
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. 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 increased 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 and 
futility at the time of the planned interim analysis according to the E-DMC Charter.
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 
COVID-19 in nonhospitalized 
symptomatic adult participants 
with COVID-19 who are at 
increased 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 
symptomatic COVID-19 who are at 
increased risk of progression to 
severe disease ,who did not receive 
COVID-19 therapeutic mAb 
treatment and were treated ≤3 days 
after COVID-19 symptom onset. This
will be estimated without regard to
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 increased 
Incidence of TEAEs.
Incidence of SAEs and AEs leading 
to discontinuations.
Not applicable. 


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Objectives
Endpoints
Estimands
risk of progression to severe 
disease.

To compare the efficacy of 
PF-07321332/ritonavir to
placebo for the treatment of 
COVID-19 in nonhospitalized
symptomatic adult participants 
with COVID-19 who are at 
increased 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 
symptomatic COVID-19 who are at 
increased risk of progression to 
severe disease and who did not 
receive COVID-19 therapeutic mAb 
treatment. 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 increased 
risk of progression to severe 
disease.
Time (days) to sustained alleviation 
of all targeted signs/symptoms 
through Day 28.
Proportion of participants with 
severe signs/symptoms attributed to 
COVID-19 through Day 28.
Time (days) to sustained resolution 
of all targeted signs/symptoms 
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.
The absolute difference in median 
time to sustained alleviation or 
resolution of symptoms for all non-
hospitalized adult patients with 
COVID-19 who are at increased risk 
of progression to severe disease. This 
will be estimated irrespective of 
adherence to randomized treatment.

To compare 
PF-07321332/ritonavir to 
placebo for all-cause mortality in 
nonhospitalized symptomatic 
adult participants with 
COVID-19 who are at increased 
risk of progression to severe 
disease.
Proportion of participants with 
death (all cause) through Week 24.

Not applicable.

To determine the PK of 
PF-07321332 in nonhospitalized 
symptomatic adult participants 
with COVID-19 who are at 
increased 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 symptomatic 
adult participants with 
COVID-19 who are at increased 
risk of progression to severe 
disease.
Viral titers measured via RT-PCR in 
nasal swabs over time.

Not applicable.


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Objectives
Endpoints
Estimands

To compare 
PF-07321332/ritonavir to 
placebo for COVID-19-related 
medical visits in nonhospitalized 
symptomatic adult participants 
with COVID-19 who are at 
increased risk of progression to 
severe disease.
Number of COVID-19 related 
medical visits through Day 28.

Not applicable.

To compare 
PF-07321332/ritonavir to 
placebo for COVID-19-related 
hospitalizations in 
nonhospitalized symptomatic 
adult participants with 
COVID-19 who are at increased 
risk of progression to severe 
disease.
Number of days in hospital and ICU 
stay in participants with COVID-19 
related hospitalization.

Not applicable.
4. STUDY DESIGN
4.1. Overall Design
This Phase 2/3, randomized, double-blind, placebo-controlled study in approximately 
3000 symptomatic 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 randomized (1:1) 
to receive PF-07321332 and ritonavir or placebo orally q12h for 5 days (10 doses total). 
Randomization will be stratified by geographic region and by whether participants have 
received/are expected to receive treatment with COVID-19 therapeutic mAbs based on the 
site investigator’s assessment at time of randomization. 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.  
Enrollment of participants who have received/are expected to receive COVID-19 therapeutic 
mAb treatment is expected to be approximately 20% and will be limited to approximately 
25% of participants. Enrollment of participants that had COVID-19 symptom onset >3 days 
prior to randomization is expected to be approximately 25% and will be limited to a total of 
approximately 1000 participants.
The total study duration is up to 24 weeks and includes a screening period of no more than 
48 hours, 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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An independent E-DMC will review unblinded data to ensure the safety of participants on an 
ongoing basis 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 60 participants have completed Day 10 of the study, at which 
point enrollment will be paused pending E-DMC review of the safety data. After 
review of the sentinel cohort, the frequency of safety reviews may be reduced 
subsequently based on E-DMC recommendations.

Proof-of-concept assessment: The E-DMC will review viral load data when 
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.

Interim analysis: A planned interim analysis for efficacy and futility with a sample 
size re-estimation will be done after approximately 45% of participants in the mITT 
analysis set complete the Day 28 assessments (ie, 28 days after randomization). 
Subsequent to the planned interim analysis, there will be 2 analyses for reporting the results 
of this study. The primary analysis will be performed after all participants have completed 
the Day 34 visit. The follow-up analysis will be performed after all participants have 
completed the Week 24 visit. 
4.2. Scientific Rationale for Study Design
This study evaluates safety and the potential effect of an investigational agent on reducing 
COVID-19 related hospitalizations and death (all cause), and, as a secondary endpoint, the 
duration and severity of COVID-19-associated symptoms because participants are 
symptomatic upon entry to this study. 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 hospitalizations and/or death in high-risk participants, as well as 
reducing SARS CoV-2 shedding on NP swabs and time to symptom resolution.3,25,26 Efficacy 
assessments (including participant reported COVID-19 symptoms and severity, 
COVID-19-related medical visits, and vital status) 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. Placebo was selected 
as the comparator because there is no- globally approved SoC treatment for this patient 
population as of June 2021. Participants in either treatment group may receive SoC therapy 
so long as it is not prohibited under Section 5.1 or Appendix 8. Because the NIH COVID-19 
Treatment Guidelines panel29 recommends use of the available EUA mAb therapies for the 
treatment of outpatients with mild to moderate COVID-19 who are high risk of clinical 


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progression, participants enrolled in the US (and other countries, depending on availability), 
may receive COVID-19 therapeutic mAb as SoC treatment. Randomization will be stratified 
at entry based by geographic region and by whether participants have received/are expected 
to receive a COVID-19 therapeutic mAb treatment (yes/no).
Because of limited in-human dosing before this Phase 2/3 study, an early safety analysis 
(with enrollment pause) will be conducted by the E-DMC following enrollment of a sentinel 
cohort of 60 participants. Thereafter, if no clinically significant safety signals are identified, 
enrollment will resume with the E-DMC conducting frequent safety reviews as outlined in 
the E-DMC Charter. 
4.2.1. Diversity of Study Population
Reasonable attempts will be made to enroll participants to ensure the study population is 
representative of the patient population that will be treated with PF-07321332/ritonavir in 
clinical practice.
4.2.2. Choice of Contraception/Barrier Requirements 
Studies to evaluate the developmental toxicity of PF-07321332 have not been conducted. 
Therefore, the use of a highly effective method of contraception is required (see Appendix 4).
4.2.3. Collection of Retained Research Samples
Retained Research Samples will be collected and stored for further analyses which may, for 
example, provide greater understanding of the study intervention.
4.3. Justification for Dose
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.


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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.
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 
prescreener for study recruitment purposes will include collection of information, that 
reflects the enrollment of a diverse participant population including, where permitted under 
local regulations, age, sex, 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.


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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. 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. Has at least 1 characteristic or underlying medical condition associated with an 
increased risk of developing severe illness from COVID-19 including:

≥60 years of age;

BMI >25;

Current smoker (cigarette smoking within the past 30 days) and history of at 
least 100 lifetime cigarettes;

Immunosuppressive disease (eg, bone marrow or organ transplantation or 
primary immune deficiencies) OR prolonged use of immune-weakening 
medications:
o
Has received corticosteroids equivalent to prednisone ≥20 mg daily for 
at least 14 consecutive days within 30 days prior to study entry.
o
Has received treatment with biologics (eg, infliximab, ustekinumab), 
immunomodulators (eg, methotrexate, 6MP, azathioprine) or cancer 
chemotherapy within 90 days prior to study entry.
o
HIV infection with CD4 cell count <200 mm3 and a viral load less than 
400 copies/mL

Chronic lung disease (if asthma, requires daily prescribed therapy);

Known diagnosis of hypertension;

CVD, defined as history of any of the following: myocardial infarction, 
stroke, TIA, HF, angina with prescribed nitroglycerin, CABG, PCI, carotid 
endarterectomy, and aortic bypass;

Type 1 or Type 2 diabetes mellitus;

CKD provided the participant does not meet Exclusion Criterion 5;

Sickle cell disease;


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
Neurodevelopmental disorders (eg, cerebral palsy, Down’s syndrome) or other 
conditions that confer medical complexity (eg, genetic or metabolic 
syndromes and severe congenital anomalies);

Active cancer, other than localized skin cancer, including those requiring 
treatment as long as the treatment is not among the prohibited medications 
that must be administered/continued during the trial period;

Medical-related technological dependence (eg, CPAP [not related to 
COVID-19]).
5. Participants who are willing and able to comply with all scheduled visits, treatment 
plan, laboratory tests, lifestyle considerations, and other study procedures.
Informed Consent:
6. Capable of giving signed informed consent as described in Appendix 1, which 
includes compliance with the requirements and restrictions listed in the ICD and in 
this protocol.
5.2. Exclusion Criteria
Participants are excluded from the study if any of the following criteria apply:
Medical Conditions:
1. History of hospitalization for the medical treatment of COVID-19.
2. 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.)
3. 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.
4. 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.
5. Receiving dialysis or have known moderate to severe renal impairment
[ie, eGFR <45 mL/min/1.73 m2 within 6 months of the screening visit, using the 
serum creatinine-based CKD-EPI formula].30
6. Known HIV infection with a viral load greater than 400 copies/mL or taking 
prohibited medications for HIV treatment (from known medical history within past 
6 months of the screening visit) (Appendix 8).


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7. Suspected or confirmed concurrent active systemic infection other than COVID-19 
that may interfere with the evaluation of response to the study intervention.
8. Any comorbidity requiring hospitalization and/or surgery within 7 days prior to study 
entry, or that is considered life threatening within 30 days prior to study entry, as 
determined by the investigator.
9. History of hypersensitivity or other contraindication to any of the components of the 
study intervention, as determined by the investigator.
10. Other medical or psychiatric condition including recent (within the past year) or 
active suicidal ideation/behavior or laboratory abnormality that may increase the risk 
of study participation or, in the investigator’s judgment, make the participant 
inappropriate for the study.
Prior/Concomitant Therapy:
11. Current or expected use of any medications or substances that are highly dependent 
on CYP3A4 for clearance and for which elevated plasma concentrations may be 
associated with serious and/or life-threatening events during treatment and for 4 days 
after the last dose of PF-07321332/ritonavir (See Appendix 8).
12. Concomitant use of any medications or substances that are strong inducers of 
CYP3A4 are prohibited within 28 days prior to first dose of PF-07321332/ritonavir 
and during study treatment (see Appendix 8).
13. Has received or is expected to receive convalescent COVID-19 plasma.
14. Has received or is expected to receive any dose of a SARS-CoV-2 vaccine before the 
Day 34 visit.
15. Is unwilling to abstain from participating in another interventional clinical study with 
an investigational compound or device, including those for COVID-19 therapeutics, 
through the long-term follow-up visit.
Prior/Concurrent Clinical Study Experience:
16. Previous administration with any investigational drug or vaccine within 30 days (or as 
determined by the local requirement) or 5 half-lives preceding the first dose of study 
intervention used in this study (whichever is longer). 
17. Known prior participation in this trial or other trial involving PF-07321332.


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Diagnostic Assessments:
18. 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);

Absolute neutrophil count <1000/mm3.

GFR <45 mL/min/1.73 m2 within 6 months of the screening visit, using the serum 
creatinine-based CKD-EPI formula30
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.
19. Oxygen saturation of <92% on room air obtained at rest within 24 hours prior to 
randomization.
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:
20. Females who are pregnant or breastfeeding.
21. Investigator site staff or Pfizer employees directly involved in the conduct of the 
study, site staff otherwise supervised by the investigator, and their respective family 
members. 
5.3. Lifestyle Considerations
5.3.1. Contraception
The investigator or his or her designee, in consultation with the participant, will confirm that 
the participant has selected an appropriate method of contraception for the individual 
participant and his or her partner(s) from the permitted list of contraception methods (see 
Appendix 4, Section 10.4.4) and will confirm that the participant has been instructed in its 
consistent and correct use. At time points indicated in the SoA, the investigator or designee 
will inform the participant of the need to use highly effective contraception consistently and 
correctly and document the conversation and the participant’s affirmation in the participant’s 
chart (participants need to affirm their consistent and correct use of at least 1 of the selected 
methods of contraception) considering that their risk for pregnancy may have changed since 
the last visit. In addition, the investigator or designee will instruct the participant to call 


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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.
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 
(or PF-07321332 100 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, 100 mg 
0 mg
100 mg
0 mg


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Study Interventions(s)
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 
country 
requirement.
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 
per country 
requirement.
Current/Former 
Name(s) or Alias(es)
PF-07321332
NA
ritonavir
NA
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 


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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. 
For the sentinel cohort only (Phase 2): Some participants in this sentinel cohort may 
receive PF-07321332 100 mg tablets or placebo for PF-07321332. In this instance, 
PF-07321332 100 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 100 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:

3 tablets of PF-07321332 100 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 
(or 3 tablets of PF-07321332 100 mg tablets, if sentinel cohort) or placebo and 1 capsule of 
ritonavir 100 mg or placebo at the same time. 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 
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 


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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 
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.


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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.
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 at a minimum 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. This team will only be unblinded at the group level and not have access to 
individual participant assignments.


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Unless efficacy is demonstrated at an interim analysis, 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.
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/placebo or ritonavir/placebo alone for 2 
consecutive doses.

Participants who have an overall study intervention compliance of <80% or >115%. 


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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/placebo greater than 900 mg or ritonavir/placebo 
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).
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 


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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.
In countries in which mAb are authorized or approved and considered the SoC, all 
participants will be referred locally for treatment with mAb as deemed appropriate by the 
investigator and local guidelines and this referral should be documented. Notwithstanding, 
this mAb treatment is not mandatory for participation in this study.
Prohibited During the Study
Participants should not receive 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 cytochrome P450 (CYP) 3A4. 
Therefore, concomitant use of any medications or substances that are strong inducers of 
CYP3A4 are prohibited within 28 days prior to dosing of study intervention and during study 
treatment.
Additionally, PF-07321332 and ritonavir are inhibitors of CYP3A4. Therefore, medications 
highly dependent on CYP3A4 for clearance and for which elevated plasma concentrations 
may be associated with serious and/or life-threatening events are not permitted during dosing 
of PF-07321332/ritonavir and for 4 days after the last dose of PF-07321332/ritonavir. 
Because ritonavir 100 mg every 12 hours is being used to boost the exposure of 
PF-07321332, no additional DDIs are expected other than those associated with ritonavir 
100 mg q12h, based on in vitro assessments 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 of Grade 3 severity or greater and considered by the investigator to be related to 
study intervention;

SAE considered by the investigator to be related to study intervention;

Requirement for prohibited concomitant medication;

Death;

Pregnancy;

Study terminated by sponsor;

Withdrawal by participant or legally authorized representative

Miss more than 2 consecutive doses of study intervention.
In the event a participant is hospitalized, study intervention may continue to be administered, 
as feasible, and based on medical judgement of the investigator.
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/1.73m2 the participant will be instructed to discontinue 
any remaining study intervention doses as soon as study staff become aware of the eGFR 
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 Section 7.2.1) 
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. There will be an additional optional up to 4 mL of blood 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 administration, and 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, 24h), 
thus providing an accurate representation of the participant’s experience at that time. The 
participant is able to make revisions to incorrect entries before pressing the save or submit 
button. In the event that a participant becomes aware of an error in data after the entry is 
saved, a change to the diary data may only be made by the investigator submitting a data 
clarification form. Data reported in the participant diary will be transferred electronically to a 
third-party vendor, where they will be available for review by investigators and the sponsor 
or delegate at all times via an internet-based portal.
8.1.2. COVID-19-Related Medical Visit Details
Details of participants’ COVID-19-related medical visits (ie, hospitalization, practitioner’s 
office, home healthcare services, telemedicine, urgent care, emergency room ≤24h, extended 


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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 10).31 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. 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.31
8.1.5.2. WPAI
COVID-19 impacts manual and office-based work, and results in missed work due to illness 
or quarantine and loss in of productivity.32 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 


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disease on absenteeism, presenteeism, and overall productivity in a manner that can also be 
monetized.33
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 = 
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.33 The WPAI-COVID-19 will be completed during site visits, as specified 
in the SoA.
8.1.5.3. 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 health technologies assessment 
(HTA).34-36 Recently, a version was developed called EQ-5D-5L with 5 response levels on 
each dimension compared to the 3 response levels in the Euroquol Quality of Life 
5-Dimension 3-Level Scale (EQ-5D-3L).34-40
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.34,36,38,39 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.37,41 The EQ-5D-5L 
should be completed as described in the Schedule of Activities.
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 
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.


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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. Electrocardiograms
Standard 12-lead ECGs utilizing limb leads (with a 10 second rhythm strip) should be 
collected at times specified in the SoA section of this protocol using an ECG machine that 
automatically calculates the heart rate and measures PR, QT, and QTc intervals and QRS 
complex. Alternative lead placement methodology using torso leads (eg, Mason-Likar) 
should not be used given the potential risk of discrepancies with ECGs acquired using 
standard limb lead placement. All scheduled ECGs should be performed after the participant 
has rested quietly for at least 10 minutes in a supine position. Triplicate 12-lead ECGs 
obtained at a minimum at baseline/Day 1, should be obtained approximately 2 to 4 minutes 
apart.
ECG data may be submitted to a central laboratory for measurement. The final ECG report 
from the central laboratory should be maintained in the participant’s source documentation 
and be the final interpretation of the ECG recording. Any clinically significant changes from 
the baseline/Day 1 ECG may potentially be AEs (Appendix 7) and should be evaluated 
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If a) a postdose QTcF interval remains ≥60 msec from the baseline and is >450 msec; or 
b) an absolute QT value is ≥500 msec for any scheduled ECG for greater than 4 hours (or 
sooner, at the discretion of the investigator); or c) QTcF intervals get progressively longer, 
the participant should undergo continuous ECG monitoring.
In some cases, it may be appropriate to repeat abnormal ECGs to rule out improper lead 
placement as contributing to the ECG abnormality. It is important that leads be placed in the 
same positions each time in order to achieve precise ECG recordings. If a machine read QTc 
value is prolonged, as defined above, repeat measurements may not be necessary if a 
qualified medical provider’s interpretation determines that the QTcF values are in the 
acceptable range.
ECG values of potential clinical concern are listed in Appendix 7.
8.2.6. Clinical Safety Laboratory Assessments 
See Appendix 2 for the list of clinical safety laboratory tests to be performed and the SoA for 
the timing and frequency. All protocol required laboratory assessments, as defined in 
Appendix 2, must be conducted in accordance with the laboratory manual and the SoA. 
Unscheduled clinical laboratory measurements may be obtained at any time during the study 
to assess any perceived safety issues.  
Laboratory safety parameters will be graded according to the Division of AIDS (DAIDS) 
Table for Grading the Severity of Adult and Pediatric Adverse Events42, version 2.1. The 
investigator must review the laboratory report, document this review, and record any 
clinically relevant changes occurring during the study in the AE section of the CRF. 
Clinically significant abnormal laboratory findings are those which are not associated with 
the underlying disease, unless judged by the investigator to be more severe than expected for 
the participant's condition.
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.
8.2.7. 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 


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tests may also be repeated if requested by IRBs/ ECs or if required by local regulations. If a 
urine test cannot be confirmed as negative (eg, an ambiguous result), a serum pregnancy test 
is required. In such cases, the participant must be excluded if the serum pregnancy result is 
positive.
If a participant requiring pregnancy testing cannot visit a local laboratory, a home urine 
pregnancy testing kit with a sensitivity of at least 25 mIU/mL may be used by the participant 
to perform the test at home, if compliant with local regulatory requirements. The pregnancy 
test outcome should be documented in the participant’s source documents/medical records. If 
the pregnancy test is positive, the EDP should be reported (Section 8.3.5.1). Confirm that the 
participant is adhering to the contraception method(s) required in the protocol.
8.3. Adverse Events, Serious Adverse Events, and Other Safety Reporting
The definitions of an AE and an SAE can be found in Appendix 3.
AEs may arise from symptoms or other complaints reported to the investigator by the 
participant (or, when appropriate, by a caregiver, surrogate, or the participant's legally 
authorized representative), or they may arise from clinical findings of the Investigator or 
other healthcare providers (clinical signs, test results, etc.).
The investigator and any qualified designees are responsible for detecting, documenting, and 
recording events that meet the definition of an AE or SAE and remain responsible to pursue 
and obtain adequate information both to determine the outcome and to assess whether the 
event meets the criteria for classification as an SAE or caused the participant to discontinue 
the study intervention (see Section 7.1). 
During the active collection period as described in Section 8.3.1, each participant will be 
questioned about the occurrence of AEs in a nonleading manner.
In addition, the investigator may be requested by Pfizer Safety to obtain specific follow up 
information in an expedited fashion.
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.


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If the participant withdraws from the study and also withdraws consent for the collection of 
future information, the active collection period ends when consent is withdrawn.
If a participant permanently discontinues or temporarily discontinues study intervention 
because of an AE or SAE, the AE or SAE must be recorded on the CRF and the SAE 
reported using the CT SAE Report Form.
Investigators are not obligated to actively seek information on AEs or SAEs after the 
participant has concluded study participation. However, if the investigator learns of any SAE, 
including a death, at any time after a participant has completed the study, and he/she 
considers the event to be reasonably related to the study intervention, the investigator must 
promptly report the SAE to Pfizer using the CT SAE Report Form.
8.3.1.1. Reporting SAEs to Pfizer Safety
All SAEs occurring in a participant during the active collection period as described in 
Section 8.3.1 are reported to Pfizer Safety on the CT SAE Report Form immediately upon
awareness and under no circumstance should this exceed 24 hours, as indicated in 
Appendix 3. The investigator will submit any updated SAE data to the sponsor within 
24 hours of it being available.
8.3.1.2. Recording Nonserious AEs and SAEs on the CRF
All nonserious AEs and SAEs occurring in a participant during the active collection period, 
which begins after obtaining informed consent as described in Section 8.3.1, will be recorded 
on the AE section of the CRF.
The investigator is to record on the CRF all directly observed and all spontaneously reported 
AEs and SAEs reported by the participant.
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 


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and illnesses, must be provided. In the case of a participant death, a summary of available 
autopsy findings must be submitted as soon as possible to Pfizer Safety. 
Further information on follow up procedures is given in Appendix 3.
8.3.4. Regulatory Reporting Requirements for SAEs
Prompt notification by the investigator to the sponsor of an SAE is essential so that legal 
obligations and ethical responsibilities toward the safety of participants and the safety of a 
study intervention under clinical investigation are met.
The sponsor has a legal responsibility to notify both the local regulatory authority and other 
regulatory agencies about the safety of a study intervention under clinical investigation. The 
sponsor will comply with country-specific regulatory requirements relating to safety 
reporting to the regulatory authority, IRBs/ECs, and investigators.
Investigator safety reports must be prepared for SUSARs according to local regulatory 
requirements and sponsor policy and forwarded to investigators as necessary.
An investigator who receives SUSARs or other specific safety information (eg, summary or 
listing of SAEs) from the sponsor will review and then file it along with the SRSD(s) for the 
study and will notify the IRB/EC, if appropriate according to local requirements.
8.3.5. Environmental Exposure, Exposure During Pregnancy or Breastfeeding, and 
Occupational Exposure
Environmental exposure, occurs when a person not enrolled in the study as a participant 
receives unplanned direct contact with or exposure to the study intervention. Such exposure 
may or may not lead to the occurrence of an AE or SAE. Persons at risk for environmental 
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.


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8.3.5.1. Exposure During Pregnancy
An EDP occurs if: 

A female participant is found to be pregnant while receiving or after discontinuing 
study intervention. 

A male participant who is receiving or has discontinued study intervention exposes a 
female partner prior to or around the time of conception.

A female is found to be pregnant while being exposed or having been exposed to 
study intervention due to environmental exposure. Below are examples of 
environmental EDP:  

A female family member or healthcare provider reports that she is pregnant after 
having been exposed to the study intervention by ingestion.

A male family member or healthcare provider who has been exposed to the study 
intervention by ingestion then exposes his female partner prior to or around the 
time of conception.
The investigator must report EDP to Pfizer Safety within 24 hours of the investigator’s 
awareness, irrespective of whether an SAE has occurred. The initial information submitted 
should include the anticipated date of delivery (see below for information related to 
termination of pregnancy). 

If EDP occurs in a participant or a participant’s partner, the investigator must report 
this information to Pfizer Safety on the CT SAE Report Form and an EDP 
Supplemental Form, regardless of whether an SAE has occurred. Details of the 
pregnancy will be collected after the start of study intervention and until a minimum
of 28 calendar days after the last administration of study intervention.

If EDP occurs in the setting of environmental exposure, the investigator must report 
information to Pfizer Safety using the CT SAE Report Form and EDP Supplemental 
Form. Since the exposure information does not pertain to the participant enrolled in 
the study, the information is not recorded on a CRF; however, a copy of the 
completed CT SAE Report Form is maintained in the investigator site file.
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).


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Abnormal pregnancy outcomes are considered SAEs. If the outcome of the pregnancy meets 
the criteria for an SAE (ie, ectopic pregnancy, spontaneous abortion, intrauterine fetal 
demise, neonatal death, or congenital anomaly in a live-born baby, a terminated fetus, an 
intrauterine fetal demise, or a neonatal death), the investigator should follow the procedures 
for reporting SAEs. Additional information about pregnancy outcomes that are reported to 
Pfizer Safety as SAEs follows: 

Spontaneous abortion including miscarriage and missed abortion;

Neonatal deaths that occur within 1 month of birth should be reported, without regard 
to causality, as SAEs. In addition, infant deaths after 1 month should be reported as 
SAEs when the investigator assesses the infant death as related or possibly related to 
exposure to the study intervention. 
Additional information regarding the EDP may be requested by the sponsor. Further 
follow-up of birth outcomes will be handled on a case-by-case basis (eg, follow-up on 
preterm infants to identify developmental delays). In the case of paternal exposure, the 
investigator will provide the participant with the Pregnant Partner Release of Information 
Form to deliver to his partner. The investigator must document in the source documents that 
the participant was given the Pregnant Partner Release of Information Form to provide to his 
partner.
8.3.5.2. Exposure During Breastfeeding
An exposure during breastfeeding occurs if: 

A female participant is found to be breastfeeding while receiving or after 
discontinuing study intervention.

A female is found to be breastfeeding while being exposed or having been exposed to 
study intervention (ie, environmental exposure). An example of environmental 
exposure during breastfeeding is a female family member or healthcare provider who 
reports that she is breastfeeding after having been exposed to the study intervention 
by ingestion.  
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.


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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.
All AESIs must be reported as an AE or SAE following the procedures described in 
Sections 8.3.1 through 8.3.4. An AESI is to be recorded as an AE or SAE on the CRF. In 
addition, an AESI that is also an SAE must be reported using the CT SAE Report Form.
8.3.8.1. Lack of Efficacy
The investigator must report signs, symptoms, and/or clinical sequelae resulting from lack of 
efficacy. Lack of efficacy or failure of expected pharmacological action is reportable to 
Pfizer Safety only if associated with an SAE.  
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.


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Safety Event
Recorded on the CRF
Reported on the CT SAE Report 
Form to Pfizer Safety Within 
24 Hours of Awareness
Medication errors All (regardless of whether 
associated with an AE)
Only if associated with an SAE
Medication errors include:

Medication errors involving participant exposure to the study intervention;

Potential medication errors or uses outside of what is foreseen in the protocol that do 
or do not involve the study participant.

The administration of expired study intervention

The administration of an incorrect study intervention

The administration of an incorrect dosage

The administration of study intervention that has undergone temperature excursion 
from the specified storage range, unless it is determined by the sponsor that the study 
intervention under question is acceptable for use

The administration of study intervention consistent with the medication error 
descriptions in Section 6.4.
Such medication errors occurring to a study participant are to be captured on the medication 
error page of the CRF, which is a specific version of the AE page.
In the event of a medication dosing error, the sponsor should be notified within 24 hours.
Whether or not the medication error is accompanied by an AE, as determined by the 
investigator, the medication error is recorded on the medication error page of the CRF and, if 
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 


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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. 
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.


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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
 
 
 
 
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 
CCI
CCI
C
C
I


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(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 
is outlined here and further detailed in a SAP, which will be maintained by the sponsor. The 
SAP may modify what is outlined in the protocol where appropriate; however, any major 
modifications of the primary endpoint definitions or their analyses will also be reflected in a 
protocol amendment.
CCI


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9.1. Statistical Hypotheses
The primary hypothesis to be tested is whether or not there is a difference in proportion of 
participants with COVID-19 related hospitalization (as defined in Section 8.1.2) or death 
from any cause through Day 28 between PF-07321332/ritonavir and placebo. The statistical 
hypothesis is as follows:
Where π PF-07321332 and πplacebo are the proportion of participants with hospitalization or death 
through Day 28. 
Following the positive test of the primary endpoint, sequential testing will be performed for 
the following 2 secondary endpoints:
1. Proportion of participants with COVID-19 related hospitalization or death from any 
cause through Day 28 who did not receive COVID-19 therapeutic mAb treatment, 
regardless of their onset of COVID-19 related signs and symptoms.
2. Time (days) to sustained alleviation of all targeted signs/symptoms through Day 28.
Other secondary endpoints will be subsequently tested following the Hochberg procedure.43
9.1.1. Estimands
9.1.1.1. Primary Estimand/Co-Primary Estimands
The primary estimand is the difference in proportions of patients experiencing 
COVID-19-related hospitalization or death from any cause through Day 28 in 
nonhospitalized adult participants with symptomatic COVID-19 who are at increased risk of 
progression to severe disease (as defined in Section 5.1), who did not receive COVID-19 
therapeutic mAb treatment, and were treated ≤3 days after COVID-19 symptom onset. This 
will be estimated without regard to adherence to randomized treatment.
9.1.1.2. Secondary Estimands
The estimand associated with the key secondary efficacy objective 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 symptomatic COVID-19 who 
are at increased risk of progression to severe disease and who did not receive COVID-19 
therapeutic mAb treatment. This will be estimated without regard to adherence to 
randomized treatment.
The estimand associated with the secondary efficacy objective regarding the duration and 
severity of signs and symptoms is the absolute difference in median time to sustained 
Ho:   πPF-7321332 - πplacebo = 0
versus 
(1)
Ha:  π PF-7321332 - πplacebo ്0


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alleviation or resolution of symptoms for all nonhospitalized adult patients with 
COVID-19 who are at increased risk of progression to severe disease. This will be estimated 
irrespective of adherence to randomized treatment.
The hospitalization/death rate through Day 28 is considered the main clinical outcome 
measure and signs/symptom duration is considered key secondary for this study and so 
estimands for these measures are presented. Estimands for the other outcome measures that 
are considered supportive of the primary outcome measures and of the sign/symptoms 
duration and severity outcome measure are not presented.
9.2. Analysis Sets
For purposes of analysis, the following analysis sets are defined:
Participant Analysis Set
Description
Full Analysis Set (FAS)
All participants randomly assigned to study intervention.
Safety Analysis Set 
(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.
Modified Intent-To-Treat 
(mITT)
All participants randomly assigned to study intervention, 
who take at least 1 dose of study intervention, with at least 
1 postbaseline visit through Day 28, who at baseline did 
not receive nor were expected to receive COVID-19 
therapeutic mAb treatment, and 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-
Treat1 (mITT1)
All participants randomly assigned to study intervention, 
who take at least 1 dose of study intervention, with at least 
1 postbaseline visit through Day 28 and who at baseline 
did not receive nor were expected to receive COVID-19 
therapeutic mAb treatment. Participants will be analyzed 
according to the study intervention to which they were 
randomized.
Modified Intent-To-
Treat2 (mITT2)
All participants randomly assigned to study intervention, 
who take at least 1 dose of study intervention, and with at 
least 1 postbaseline visit through Day 28. Participants will 
be analyzed according to the study intervention to which 
they were randomized.
Per-Protocol (PP)
All participants in the mITT set without important protocol 
deviations considered to impact the interpretation of the 
primary efficacy endpoint.  Protocol deviations will be 
reviewed to generate the list of participants with significant 
deviations to be excluded from the PP analysis set. The PP 


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Participant Analysis Set
Description
exclusion criteria will be finalized prior to breaking the 
blind.
For the primary efficacy analysis, the mITT set will be used and will be the primary analysis. 
A secondary analysis of the primary endpoint will be performed and will use the mITT2 
analysis set. For all other efficacy analyses, mITT, mITT1 and mITT2 sets will be used, as 
defined in the SAP. The PP analysis set will be used in the analyses of primary efficacy 
endpoint. 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.
9.3.1. General Considerations
Descriptive statistics for all efficacy endpoints by treatment group and visit will be provided. 
The number of participants screened, randomized to the double blind treatment phase, 
completing the study drug administration, and completing the study will be summarized from 
the FAS. The reason for all discontinuations will be summarized by treatment group. 
Baseline demographic and other characteristics will be tabulated for the FAS and 
summarized by treatment group. Quantitative variables will be described by standard 
descriptive statistics (mean, standard deviation, minimum, and maximum), and qualitative 
variables will be summarized by frequency tables with number and proportion in each 
category (with the corresponding sample sizes).
For continuous endpoints, 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.
For binary endpoints, proportion of participant with the event will be summarized for each 
group. Treatment comparison between the group will be presented as the difference of 
proportions with its 95% confidence interval using a similar analysis method as the primary 
endpoints.
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. 
For time-to-event endpoints (ie, time [days] to sustained alleviation/resolution of all targeted 
signs/symptoms through Day 28 and duration of each targeted COVID‑19 sign/symptom), 


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2 analyses will be provided: (1) a Cox proportional hazard regression model where the 
estimate of the hazard ratio for treatment (PF-07321332 vs placebo), its CI, and p‑value will 
be provided; and (2) Kaplan-Meier analysis where tabular summaries of the Kaplan‑Meier 
curves providing the median, quartiles, and range will be provided for each treatment group. 
In addition, the KM curves will be presented graphically. 
Imputation of missing data within efficacy variables and endpoints will be computed 
according to the rules specified in the SAP. 
9.3.2. Primary Endpoint(s)/Estimand(s) Analysis
The primary efficacy analysis will be conducted using the mITT population. 
The cumulative proportion of participants hospitalized for the treatment of COVID-19 or 
dying during the first 28 days of the study will be estimated for each treatment group using 
the Kaplan-Meier method to take account of losses to follow-up and summarized graphically 
for each treatment group. The estimand is then the difference of the proportions in the 2 
groups and its 95% CI will be presented, as well as, the associated Wald Test. For the 95% 
CI, the corresponding estimate of the standard error is computed using Greenwood’s 
formula.1 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. 
The above primary analysis will be conducted for the planned interim analysis as well. Two-
sided 95% CI (adjusted for the planned interim analysis) and associated p-value for the null 
hypothesis of no difference between treatment groups will be presented. Significance level 
will be determined using the O’Brien-Fleming approach at the interim analysis and the final 
analysis. The overall significance level is set at 5% (2 sided). 
For participants who complete Day 28 assessment (Day 34), they will be censored at their 
last visits. For participants who discontinue before Day 28 assessment or are lost to follow 
up, they will be censored at the last known date in the study.
The secondary analysis associated with primary endpoint will be conducted using the mITT2 
population set. 


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Supplemental analyses will be performed to the primary efficacy endpoint:
1. An analysis in the mITT analysis set of the primary endpoint where participants that 
received a therapeutic COVID-19 mAb treatment post-baseline will be considered as 
an event for the endpoint (in addition to hospitalization for COVID-19 and death due 
to any cause) with mAb treatment date as the time of event.
2. A logistic regression model will be fitted to the primary endpoint of 
hospitalization/death 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 adjusting for baseline covariates (such as age, gender, 
etc.) as additive terms to the primary model, if necessary.
3. A completers (participants with Day 28 assessment) only analysis similar to the 
primary efficacy analysis will be conducted.
9.3.3. Key Secondary Efficacy Endpoint(s)/Estimand(s) Analysis
Proportion of participants with COVID-19 related hospitalization or death due to any 
cause through Day 28
The first key secondary efficacy endpoint is the proportion of participants with COVID-19 
related hospitalization or death due to any cause through Day 28 in the mITT1 analysis set. 
The analysis for this endpoint is similar to the primary endpoint, but using the mITT1 
analysis set.
Time to sustained alleviation and time to sustained resolution of targeted COVID-19 
sign/symptoms through Day 28
The key secondary endpoints of sustained alleviation and resolution will be defined for all 
targeted COVID-19 associated symptoms based on self-assessment. 
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.
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. 
For any symptoms not present at baseline, it must be absent at the last possible available day 
(prior to or at Day 25) to be counted as sustained alleviation/resolution. For symptoms with 
no reported severity in baseline, the symptom will have to be absent in order to consider 
alleviated/resolved (missing severity at baseline will be treated as mild).


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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.

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 with all targeted symptoms absent 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 die from any cause 
during the 28-day period will be classified as not achieving sustained symptom 
alleviation/resolution and will be censored at day 25.
Cox proportional hazard model analyses will be used for time to sustained symptom
alleviation/resolution.
Time to sustained symptom alleviation/resolution will be summarized graphically using 
Kaplan-Meier plots for each of the treatment groups, the analyses will be done using mITT 
population, mITT1 population, and the mITT2 population.
9.3.4. Secondary Endpoint(s)/Estimand(s) Analyses

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


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•
PK of PF-07321332 
•
Viral titers (RT-PCR) measured in nasal swabs over time
•
Number of COVID-19 related medical visits through Day 28.
•
Number of days in hospital and ICU stay in participants with COVID-19 related 
hospitalization.
Details on the definitions and analyses of secondary endpoints will be described in the SAP.
9.3.6. Other Safety Analyses
Safety analyses will be carried out for the Safety population.  
The safety assessments include AEs, laboratory assessments, physical examinations, and 
vital signs. No formal statistical analysis will be conducted on any of the other safety data 
listed above.
9.3.6.1. Laboratory
All clinical laboratory data will be subjected to clinical review, summarized by frequency of 
events and mean changes from baseline.
9.3.6.2. Physical Examination and Vital Signs
All physical examination and vitals will be descriptively summarized by treatment group. 
 
 
Long-term COVID-19 symptoms will be collected by telephone interviews at Weeks 12 and 
24 and PRO data (Global impression questions, EQ-5D-5L, WPAI) will be collected during 
the trial. These data are not planned to be included in the CSR.
9.3.7.1. PK Analyses 
Descriptive statistics and graphical summaries of PF-07321332 concentrations will be 
generated. PK samples will be collected as described in the SoA. Additional PK sampling 
may be collected in a subset of participants via home health, site visit, or self-collected using 
Tasso, if feasible. Ritonavir concentrations may also be reported. PK data from this study 
may be combined with other studies and analyzed using population PK approaches. Results 
from any population PK analyses will be reported outside of the clinical study report.
CCI
CCI


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9.4. Interim Analyses
A planned interim analysis for efficacy and futility with a sample size-re-estimation will be 
conducted and reviewed by an independent E-DMC after approximately 45% overall 
participants have completed the Day 28 assessments in the mITT analysis set (ie, 28 days 
after randomization). 
At the time of planning the Phase 2/3 study, there was uncertainty about the rate of 
COVID-19-related hospitalization or death in the primary analysis population, and about the 
treatment effect of PF-07321332. Hence, a sample size re-estimation will be conducted 
during the interim analysis based on conditional power. The sample size can be adjusted one 
time and the increase will be capped at 30%. A well-established method described by Cui, 
Hung, and Wang (1999)44 (implemented in EAST 6.5) will be used to control the Type I 
error probability.45
The nominal significance level for the planned interim and final proportion of 
hospitalization/death 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%.
For the interim analysis (45%), 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. The final 
p-value for rejecting H0 will be ≤0.049 (2-sided) or reject H1 with 2-sided p-value >0.049. 
The actual stopping boundaries will depend on the exact timing of the interim analysis. If the 
efficacy boundary is crossed at the interim analysis, a final analysis will be conducted as a 
supportive 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.
9.5. Sample Size Determination
The estimate of required sample size is based on data from the BLAZE-1 Phase 2/3 trial 
among participants with mild to moderate COVID-19 who were at high risk for progressing 
to severe COVID-19 and/or hospitalization at enrollment.2 During the 29-day period 
following enrollment, the proportion of placebo-treated participants with a 
COVID-19-related hospitalization/emergency department visit was 7% in the Phase 3 portion 
of the trial.3
This study is designed to have 90% statistical power to show a difference of 3.5% in the 
proportion of participants hospitalized/dying that did not receive COVID-19 therapeutic mAb 
between the treatment arms (PF-07321332/ritonavir versus placebo) and were treated 
≤3 days after COVID-19 symptom onset, using a 2-sided Type I error rate of 5%. Based on 
the above study,3 the proportion of hospitalization/death in the placebo arm is assumed to be 
7%. 


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Using EAST (Version 6.5) for a 2-sample proportion test44, the sample size needed to detect 
this difference with 90% power at a 2-sided significance level of 5% was determined to be 
1717 randomized participants. Enrollment of participants that have received/expected to 
receive COVID-19 therapeutic mAb treatment is expected to be approximately 20% and will 
be limited to approximately 25% of participants. Enrollment of participants that had 
COVID-19 symptom onset >3 days prior to randomization is expected to be approximately 
25% and will be limited to a total of approximately 1000 participants. Assuming a 5% 
dropout rate, the total sample size for this study will be approximately 3000 participants. 
Study enrollment will be stopped after approximately 1717 participants are available for the 
primary analysis.


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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 an E-DMC. The E-DMC is independent of the study team and includes 
only external members. The E-DMC charter describes the role of the E-DMC in more detail.
The E-DMC will be responsible for ongoing monitoring of the efficacy and safety of 
participants in the study according to the charter. The recommendations made by the E-DMC 
will be forwarded to the appropriate authorized Pfizer personnel for review and final 
decision. Pfizer will communicate such decisions, which may include summaries of 
aggregate analyses of safety data to regulatory authorities, investigators, as appropriate. 


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The E-DMC will review unblinded data to ensure the safety of participants on an ongoing 
basis 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 60 participants have completed Day 10 of the study, at which 
point enrollment will be paused pending E-DMC review of the safety data. After 
review of the sentinel cohort, the frequency of safety reviews may be reduced 
subsequently based on E-DMC recommendations.

Proof-of-concept assessment: The E-DMC will review viral load data when 
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.

Interim analysis: A planned interim analysis for efficacy and futility with a sample 
size re-estimation will be done after approximately 45% of participants in the mITT 
set complete the Day 28 assessments (ie, 28 days after randomization). 
The E-DMC will also review the results of planned interim analysis. Efficacy data will be 
available to the E-DMC for the interim analysis. Details of the E-DMC are specified in the 
E-DMC Charter.
The E-DMC will review all deaths that occur during the study. A pause in enrollment 
pending E-DMC review will occur if 2 participants experience a Grade 4 or higher AE that is 
deemed related to study intervention as determined by the investigator and if the sponsor 
agrees.
10.1.6. Dissemination of Clinical Study Data
Pfizer fulfills its commitment to publicly disclose clinical study results through posting the 
results of studies on www.clinicaltrials.gov (ClinicalTrials.gov), the EudraCT, and/or 
www.pfizer.com, and other public registries in accordance with applicable local 
laws/regulations. In addition, Pfizer reports study results outside of the requirements of local 
laws/regulations pursuant to its SOPs.
In all cases, study results are reported by Pfizer in an objective, accurate, balanced, and 
complete manner and are reported regardless of the outcome of the study or the country in 
which the study was conducted.
www.clinicaltrials.gov
Pfizer posts clinical trial results on www.clinicaltrials.gov for Pfizer-sponsored interventional 
studies (conducted in patients) that evaluate the safety and/or efficacy of a product, 
regardless of the geographical location in which the study is conducted. These results are 
submitted for posting in accordance with the format and timelines set forth by US law.


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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 “bona-fide scientific research” that contributes to the scientific understanding of the 
disease, target, or compound class. Pfizer will make data from these trials available 
24 months after study completion. Patient-level data will be anonymized in accordance with 
applicable privacy laws and regulations. CSRs will have personally identifiable information 
redacted.
Data requests are considered from qualified researchers with the appropriate competencies to 
perform the proposed analyses. Research teams must include a biostatistician. Data will not 
be provided to applicants with significant conflicts of interest, including individuals 
requesting access for commercial/competitive or legal purposes.
10.1.7. Data Quality Assurance
All participant data relating to the study will be recorded on printed or electronic CRF unless 
transmitted to the sponsor or designee electronically (eg, laboratory data). The investigator is 
responsible for verifying that data entries are accurate and correct by physically or 
electronically signing the CRF.
Guidance on completion of CRFs will be provided in the CRF Completion Requirements 
document.


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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 on-site monitoring), are provided in the data management plan and 
monitoring plan maintained and utilized by the sponsor or designee.
The sponsor or designee is responsible for the data management of this study, including 
quality checking of the data.
Records and documents, including signed ICDs, pertaining to the conduct of this study must 
be retained by the investigator for 15 years after study completion unless local regulations or 
institutional policies require a longer retention period. No records may be destroyed during 
the retention period without the written approval of the sponsor. No records may be 
transferred to another location or party without written notification to the sponsor. The 
investigator must ensure that the records continue to be stored securely for as long as they are 
maintained.
When participant data are to be deleted, the investigator will ensure that all copies of such 
data are promptly and irrevocably deleted from all systems.
The investigator(s) will notify the sponsor or its agents immediately of any regulatory retain  
notification in relation to the study. Furthermore, the investigator will cooperate with the 
sponsor or its agents to prepare the investigator site for the inspection and will allow the 
sponsor or its agent, whenever feasible, to be present during the inspection. The investigator 
site and investigator will promptly resolve any discrepancies that are identified between the 
study data and the participant's medical records. The investigator will promptly provide 
copies of the inspection findings to the sponsor or its agent. Before response submission to 
the regulatory authorities, the investigator will provide the sponsor or its agents with an 
opportunity to review and comment on responses to any such findings.


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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.


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Reasons for the early closure of a study site by the sponsor may include but are not limited 
to:

Failure of the investigator to comply with the protocol, the requirements of the 
IRB/EC or local health authorities, the sponsor's procedures, or the ICH GCP 
guidelines;

Inadequate recruitment of participants by the investigator; 

Discontinuation of further study intervention development.
If the study is prematurely terminated or suspended, the sponsor shall promptly inform the 
investigators, the ECs/IRBs, the regulatory authorities, and any CRO(s) used in the study of 
the reason for termination or suspension, as specified by the applicable regulatory 
requirements. The investigator shall promptly inform the participant and should assure 
appropriate participant therapy and/or follow-up.
Study termination is also provided for in the clinical study agreement. If there is any conflict 
between the contract and this protocol, the contract will control as to termination rights.
10.1.10. 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. 


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If publication is addressed in the clinical study agreement, the publication policy set out in 
this section will not apply.
10.1.11. Sponsor’s Qualified Medical Personnel
The contact information for the sponsor's appropriately qualified medical personnel for the 
study is documented in the study contact list located in the supporting study 
documentation/study portal or other electronic system. 
To facilitate access to appropriately qualified medical personnel for study-related medical 
questions or problems, participants are provided with an Emergency Contact Card (ECC) at 
the time of informed consent. The ECC contains, at a minimum, (a) protocol and study 
intervention identifiers, (b) participant’s study identification number, (c) site emergency 
phone number active 24 hours/day, 7 days per week, and (d) Pfizer Call Center number.
The ECC is intended to augment, not replace, the established communication pathways 
between the investigator, site staff, and study team. The ECC is to be used by healthcare 
professionals not involved in the research study only, as a means of reaching the investigator 
or site staff related to the care of a participant. The Pfizer Call Center number should only be 
used when the investigator and site staff cannot be reached. The Pfizer Call Center number is 
not intended for use by the participant directly; if a participant calls that number directly, he 
or she will be directed back to the investigator site.


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10.2. Appendix 2: Clinical Laboratory Tests
The following safety laboratory tests will be performed at times defined in the SoA section of 
this protocol. Additional laboratory results may be reported on these samples as a result of 
the method of analysis or the type of analyzer used by the clinical laboratory, or as derived 
from calculated values. These additional tests would not require additional collection of 
blood. Unscheduled clinical laboratory measurements may be obtained at any time during the 
study to assess any perceived safety issues
Table 1.
Protocol-Required Safety Laboratory Assessments
Hematology
Chemistry
Other
Additional Tests 
(Needed for Hy’s Law)
Hemoglobin
Hematocrit
RBC count
Platelet count
WBC count
Total neutrophils 
(Abs)
Eosinophils (Abs)
Monocytes (Abs)
Basophils (Abs)
Lymphocytes (Abs)
BUN or urea
Creatinine a
Glucose
Calcium
Sodium
Potassium
Chloride
Total CO2 (bicarbonate)
AST, ALT
Total bilirubin
Alkaline phosphatase
Albumin
Total protein
Ferritin
hsCRP
Procalcitonin
LDH
CK
Haptoglobin
Thyroid function
TSH
T4 (free)
Coagulation 
PT/aPTT
Fibrinogen
D-dimer
SARS-CoV-2 
serology (IgM, IgG)
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.30
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.
d. Results in persistent or significant disability/incapacity


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
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.


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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) 
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.***


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*
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.

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
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.
The investigator will make an assessment of intensity for each AE and SAE reported 
during the study and assign it to 1 of the following categories, which are based on the 
Division of AIDS (DAIDS) Table for Grading the Severity of Adult and Pediatric Adverse 
Events,42 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.


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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.

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.


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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.
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.


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SAE Reporting to Pfizer Safety via CT SAE Report Form

Facsimile transmission of the CT SAE Report Form is the preferred method to 
transmit this information to Pfizer Safety.

In circumstances when the facsimile is not working, notification by telephone is 
acceptable with a copy of the CT SAE Report Form sent by overnight mail or 
courier service.

Initial notification via telephone does not replace the need for the investigator to 
complete and sign the CT SAE Report Form pages within the designated reporting 
time frames.


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10.4. Appendix 4: Contraceptive and Barrier Guidance 
10.4.1. Male Participant Reproductive Inclusion Criteria
Male participants are eligible to participate if they agree to the following requirements during 
the intervention period and for at least 28 days after the last dose of study intervention, which
corresponds to the time needed to eliminate reproductive safety risk of the study 
intervention(s):

Refrain from donating sperm.
PLUS either:

Be abstinent from heterosexual intercourse with a female of childbearing potential as 
their preferred and usual lifestyle (abstinent on a long-term and persistent basis) and 
agree to remain abstinent. 
OR

Must agree to use contraception/barrier as detailed below:

Agree to use a male condom when having sexual intercourse with a woman of 
childbearing potential who is not currently pregnant.

In addition to male condom use, a highly effective method of contraception may be 
considered in WOCBP partners of male participants (refer to the list of highly 
effective methods below in Section 10.4.4).
10.4.2. Female Participant Reproductive Inclusion Criteria
A female participant is eligible to participate if she is not pregnant or breastfeeding, and at 
least 1 of the following conditions applies:

Is not a WOCBP (see definitions below in Section 10.4.3).
OR

Is a WOCBP and using a contraceptive method that is highly effective (with a 
failure rate of <1% per year), as described below, during the intervention period 
and for at least 28 days after the last dose of study intervention, which 
corresponds to the time needed to eliminate any reproductive safety risk of the 
study intervention(s). If a highly effective method that is user dependent is 
chosen, a second effective method of contraception, as described below, must also
be used. The investigator should evaluate the effectiveness of the contraceptive 
method in relationship to the first dose of study intervention. 


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Because ritonavir may reduce the effect of estradiol-containing contraceptives when agents 
are coadministered, a barrier method or other nonhormonal method of contraception must 
also be used if the participant is using estradiol-containing contraceptives.
The investigator is responsible for review of medical history, menstrual history, and recent 
sexual activity to decrease the risk for inclusion of a woman with an early undetected 
pregnancy. 
10.4.3. Woman of Childbearing Potential
A woman is considered fertile following menarche and until becoming postmenopausal 
unless permanently sterile (see below).
If fertility is unclear (eg, amenorrhea in adolescents or athletes) and a menstrual cycle cannot 
be confirmed before the first dose of study intervention, additional evaluation should be 
considered.
Women in the following categories are not considered WOCBP:
1. Premenopausal female with 1 of the following: 

Documented hysterectomy;

Documented bilateral salpingectomy;

Documented bilateral oophorectomy.
For individuals with permanent infertility due to an alternate medical cause other than the 
above, (eg, mullerian agenesis, androgen insensitivity), investigator discretion should be 
applied to determining study entry.
Note: Documentation for any of the above categories can come from the site personnel’s 
review of the participant’s medical records, medical examination, or medical history 
interview. The method of documentation should be recorded in the participant’s medical 
record for the study.
2. Postmenopausal female:

A postmenopausal state is defined as no menses for 12 months without an 
alternative medical cause.  In addition:

A high FSH level in the postmenopausal range must be used to confirm a 
postmenopausal state in women under 50 years of age and not using hormonal 
contraception or HRT. 

A female on HRT and whose menopausal status is in doubt will be required to 
use one of the nonestrogen hormonal highly effective contraception methods 
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 coadministered, 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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10.5. Appendix 5: Genetics
Use/Analysis of DNA

Genetic variation may impact a participant’s response to study intervention, 
susceptibility to, and severity and progression of disease. Therefore, where local 
regulations and IRBs/ECs allow, a blood sample will be collected for DNA analysis.

The scope of the genetic research may be narrow (eg, 1 or more candidate genes) or 
broad (eg, the entire genome), as appropriate to the scientific question under 
investigation.

The samples may be analyzed as part of a multistudy assessment of genetic factors 
involved in the response to study intervention or study interventions of this class to 
understand treatments for the disease(s) under study or the disease(s) themselves.

The results of genetic analyses may be reported in CSR or in a separate study 
summary, or may be used for internal decision making without being included in a 
study report.

The sponsor will store the DNA samples in a secure storage space with adequate 
measures to protect confidentiality. 

The samples will be retained as indicated:

Retained samples will be stored indefinitely or for another period as per local 
requirements.

Participants may withdraw their consent for the storage and/or use of their Retained 
Research Samples at any time by making a request to the investigator; in this case, 
any remaining material will be destroyed. Data already generated from the samples 
will be retained to protect the integrity of existing analyses.

Samples for genetic research will be labeled with a code. The key between the code 
and the participant’s personally identifying information (eg, name, address) will be 
held securely at the study site.


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10.6. Appendix 6: Liver Safety: Suggested Actions and Follow-Up Assessments 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
ECG Findings That May Qualify as AEs

Marked sinus bradycardia (rate <40 bpm) lasting minutes.

New PR interval prolongation >280 msec.

New prolongation of QTcF to >480 msec (absolute) or by 60 msec from baseline.

New-onset atrial flutter or fibrillation, with controlled ventricular response rate: ie, 
rate <120 bpm.

New-onset type I second-degree (Wenckebach) AV block of >30 seconds’ 
duration.

Frequent PVCs, triplets, or short intervals (<30 seconds) of consecutive ventricular 
complexes.
ECG Findings That May Qualify as SAEs

QTcF prolongation >500 msec.

New ST-T changes suggestive of myocardial ischemia.

New-onset left bundle branch block (QRS >120 msec).

New-onset right bundle branch block (QRS >120 msec).

Symptomatic bradycardia. 

Asystole:

In awake, symptom-free patients in sinus rhythm, with documented periods of 
asystole ≥3.0 seconds or any escape rate <40 bpm, or with an escape rhythm 
that is below the AV node; 

In awake, symptom-free patients with atrial fibrillation and bradycardia with 1 
or more pauses of at least 5 seconds or longer; 

Atrial flutter or fibrillation, with rapid ventricular response rate: rapid = rate 
>120 bpm.

Sustained supraventricular tachycardia (rate >120 bpm) (“sustained” = short 
duration with relevant symptoms or lasting >1 minute).


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
Ventricular rhythms >30 seconds’ duration, including idioventricular rhythm (heart 
rate <40 bpm), accelerated idioventricular rhythm (HR 40 bpm to <100 bpm), and 
monomorphic/polymorphic ventricular tachycardia (HR >100 bpm (such as 
torsades de pointes)).

Type II second-degree (Mobitz II) AV block.

Complete (third-degree) heart block.
ECG Findings That Qualify as SAEs

Change in pattern suggestive of new myocardial infarction. 

Sustained ventricular tachyarrhythmias (>30 seconds’ duration).

Second- or third-degree AV block requiring pacemaker placement.

Asystolic pauses requiring pacemaker placement.

Atrial flutter or fibrillation with rapid ventricular response requiring cardioversion.

Ventricular fibrillation/flutter.

At the discretion of the investigator, any arrhythmia classified as an adverse 
experience.
The enumerated list of major events of potential clinical concern are recommended as “alerts” or 
notifications from the core ECG laboratory to the investigator and Pfizer study team, and not to be 
considered as all inclusive of what to be reported as AEs/SAEs.


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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. 
A nonexhaustive list of prohibited and precautionary medications is provided below. If a 
medication is not listed, it should not automatically be assumed it is safe to co-administer. 
Appropriately qualified site staff will review all concomitant medications to determine if 
they are prohibited. 
The Pfizer study team is to be notified of any prohibited medications taken during the study. 
After consulting with the sponsor, the investigator will make a judgement on the ongoing 
participation of any participant with prohibited medication use during the study. 
This list of drugs prohibited for potential DDI concerns with the IMP may be revised during 
the course of the study with written notification from sponsor, to include or exclude specific 
drugs or drug categories for various reasons (eg, emerging DDI results for the IMP, 
availability of new information in literature on the DDI potential of other drugs).   
This is not an all-inclusive list. Site staff should consult with the sponsor or designee with 
any questions regarding potential DDI.


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Prohibited Medications that are Strong Inducers of CYP450 3A4a 
Due to prolonged induction of CYP450 3A4 participants must not use these medications within 28 days 
prior to randomization and during dosing of PF-07321332/placebo and ritonavir/placebo. 
Drug Class 
Specific Medication 
Clinical Comments 
Anti-infectives 
Rifampin 
Reduced concentrations of PF-
07321332/ritonavir; may result in 
suboptimal concentrations 
Anticonvulsants 
Phenytoin, Carbamazepine  
Herbal Products 
St. John’s Wort 
Prohibited Medications Dependent on CYP450 3A4 for Clearance or with other Notable 
Interactionsa 
These medications are prohibited for at least 24 hours prior to the first dose of PF-0321332/placebo 
and ritonavir/placebo, through 4 days after the last dose of PF-07321332/placebo and ritonavir/placebo. 
If a participant cannot temporarily interrupt the prohibited medication during this period, they should be 
considered ineligible.  
Drug Class 
Specific Medication 
Clinical Comments 
Alpha 1-Adrenoreceptor 
Antagonist 
Alfuzosin 
Risk of hypotension, syncope 
Analgesics 
Piroxicam, propoxyphene 
Analgesic concentrations may 
increase 
Antianginal 
Ranolazine 
Risk of cardiac arrhythmias  
Antiarrhythmics   
Dronedarone 
Risk of cardiac arrhythmias  
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 
Triazolam, oral midazolam  
Risk of prolonged sedation, 
respiratory depression, or 
hypnotic concentrations 
Miscellaneous Drugs  
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.  
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 
Anesthetic 
Methadone 
Fentanyl, oxycodone 
Buprenorphine 
Lofexidine 
Pethidine (Meperidine) 
Moderate to weak decreases in 
methadone concentrations have 
been observed 
Analgesic concentrations may 
increase 
Co-administration may increase 
concentrations of buprenorphine 
and lofexidine 
Co-administration with ritonavir 
may result in increase in 
concentration of the metabolite 
normeperidine 
Antiarrhythmics   
Amiodarone, Bepridil, Flecainide, 
Propafenone, Quinidine, Encainide, 
Disopyramide, dofetilide, lidocaine, 
mexiletine  
Risk of cardiac arrhythmias   
Anticoagulants/ 
antiplatelet  
Rivaroxaban, Vorapaxar, apixaban, 
betrixaban, dabigatran, edoxaban   
ticagrelor 
Warfarin 
Possible increased risk of 
bleeding 
Possible decreased warfarin 
effects 
Anticonvulsants 
Ethosuximide 
Eslicarbazepine 
Oxcarbazepine 
Phenobarbital 
Lamotrigine 
Divalproex 
Valproate 
Co-administration may increase 
these anticonvulsant 
concentrations or decrease 
PF-07321332 and ritonavir 
concentrations  
Co-administration may decrease 
concentration of lamotrigine, 
divalproex, and valproate 


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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 
Desipramine, Fluoxetine, 
Paroxetine 
nefazodone, Amoxapine, 
Clomipramine, Doxepin, Imipramine, 
Maprotiline 
Amitryptiline, nortryptiline, 
protryptiline, Trimipramine,  
aripiprazole
May increase antidepressant 
concentration 
Anti-infective (antibacterials)
Erythromycin 
Co-administration may increase 
erythromycin concentrations. 
Clarithromycin 
Co-administration may increase 
clarithromycin concentrations. 
(antimycobacterials)  
Bedaquiline 
Co-administration may increase 
bedaquiline concentrations 
Rifabutin 
Co-administration may increase 
rifabutin concentrations  
(antifungals) 
Isavuconazole 
Itraconazole 
Posaconazole 
Ketoconazole 
Voriconazole 
Possible increased 
concentrations of antifungal, of 
PF-07321332, or both.  
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, 
perphenazine, risperidone, 
thioridazine, ziprasidone 
Co-administration may increase 
quetiapine and increase risk of 
quetiapinerelated 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) 
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.  
(cardiac glycosides) 
Digoxin 
Co-administration increases 
digoxin concentrations. 
Eplerenone 
Co-administration increases 
eplerenone concentrations 
Ranolazine 
Co-administration increases 
ranolazine concentrations 
Ivabradine 
Co-administration increases 
ivabradine concentrations 
Corticosteroids 
(inhaled or intranasal) 
(systemic) 
(Local injections, including intra-
articular, epidural, or intra-orbital) 
Budesonide,  
ciclesonide,  
mometasone  
Betamethasone 
Budesonide 
Betamethasone, methylprednisolone, 
triamcinolone 
Co-administration can increase 
concentration of budesonide, 
ciclesonide, and mometasone 
and can result in adrenal 
insufficiency and Cushing’s 
syndrome. 
Co-administration can increase 
concentration of betamethasone, 
and budesonide and can result 
in adrenal insufficiency and 
Cushing’s syndrome. 
Co-administration can increase 
betamethasone, 
methylprednisolone, and 
triamcinolone concentrations 
and can result in adrenal 
insufficiency and Cushing’s 
syndrome 
Endothelin receptor antagonists 
Bosentan 
Bosentan should be 
discontinued at least 36 hours 
prior to the initiation of 
ritonavir 


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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 
Ergot Derivatives 
Ergonovine 
Risk of acute ergot toxicity 
(peripheral vasospasm and 
ischemia of the extremities) 
Hepatitis C direct acting antivirals 
(DAAs) 
Boceprevir, Glecaprevir/Pibrentasvir 
Simeprevir, 
Sofosbuvir/Velpatasvir/Voxilaprevir, 
Ombitasvir/Paritaprevir/ritonavir/ 
Dasabuvir, Grazoprevir/elbasvir 
Co-administration can increase 
plasma concentrations of select 
DAAs  
  
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 
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  


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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 
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 
Neuroleptic 
Pimozide 
Risk of cardiac arrhythmias  
Sedatives/ Hypnotics 
Midazolam (parenteral), alprazolam, 
bromazepam, brotizolam, 
clonazepam, cloniprazepam, 
delorazepam, diazepam, etizolam, 
eszopiclone, halazepam, 
lormetazepam, nitrazepam, 
nordiazpam, quazepam, suvorexant, 
temazepam, zaleplon, zolpidem  
Clorazepate, estazolam, flurazepam, 
Zolpidem (> 5mg daily) 
Risk of prolonged sedation, 
respiratory depression, or 
hypnotic concentrations 
Co-administration with ritonavir 
may increase dose of 
clorazepate, estazolam, and 
flurazepam. 
Co-administration may increase 
zolpidem concentration  
Miscellaneous Drugs 
Cisapride 
Dronabinol 
Eluxadoline (>75 mg twice daily) 
Flibanserin 
Co-administration may result in 
increased cisapride
concentration and possible  
cardiac arrhythmias 
Co-administration may increase 
dronabinol concentration 
Co-administration may increase 
eluxadoline concentration 
Co-administration may increase 
flibanserin 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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Hormonal Contraceptives: Estradiol-containing hormonal contraceptive medications can be 
continued while receiving investigational product, but their effectiveness may be impacted. 
Therefore, barrier methods of contraception must be used for at least one full menstrual cycle 
following completion of investigational product dosing.  
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  
No data available 
Sertraline, Bupropion 
Trazodone 
Co-administration may decrease sertraline 
and bupropion concentrations 
Co-administration with ritonavir increases 
the level/effect of trazodone by affecting 
hepatic/intestinal enzyme CYP3A4 
metabolism. Further, trazodone may 
decrease the level/effect of ritonavir by P-
glycoprotein (MDR1) efflux transporter.  
To be used with caution. 
Anticancer Agents: 
Dasatinib, imatinib, nilotinib, 
venetoclax,  
Vincristine, Vinblastine 
Co-administration of ritonavir may increase 
the concentration of dasatinib and nilotinib.   
Coadministration of ritonavir with 
venetoclax may increase concentration of 
venetoclax and increase the risk of tumor 
lysis syndrome. 
Con-administration with ritonavir may 
increase the concentrations of vincristine 
and vinblastine and develop significant 
hematologic or gastrointestinal side effects. 
  
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 


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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
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 
RTV 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 
PDE-5 Inhibitors for 
treatment of erectile 
dysfunction 
Sildenafil – ED (max dose 25 mg 
every 48 hours) 
Avanafil 
Tadalafil (max dose 10 mg every 
72 hours) 
Vardenafil (max dose 2.5 mg every 
72 hours) 
Risk of visual disturbances, hypotension, 
prolonged erection, and syncope 
Steroids (systemic) 
Dexamethasone 
Prednisone 
Co-administration with ritonavir may 
increase dose of dexamethasone and 
prednisone and may increase the risk for 
development of systemic corticosteroid 
effects including Cushing’s syndrome and 
adrenal suppression 


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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
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 Collection31
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 #6 .  
Exclusion Criterion #6: Known HIV infection with a viral load >400 copies/mL or taking 
prohibited medications for HIV treatment (from known medical history within past 6 months 
of the screening visit).
If HIV infection is known by medical interview or examination results (if any), the 
investigators must consult with the patient’s HIV treatment specialist to confirm that the HIV 
RNA level has been monitored at an appropriate frequency and the HIV RNA level has been 
≤400 copies/mL during the past 6 months before the screening visit in order to assess the 
study eligibility of that patient.


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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
Amendment 1 (02 July 2021)
Overall Rationale for the Amendment: The protocol was amended to incorporate 
regulatory feedback.
Section # and Name
Description of Change
Brief Rationale
1.1 Synopsis
Section 3.0 Objectives, 
Endpoints and Estimands
Section 9.3.4 Secondary 
Endpoint(s)/Estimand(s) 
Analyses
Removal of COVID-19 severity 
ranking endpoint.
To address regulatory feedback.
1.1 Synopsis
Section 3.0 Objectives, 
Endpoints and Estimands
Section 9.3.4 Secondary 
Endpoints
Secondary endpoint related to 
medical visits will include 
hospitalizations.
To align with program strategy.
1.2 Schema
Schema footnote was updated.
For clarification.
1.3 Schedule of Activities 
Section 8.1.5.1 Global 
Impression Questions
Section 9.3.7 Other Analyses
Addition of 3 global impression 
questions to be added to the ePRO 
daily and collected in participants 
after the sentinel cohort as 
available.
To address regulatory feedback.
Section 5.1 Inclusion Criteria
Window for positive RT-PCR test 
updated to 5 days in inclusion 
criteria. New wording: Confirmed 
SARS-CoV-2 infection as 
determined by RT-PCR in any 
specimen collected within 5 days 
prior to randomization.
To improve operational feasibility.
Section 5.2 Exclusion 
Criteria
Exclusion criterion updated with 
new wording:  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.
For clarification.
Section 9
Clarifications made to text in 
statistical section.
To address regulatory feedback.
Section 9.2 Analysis Sets
Updated mITT1 definition.
To address regulatory feedback.
Typographical errors were 
corrected and minor edits were 
made.
For clarification and to ensure 
consistency.


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Amendment 2 (02 August 2021)
Overall Rationale for the Amendment: The primary analysis set (mITT) has been refined 
to include just those participants who were treated ≤3 days after COVID-19 symptom onset 
(mITT). 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
Synopsis
Describes changes made in 
Sections 3, 4 and 9 below.
To summarize changes made in the 
document.
Section 1
Schedule of Activities
Minor edits to footnotes.
To clarify use of brackets and 
procedure requirements associated with 
the location for expected visits.
Section 3
Objectives, Endpoints and 
Estimands

Primary estimand changed to 
specify inclusion of 
participants who did not 
receive COVID-19 
therapeutic mAbs and who 
were treated ≤3 days after 
COVID-19 symptom onset.

A key secondary efficacy 
endpoint (proportion of 
participants with 
COVID-19-related 
hospitalization or death due 
to any cause through Day 
28) was added.

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 treated ≤3 days after 
COVID-19 symptom onset.

The key secondary efficacy 
endpoint was added  as a 
consequence of the change in 
primary efficacy analysis and the 
analysis will include participants 
regardless of their symptom onset.
Section 4
Study Design
Sample size to be increased from 
2260 to approximately 3000 
participants.
Changes are a consequence of the 
change in primary efficacy analysis.  
The primary efficacy analysis set has 
been refined to include just those 
participants who were treated ≤3 days 
after COVID-19 symptom onset 
(mITT). Sample size has been adjusted, 
and the analysis of all participants is 
now a secondary analysis. 
Section 6
Study Intervention(s) and 
Concomitant Therapy
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.
Section 6
Blinding of the Sponsor
Language was added to clarify 
that the study will be unblinded 
To provide additional information and 
clarification in the process of 
unblinding.


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Section # and Name
Description of Change
Brief Rationale
after all participants have 
completed the Day 34 visit.
Section 8
Assessments and Procedures
Text updated to make statement 
consistent with the SoA regarding 
follow-up pregnancy test being at 
Day 34 visit.
Correction made to Section 8 that 
follow-up pregnancy test is not at end 
of study, but rather is at Day 34 visit.
Section 9 Statistical 
Considerations

Primary estimand changed to 
specify patients who did not 
receive COVID-19 
therapeutic mAb, and who 
were treated ≤3 days after 
COVID-19 symptom onset.

mITT analysis set added that 
includes participants who did 
not receive nor were 
expected to receive 
COVID-19 therapeutic mAb, 
and who were treated 
≤3 days after COVID-19 
symptom onset.  

Changed the analysis set for 
the primary efficacy analysis 
from mITT1 to mITT. Key 
secondary efficacy endpoint 
was added and analysis will 
be conducted using the 
mITT1 analysis set.  

Enrollment of participants 
that had COVID-19 
symptom onset >3 days prior 
to randomization is expected 
to be approximately 25% and 
will be limited to 
approximately 
1000 participants.

Updated total sample size 
(from 2260 to approximately 
3000 participants).
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 treated ≤3 days after 
COVID-19 symptom onset. Additional 
section changes are a consequence of 
the change in primary efficacy analysis. 
Primary efficacy analysis set is now 
based on participants treated ≤3 days 
after COVID-19 symptom onset. 
Sample size has been adjusted and the 
key secondary efficacy endpoint 
analysis will include participants 
regardless of their symptom onset. 
Section 10
Supporting Documentation 
and Operational 
Considerations
Age for those postmenopausal 
females requiring FSH test at 
screening updated from under 
60 years to under 50 years to be 
consistent with the SoA
For clarification and to ensure 
consistency.
Appendix 10
Added Japan country-specific 
guidance regarding Exclusion 
Criterion #6. 
To incorporate country-specific 
changes into the global protocol.


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Section # and Name
Description of Change
Brief Rationale
Throughout the protocol
Typographical errors were 
corrected and minor edits were 
made.
For clarification and to ensure 
consistency.
Amendment 3 (26 October 2021)
Overall Rationale for the Amendment: To include an additional planned interim analysis 
for efficacy and futility to be done after approximately 70% of participants in the mITT 
analysis set complete the Day 28 assessments (ie, 28 days after randomization).
Section # and Name
Description of Change
Brief Rationale
Section 1.1
Synopsis
Describes changes made in 
Sections 4 and 9 below.
Correction made in 
description of the first interim 
analysis to show that it was 
planned for efficacy and 
futility, rather than efficacy 
and safety.
Primary 
Endpoint(s)/Estimand(s) 
Analysis: updated to include 
primary analysis conducted 
for 2 planned interim analyses.
Added approximately to the 
following statement: 
Enrollment of participants that 
had COVID-19 symptom 
onset >3 days prior to 
randomization is expected to 
be approximately 25%, and 
will be limited to a total of 
approximately 
1000 participants
Sample Size Determination: 
text updated: To allow for a 
5% dropout rate, enrollment 
will be stopped after 
approximately 1870 
participants have been 
enrolled to ensure at least 
1779 participants are available 
for the primary analysis.
Sample size increased from 
approximately 3000 
participants to approximately 
To summarize changes made in the 
document.


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Section # and Name
Description of Change
Brief Rationale
3100 participants due to 
addition of second interim 
analysis.
Section 1.2
Schema
Added new Schema per PACL 
12 August 2021
To correct a formatting error.
Section 1.3
Schedule of Activities
Information added from 
12 August 2021 PACL under 
“other laboratory 
assessments”
Clarifications made to Day 1 
and Day 5 PK sample 
collection text. 
ET pregnancy added. 
Text added to clarify that 
targeted physical 
examinations will be 
completed at the following in-
person visits: Days 14 and 34, 
and ET (prior to Day 34). 
Text from Section 7.1.1 
repeated in this section to 
clarify that post screening 
eGFR result of 
<45 mL/min/1.73m2 should 
result in discontinuation of 
study intervention.
Staff review of study diary 
added at Days 1 and 3 to 
ensure that it is reviewed 
during first few days of study.
Text added to footnotes to 
clarify that telemedicine visits 
may be conducted in-person at
the discretion of the 
investigator.
To update as per PACL 12 August 2021 
and to clarify other language in the 
Schedule of Assessments.
Section 2.3.3 
Overall Benefit/Risk 
Conclusion
Text updated to clarify that the 
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 and futility at the time of 
the interim analyses.
To be consistent with the rest of the 
document.
Section 4.1
Overall Design
Sample size updated from 
approximately 3000 
participants to approximately
3100 participants due to 
To provide a more comprehensive 
description of the overall study design.


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Section # and Name
Description of Change
Brief Rationale
addition of second interim 
analysis.
Language added to Section 4.1 
information already included 
in the protocol, in order to 
describe the expected 
percentage of participants who 
will fall in to the mAb 
treatment group and the 
capping of participants with 
symptom onset >3 days.
Added information about the 
addition of a second interim 
analysis. 
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 7.1
Discontinuation of Study 
Intervention
Updated text about 
discontinuation of study 
intervention due to an AE.
Removed requirement to 
discontinue study intervention 
if a participant is hospitalized 
during the active treatment 
period.
Added that in the event a 
participant is hospitalized, 
study intervention may 
continue to be administered, 
as feasible, and based on 
medical judgement of the 
investigator.
AE language updated to clarify that 
not all AEs will result in 
discontinuation of study 
intervention.
Updated in order to allow the 
investigator to use medical 
judgment to decide whether 
participant will remain on study 
intervention during hospitalization.
Section 9 
Statistical Considerations

9.3.1 General 
Considerations: Mean and 
SEM removed from tabular 
summaries of the 
Kaplan-Meier curves.

9.3.2 Primary 
Endpoint(s)/Estimand(s) 
Analysis: updated to include 
primary analysis conducted 
for 2 planned interim 
analyses.
With the addition of a second interim 
analysis while controlling for the 
overall significance level of 5%, an 
adjustment is applied to the sample size 
such that approximately 60 additional 
participants are needed for the primary 
analysis resulting in a total of 1779 
participants instead of the original 1717 
participants. Therefore, the updated 
total sample size based on this second 
interim analysis is 3100 participants 
instead of 3000 participants.


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Section # and Name
Description of Change
Brief Rationale
 
 
 
 
•
9.4. Interim Analyses: 
Second interim analysis 
added. 
•
9.5 Sample Size 
Determination: text updated: 
To allow for a 5% dropout 
rate, enrollment will be 
stopped after approximately 
1870 participants have been 
enrolled to ensure at least 
1779 participants are 
available for the primary 
analysis.
•
Total sample size changed 
from 3000 to 3100 
participants.
Section 10 
Supporting documentation 
and Operational 
considerations
•
Second interim analysis 
added.
To add the addition of the second 
interim analysis to the Data Monitoring 
Committee description under 
Committee Structure.
Appendix 8
Updated with information from 
PACL and additional updates.
Corrections and updates to the list of 
precautionary and prohibited 
medications
Throughout the protocol
Typographical errors were 
corrected and minor edits were 
made.
For clarification and to ensure 
consistency.
C
C
I


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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
maximum observed concentration
CO2
carbon dioxide (bicarbonate)
CONSORT
Consolidated Standards of Reporting Trials
COVID-19
coronavirus disease 2019
CPAP
Continuous positive airway pressure
CRF
case report form
CRO
contract research organization
CSR
clinical study report
CT
clinical trial
Ctrough
predose concentration
CVD
cardiovascular disease
CYPx
cytochrome P450


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Abbreviation
Term
DAA
direct acting antivirals
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
epidermal growth factor receptor
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
HDPE
high-density polyethylene


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Abbreviation
Term
HF
heart failure
HIV
human immunodeficiency virus
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
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
IV
intravenous(ly)
IWR
interactive Web-based response
KM
Kaplan Meier
LDH
lactate dehydrogenase
LFT
liver function test
mAb
monoclonal antibody
MAD
multiple ascending dose
MDR1
multidrug resistance mutation
mITT
modified intent-to-treat 
MMRM
mixed-effect model repeated measure
msec
millisecond
MRC-5
human lung epithelial cells-5
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
PCI
percutaneous coronary intervention
PDE-5
phosphodiesterase


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Abbreviation
Term
PK
pharmacokinetic(s)
PP
per-protocol
PRO
patient reported outcomes
PT
prothrombin 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
RT-PCR
reverse transcription polymerase chain reaction
RTV
ritonavir
SAD
single ascending dose
SAE
serious adverse event
SAP
statistical analysis plan
SARS-CoV-2
severe acute respiratory syndrome coronavirus 2
SAS
safety analysis set
SCR
serum creatinine
SEM
standard error of the mean
SoA
schedule of activities
SoC
standard of care
SOC
system organ class
SOP
standard operating procedure
SRSD
single reference safety document
SUSAR
suspected unexpected serious adverse reaction
T4
thyroxine
TBili
total bilirubin
TEAE
treatment-emergent adverse event
TIA
transient ischemic attack
TSH
thyroid-stimulating hormone
ULN
upper limit of normal
US
United States
USPI
United States Prescribing Information; United States Package 
Insert
VAS
visual analogue scale
WBC
white blood cell
WHO
World Health Organization
WOCBP
woman/women of childbearing potential
WPAI
Work Productivity and Impairment


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https://rsc.niaid.nih.gov/sites/default/files/daidsgradingcorrectedv21.pdf. Accessed 
on: 10 Jun 2021.
43.
Benjamini Y, Hochberg Y. Controlling the false discovery rate: a practical and 
powerful approach to multiple testing. Journal of the Royal statistical society: series 
B. 1995;57(1):289-300.


PF-07321332
Protocol C4671005
Final Protocol Amendment 4, 20 November 2021
PFIZER CONFIDENTIAL 
Page 126
44.
Cui L, Hung HM, Wang SJ. Modification of sample size in group sequential clinical 
trials. Biometrics. 1999;55(3):853-7.
45.
US Food and Drug Administration. Guidance for industry: adaptive design clinical 
trials for drugs and biologics November 2019. . Report Number: 16 June 2021. 
Available from: https://www.fda.gov/regulatory-information/search-fda-guidance-
documents/assessing-covid-19-related-symptoms-outpatient-adult-and-adolescent-
subjects-clinical-trials-drugs. Accessed on: 01 July 2021.


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SAP_001.pdf: 
Protocol C4671005 (PF-07321332) Statistical Analysis Plan
PFIZER CONFIDENTIAL 
Page 1
Protocol C4671005
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 INCREASED RISK 
OF PROGRESSING TO SEVERE ILLNESS
Statistical Analysis Plan 
(SAP)
Version:
1.5 (Amendment)
Date:
28APR2022


Protocol C4671005 (PF-07321332) Statistical Analysis Plan
PFIZER CONFIDENTIAL 
Page 2
TABLE OF CONTENTS
LIST OF TABLES.....................................................................................................................4
LIST OF FIGURES ...................................................................................................................4
APPENDICES ...........................................................................................................................4
1. VERSION HISTORY............................................................................................................5
2. INTRODUCTION ...............................................................................................................11
2.1. Study Objectives, Endpoints, and Estimands..........................................................11
2.1.1. Primary Estimand .......................................................................................12
2.1.2. Secondary Estimands..................................................................................12
2.2. Study Design ...........................................................................................................12
2.3. Sample Size Determination.....................................................................................14
3. ENDPOINTS AND BASELINE VARIABLES:  DEFINITIONS AND 
CONVENTIONS ................................................................................................................14
3.1. Primary Endpoint ....................................................................................................14
3.2. Secondary Endpoint(s) ............................................................................................14
3.4. Baseline Variables...................................................................................................15
3.5. Stratification Variables............................................................................................15
3.6. Safety Endpoints .....................................................................................................16
3.6.1. Adverse Events...........................................................................................16
3.6.2. Medical History ..........................................................................................17
3.6.3. Height and Weight......................................................................................17
3.6.4. Laboratory Data..........................................................................................17
3.6.5. Vital Signs ..................................................................................................17
4. ANALYSIS SETS (POPULATIONS FOR ANALYSIS)...................................................17
5. GENERAL METHODOLOGY AND CONVENTIONS....................................................18
5.1. Hypotheses and Decision Rules ..............................................................................18
5.2. General Methods .....................................................................................................19
5.2.1. Analyses for Binary Endpoints...................................................................19
5.2.2. Analyses for Continuous Endpoints ...........................................................20
5.2.3. Analyses for Categorical Endpoints ...........................................................20
5.2.4. Analyes for Count Endpoints......................................................................20
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Protocol C4671005 (PF-07321332) Statistical Analysis Plan
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5.2.5. Analyses for Time-to-Event Endpoints ......................................................20
5.3. Methods to Manage Missing Data ..........................................................................20
6. ANALYSES AND SUMMARIES ......................................................................................21
6.1. Primary Endpoint ....................................................................................................21
6.1.1. Primary Endpoint/Estimand Analysis.........................................................21
6.1.1.1. Main Analysis ...........................................................................21
6.1.1.2. Supplementary Analyses...........................................................22
6.2. Secondary Endpoint(s) ............................................................................................23
6.2.1. Proportion of Participants with COVID-19 Related Hospitalization 
or Death due to All Cause through Day 28 in mITT1 Analysis Set ................23
6.2.2. Incidence of Treatment Emergent Adverse Events (TEAEs).....................23
6.2.3. Incidence of SAEs and AEs Leading to Discontinuations .........................23
6.2.4. Time (days) to Sustained Alleviation and Time to Resolution of 
Targeted COVID-19 Sign/Symptoms through Day 28....................................23
6.2.5. Proportion of Participants with Severe Signs/Symptoms Attributed to 
COVID-19 through Day 28 .............................................................................24
6.2.6. Duration of Each Targeted COVID-19 Sign/Symptom through Day 
28......................................................................................................................25
6.2.7. Progression to a Worsening Status in 1 or More Self-reported 
COVID-19 Associated Symptoms through Day 28.........................................26
6.2.8. Proportion of Participants with a Resting Peripheral Oxygen 
Saturation ≥95% at Days 1 and 5.....................................................................26
6.2.9. Proportion of Participants with Death (all-cause) Through Week 24 ........27
6.2.10. PF-07321332 Plasma PK in Plasma and Whole Blood (if feasible) ........27
6.2.11. Viral Titers Measured via RT-PCR in Nasal Swabs Over Time..............27
6.2.12. Number of COVID-19 Related Medical Visits ........................................28
6.2.13. Number of Days in Hospital and ICU Stay in Participants with 
COVID-19 Related Hospitalization.................................................................28
6.4. Subset Analyses.......................................................................................................28
6.5. Baseline and Other Summaries and Analyses.........................................................30
6.5.1. Baseline Summaries....................................................................................30
6.5.2. Study Conduct and Participant Disposition................................................30
6.5.3. Study Treatment Exposure .........................................................................30
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Protocol C4671005 (PF-07321332) Statistical Analysis Plan
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6.5.4. Prior and Concomitant Medications...........................................................30
6.6. Safety Summaries and Analyses .............................................................................30
6.6.1. Adverse Events...........................................................................................30
6.6.2. Laboratory Data..........................................................................................31
6.6.3. Vital Signs ..................................................................................................31
6.6.4. Electrocardiograms.....................................................................................31
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.
C4671005 Study Design ...........................................................................13
APPENDICES
Appendix 1. Summary of Efficacy Analyses...........................................................................34
Appendix 2. Data Derivation Details.......................................................................................40
Appendix 2.1. Definition and Use of Visit Windows in Reporting.........................................40
Appendix 3. List of Abbreviations...........................................................................................41
Appendix 4. List of pre-specified AESIs.................................................................................42
Appendix 5. COVID-19 Signs/Symptoms...............................................................................43


Protocol C4671005 (PF-07321332) Statistical Analysis Plan
PFIZER CONFIDENTIAL 
Page 5
1. VERSION HISTORY
Table 1.
Summary of Changes
Version/
Date
Associated
Protocol 
Amendment
Rationale
Specific Changes
1.0
1.0
SAP original version
1.1
2.0
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. 
The primary analysis 
set (mITT) has been 
refined to include just 
those participants who 
were treated ≤3 days 
after COVID-19 
symptom onset
(mITT).
As of protocol amendment 2, dated 
02 August 2021 the following changes have
been incorporated:

On Section 2.1.1 the primary 
estimand changed to specify 
inclusion of participants who did not 
receive COVID-19 therapeutic 
mAbs and who were treated ≤3 days 
after COVID-19 symptom onset.

On Section 2.1.2 the key secondary 
efficacy endpoint was added as a 
consequence of the change in 
primary efficacy analysis and the 
analysis will include participants 
regardless of their symptom onset
mITT2).

Updated sample size in Section 2.3 
from 2260 to approximately 
3000 participants.  Enrollment of 
participants that had COVID-19 
symptom onset >3 days prior to 
randomization is expected to be 
approximately 25% and will be 
limited to approximately 
1000 participants. Sample size has 
been adjusted, and the analysis of all 
participants is now a secondary 
analysis.

Updated definition of baseline visit 
and baseline derived variables 
(Section 3.4).


Protocol C4671005 (PF-07321332) Statistical Analysis Plan
PFIZER CONFIDENTIAL 
Page 6

Added definition of stratification 
variable geographical region 
(Section 3.5).

Added list of stratification variables 
by analyses population (Section 3.5).

Throughout the document, replaced 
“subject” by “participant”.

Analyses populations mITT, mITT1 
and mITT2 populations were 
updated (Section 4). mITT analysis 
set added now includes participants 
who did not receive nor were 
expected to receive COVID-19 
therapeutic mAb, and who were 
treated ≤3 days after COVID-19 
symptom onset.  

Changed analysis set for the primary 
efficacy analysis from mITT1 to 
mITT (Section 4).

Added sequential testing for efficacy 
secondary endpoints (Section 5.1).

Updated Section 5.2.2 to include the 
ANCOVA model or change from 
baseline to Day 5 of viral load data
(POC analysis).

Added details on methods of 
handling missing data (Section 5.3).

Updated Section 6.1.1.1 due to the 
change in primary analysis. Two 
new sensitivity analyses were added 
as well. 

Updated Section 6.1.1.2 on logistic 
regression analysis model. 

Updated analyses populations for all 
secondary efficacy 


Protocol C4671005 (PF-07321332) Statistical Analysis Plan
PFIZER CONFIDENTIAL 
Page 7
endpoints/analyses (Sections 6.2.3 
up to 6.2.12).

Updated statistical methodology for 
three secondary efficacy endpoints 
(Section 6.2.5 and 6.2.8), logistic 
regression is used instead the 
previous KM methodology.

Added two subgroup analyses (by 
baseline serology status & baseline 
viral load) for two secondary 
endpoints (Section 6.2.4 and 6.2.5).

Updated Table of summary of 
efficacy analysis in Appendix 1 to 
reflect the protocol amendment 
changes in analyses populations, a 
new key secondary analysis of 
primary endpoint, POC analysis and 
logistic regression model as 
statistical analyses for three 
secondary efficacy endpoints 
previously analysed by KM method.

Table of summary of efficacy 
analyses in Appendix 1.

Appendix 1 changed analyses 
populations, as well as 
methodologies for secondary 
endpoints (ie. logistic regression for 
secondary endpoints).

Updated visit window for efficacy 
endpoints to Appendix 2. 

Added Appendix 4 with list of 
adverse events of special interest.

Added Appendix 5 with list of 
Targeted signs/symptoms.
As of DMC Blinded Data Review, dated 
01Oct 2021 the following changes have
been incorporated:


Protocol C4671005 (PF-07321332) Statistical Analysis Plan
PFIZER CONFIDENTIAL 
Page 8

Clarified text for sustained 
alleviation analysis (Section 6.2.4).

Updated Section 6.2.5 categories 
labels for vomiting, diarrhea, sense 
of smell and sense of taste 
signs/symptoms. 

Updated sections 6.2.5, 6.2.7,-6.2.8, 
6.2.9 on statistical methodology for 
the logistic regression model. 

Updated Section 6.2.11 to include a 
sensitivity analyses for change from 
baseline and Day 5 in viral load.
These are the samples that will be 
used on the proof-of-concept (POC) 
analysis. 

Updated Section 6.5.2 to reflect 
changes to disposition tables based 
on DMC blinded data reviews.

Clarified language regarding safety 
analyses (Section 6.6).

Updated Section 6.6.2 to include 
laboratory shift tables/analyses.

Section 7.1 has been updated and 
references the interim analysis plan 
SAP. 
V1.2
3.0
To include an 
additional planned 
interim analysis for 
efficacy and futility to 
be done after 
approximately 70% of 
participants in the 
mITT analysis set 
complete the Day 28 
assessments 
(ie, 28 days after
randomization).

Updated Section 2.3 with sample 
size increased from approximately 
3000 to approximately 3100 due to 
addition of second interim analysis.

Updated Section 2.3 text to allow for 
a 5% dropout rate, enrollment will 
be stopped after approximately 
1870 participants have been enrolled 
to ensure at least 1779 participants 
are available for the primary 
analysis. Current language matches 
language in protocol.


Protocol C4671005 (PF-07321332) Statistical Analysis Plan
PFIZER CONFIDENTIAL 
Page 9

Changed sequential testing order for 
efficacy secondary endpoints 
(Section 5.1) to match protocol.

Updated Section 6.1.1.1 due to the 
addition of second interim analysis.  

Updated Section 6.1.1.1 a new 
sensitivity analyses were added as 
well.

Clarification regarding the 
stratification variables specified on 
Section 3.5 was added to Sections 
6.1.1.2, 6.2.4, 6.2.7 and 6.2.11.

Updated Section 7.1 text to include a 
second interim analysis. Interim 
analysis methodology was updated 
throughout the section. 

Updated visit window for Day 34 for 
efficacy endpoints to Appendix 2. 

To remove the second interim (70% 
interim that was added under 
amendment # 3) from the protocol  
because the objective of the planned 
45% IA met.

To include the sensitivity analysis 
requested by FDA.

Updated to include additional 
analysis for severe targeted signs 
and symptoms of COVID-19.

Updated to included subgroup 
analysis for mITT & mITT1.

Due to limited number of 
participants enrolled in Brazil, 
Brazil region will combine with rest 
of the World region.


Protocol C4671005 (PF-07321332) Statistical Analysis Plan
PFIZER CONFIDENTIAL 
Page 10

To include the sensitivity analysis 
excluding all participants from 
Site1470.

Updated to include the sensitivity 
analysis excluding all data from 
India Sites.

Updated the section of the sample 
size due to removal of second interim 
analysis.
V1.3
4.0

Updated visit window for Day 34 for 
efficacy endpoints to Appendix 2. 

To remove the second interim 
(70% interim that was added under 
amendment #3) from the protocol  
because the objective of the planned 
45% IA met.

To include the sensitivity analysis 
requested by FDA.

Updated to include additional 
analysis for severe targeted signs 
and symptoms of COVID-19.

Updated to included subgroup 
analysis for mITT & mITT1.

Due to limited number of 
participants enrolled in Brazil, 
Brazil region will combine with rest 
of the World region.

To include the sensitivity analysis 
excluding all participants from 
Site1470.

Updated to include the sensitivity 
analysis excluding all data from 
India Sites.


Protocol C4671005 (PF-07321332) Statistical Analysis Plan
PFIZER CONFIDENTIAL 
Page 11

Updated the section of the sample 
size due to removal of second interim 
analysis.
V1.4
4
To update the mITT, 
mITT1 and mITT2 
population definition  
based on FDA request. 

Section 4 is updated to modify 
mITT, mITT1 and mITT2 
populations as requested by FDA.
V1.5
4
To add additional 
efficacy analyses at 
Week 12 and Week 24
and additional 
analyses clarifications.

Updated Section 6.2.5 by adding an 
additional analyses: Summary of 
Proportion of Participants with Any 
Signs/Symptoms Attributed to 
COVID-19 at Week 12 and 
Week 24.

Updated Section 6.2.9 to allow the 
possibility of cells with zero counts.

Updated/added more information for 
analysis sets in Section 4 handling 
duplicate enrollment for IA and 
PCD primary efficacy analyses. 

Updated Appendix 1 with sensitivity 
analysis for IA and PCD primary 
efficacy analyses.
For the entire document, text in Italic format will represent language copied directly from 
protocol.
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 
increased risk of progressing to severe illness.
2.1. Study Objectives, Endpoints, and Estimands
Primary Efficacy Objective: To compare the efficacy of PF-07321332/ritonavir to placebo 
for the treatment of COVID-19 in nonhospitalized symptomatic adult participants with 
COVID-19 who are at increased risk of progression to severe disease.


Protocol C4671005 (PF-07321332) Statistical Analysis Plan
PFIZER CONFIDENTIAL 
Page 12
Secondary Efficacy Objective: 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 increased 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 increased risk of progression to severe disease.
2.1.1. Primary Estimand
The difference in proportions of patients experiencing COVID19 related hospitalization or 
death from any cause through Day 28 in nonhospitalized adult patients with symptomatic 
COVID-19 who are at increased risk of progression to severe disease (as defined in 
Section 5.1 in Protocol) who did not receive COVID-19 therapeutic mAb treatment, and were 
treated ≤3 days after COVID-19 symptom onset. This will be estimated without regard to 
adherence to randomized treatment.
2.1.2. Secondary Estimands
The estimand associated with the key secondary efficacy objective 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 symptomatic COVID-19 who 
are at increased risk of progression to severe disease and who did not receive COVID-19 
therapeutic mAb treatment. This will be estimated without regard to adherence to 
randomized treatment.
The estimand associated with the secondary efficacy objective regarding the duration and 
severity of signs and symptoms is the absolute difference in median time to sustained 
alleviation or resolution of symptoms for all nonhospitalized adult patients with COVID 19 
who are at increased risk of progression to severe disease. This will be estimated irrespective 
of adherence to randomized treatment.
The hospitalization/death rate through Day 28 is considered the main clinical outcome 
measure and signs/symptom duration is considered key secondary for this study and so 
estimands for these measures are presented. Estimands for the other outcome measures that 
are considered supportive of the primary outcome measures and of the sign/symptoms 
duration and severity outcome measure are not presented.
2.2. Study Design
This Phase 2/3, randomized, double-blind, placebo-controlled study in approximately 
2260 symptomatic 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 randomized (1:1) to 
receive PF-07321332 and ritonavir or placebo orally q12h for 5 days (10 doses total). 
Randomization will be stratified by geographic region and by whether participants have
received/are expected to receive treatment with COVID-19 therapeutic mAbs based on the


Protocol C4671005 (PF-07321332) Statistical Analysis Plan
PFIZER CONFIDENTIAL 
Page 13
site investigator’s assessment at time of randomization. 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, 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 to ensure the safety of participants on an 
ongoing basis 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 60 participants have completed Day 10 of the study, at which 
point enrollment will be paused pending E-DMC review of the safety data. After 
review of the sentinel cohort, the frequency of safety reviews may be reduced 
subsequently based on E-DMC recommendations.

Proof-of-concept assessment: The E-DMC will review viral load data when 
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.

Formal interim analysis: A planned formal interim analysis for efficacy and futility 
with a sample size re-estimation will be done after approximately 45% of participants 
in the mITT analysis set complete the Day 28 assessments.
Subsequent to the planned interim analyses, there will be 2 analyses for reporting the results 
of this study. The primary analysis will be performed after all participants have completed 
the Day 34 visit. The follow-up analysis will be performed after all participants have 
completed the Week 24 visit. The study schematic is provided in Figure 1.
Figure 1.
C4671005 Study Design


Protocol C4671005 (PF-07321332) Statistical Analysis Plan
PFIZER CONFIDENTIAL 
Page 14
2.3. Sample Size Determination
This study is designed to have 90% statistical power to show a difference of 3.5% in the 
proportion of participants hospitalized/dying that did not receive COVID-19 therapeutic 
mAb between the treatment arms (PF07321332/ritonavir versus placebo) and were treated 
≤3 days after COVID-19 symptom onset, using a 2-sided Type I error rate of 5%. Based on 
the BLAZE study2, the proportion of hospitalization/death in the placebo arm is assumed to 
be 7%. 
Using EAST (Version 6.5) for a 2 sample proportion test1, the sample size needed to detect a 
3.5% difference with 90% power at a 2-sided significance level of 5% was determined to be 
1717 randomized participants. Enrollment of participants who at baseline had received or 
were expected to receive COVID-19 therapeutic mAb treatment is estimated to be 
approximately 20% of participants and limited/capped to 25% enrollment. 
Enrollment of participants that had COVID-19 symptom onset >3 days prior to 
randomization is expected to be approximately 25% and will be limited to approximately 
1000 participants. Assuming a 5% dropout rate, the total sample size for this study will be 
approximately 3000 participants.
To allow for a 5% dropout rate, enrollment will be stopped after approximately 
1717 participants are available for the primary analysis. 
3. ENDPOINTS AND BASELINE VARIABLES: DEFINITIONS AND 
CONVENTIONS
3.1. Primary Endpoint

Proportion of participants with COVID-19 related hospitalization or death from any 
cause through Day 28. 
3.2. Secondary Endpoint(s)

The first key secondary efficacy endpoint is the proportion of participants with 
COVID-19 related hospitalization or death due to any cause through Day 28 in the 
mITT1 analysis set.

Incidence of treatment emergent adverse events (TEAEs).

Incidence of SAEs and AEs leading to discontinuations.

Time (days) to sustained alleviation of all targeted signs/symptoms through Day 28.

Proportion of participants with severe signs/symptoms attributed to COVID-19 
through Day 28.

Time (days) to sustained resolution of all targeted signs/symptoms through Day 28.


Protocol C4671005 (PF-07321332) Statistical Analysis Plan
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Page 15
•
Duration of each targeted COVID-19 sign/symptom.
•
Progression to a worsening status in 1 or more self reported COVID19 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.
•
Number of COVID-19 related medical visits.
•
Number of days in hospital and ICU stay in participants with COVID-19 related 
hospitalization.
3.4. Baseline Variables
For viral load data, baseline visit is set up according to study days of Day -2 to Day 1. Only 
results that are within 1 hour post start of dosing will be treated as Baseline data. Laboratory 
assessments Signs and Symptoms, Vital Signs and ECG: Baseline window will be Day -2 to 
Day 1, without any consideration to the time factor.
The following baseline variables will be used in efficacy analyses. See below a list of derived 
baseline variables based on baseline viral load data:
•
Baseline viral load defined as: <104 copies/mL vs ≥104 copies/mL.
•
Baseline viral load defines as: <107 copies/mL vs ≥107 copies/mL.
•
Baseline serology status defined as positive or negative.
3.5. Stratification Variables
Randomization will be stratified by geographic region and whether participants had received
or were expected to receive COVID-19 therapeutic mAb treatment (yes/no) based on the site 
investigator’s assessment at the time of randomization. Randomization for the strata where 
participants had received or were expected to receive COVID-19 therapeutic mAb treatment 
will be capped at a maximum of 25% enrollment. Unless otherwise indicated analyses will 
include calculated values for quantitative stratification variables. Geographical region is 
defined as follows:
CCI


Protocol C4671005 (PF-07321332) Statistical Analysis Plan
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
US region: country of the United States, including Puerto Rico.

Europe region: countries of Bulgaria, Czech Republic, Hungary, Netherlands, Poland, 
Spain, and Ukraine.

Brazil region: country of Brazil.

India region: country of India.

Rest of the World region: countries of Argentina, Colombia, Japan, Malaysia, 
Mexico, Peru, Russian Federation, South Africa, Republic of Korea, Taiwan, 
Thailand, and Turkey. 
If a region enrolled <10 participants, the region will be combined with the “rest f the word” 
region. 
Baseline and stratification variables above defined will be applied to the analyses depending 
on the analysis population used:

mITT analyses will include the following stratification variables: Baseline viral load, 
baseline serology status, geographic region.

mITT1 analysis will include: Baseline viral load, baseline serology status, geographic 
region and symptom onset days to first dose date (≤3 days, >3 days).

mITT2 analyses will include: Baseline viral load, baseline serology status, geographic 
region, received or were expected to receive mAb treatment (yes/no) and symptom 
onset days to first dose date (≤3 days, >3 days).
3.6. Safety Endpoints
The safety endpoints of this study are: 

Incidence of TEAEs.

Incidence of SAEs and AEs leading to discontinuations.
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 Treatment-
Emergent Adverse Event (TEAE) if the event started on or after the study medication start 
date and time. 


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3.6.2. Medical History
Medical history in addition to COVID-19 disease history and demographics will be collected 
at screening. Smoking status will be collected. Medication history of prescription or 
nonprescription drugs (including vaccinations), and dietary and herbal supplements taken 
within 30 days prior to the planned first dose will be collected.
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.  
Modified Intent-To-Treat 
(mITT)
All participants randomly assigned to study intervention, who 
take at least 1 dose of study intervention, who at baseline did 
not receive nor were expected to receive COVID-19 therapeutic 
mAb treatment and were treated ≤3 days of COVID-19 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,  and who at baseline 


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Population
Description
did not receive nor were expected to receive COVID-19 
therapeutic mAb treatment. Participants will be analyzed 
according to the study intervention to which they were 
randomized.
Modified Intent-To-Treat 
2 (mITT2)
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 mITT set without important protocol 
deviations considered to impact the interpretation of the 
primary efficacy endpoint. Protocol deviations will be reviewed 
to generate the list of participants with significant deviations to 
be excluded from the PP analysis set. The PP exclusion criteria 
will be finalized prior to breaking the blind.
For the primary efficacy analysis, the mITT set will be used and will be the primary analysis. 
A secondary analysis of the primary efficacy endpoint will be performed and will use mITT1 
and mITT2 analysis set. For all other efficacy analyses mITT, mITT1, and mITT2 sets will be 
used (3 sets of analyses). The PP analysis set will be used in the analyses of primary efficacy 
endpoint. The Safety Analysis Set will be used in the analyses of the safety data.  
For efficacy related analysis (mITT, mITT1 and mITT2), if a participant enters/is randomized 
into the study multiple times, a sensitivity analysis based on IA and PCD efficacy data will be 
conducted on the primary endpoint and all sensitivity analysis regarding primary endpoint. The 
data associated with first randomization will be included in the above sensitivity analyses 
conducted. 
5. GENERAL METHODOLOGY AND CONVENTIONS
5.1. Hypotheses and Decision Rules
The primary hypothesis to be tested is whether or not there is a difference in proportion of 
participants with COVID-19 related hospitalization or death from any cause through Day 28
between PF-7321332/ ritonavir and placebo. The statistical hypothesis is as follows:
Ho:   πPF-7321332 - πplacebo = 0
versus 
(1)
Ha:  π PF-7321332 - πplacebo ്0
Where p PF-7321332 and pplacebo are the proportion of participants with hospitalization or death 
through Day 28. The hypotheses will be tested at an overall significant level of 5% (2-sided).


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Following the positive test of the primary endpoint, sequential testing will be performed for 
the following 2 secondary endpoints:

Proportion of participants with COVID-19 related hospitalization or death from any 
cause through Day 28 who did not receive COVID-19 therapeutic mAb treatment, 
regardless of their onset of COVID-19 related signs and symptoms.

Time (days) to sustained alleviation of all targeted signs/symptoms through Day 28.
The time to sustained alleviation of all targeted signs/symptoms through Day 28 will be 
tested first. If this test is positive, then will continue with second endpoint. The hypotheses 
will be tested at an overall level of 5% (2-sided).
Other secondary endpoints listed below will be subsequently tested following the Hochberg 
procedure1: 
1. Time (days) to sustained resolution of all targeted signs/symptoms through Day 28.
2. Proportion of participants with a resting peripheral oxygen saturation ≥95% at 
Days 1 and 5.
3. Number of COVID-19 related medical visits.
5.2. General Methods
All data will be presented by treatment group. Descriptive statistics will be provided for 
efficacy endpoints. 
The number of participants screened, randomized to the double-blind treatment phase, 
completing the study drug administration, and completing the study will be summarized from 
the FAS. The reason for all discontinuations will be summarized by treatment group.
Baseline demographic and other characteristics will be tabulated for the FAS and
summarized by treatment group. Quantitative variables will be described by standard
descriptive statistics (mean, standard deviation, median and range), and qualitative variables 
will be summarized by frequency tables with number and proportion in each category (with 
the corresponding sample sizes).
5.2.1. Analyses for Binary Endpoints
For binary endpoints (ie, proportion of participants with COVID-19 related hospitalization or 
death from any cause through Day 28, proportion of participants with severe targeted
signs/symptoms attributed to COVID-19 through Day 28, worsening status in 1 or more self
reported COVID19 associated targeted signs/symptoms through Day 28 and proportion of 
participants with death (all-cause) through Week 24), proportion of participant with the event 
will be summarized for each group. Treatment comparison between the group will be 


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presented as the difference of proportions with its 95% confidence intervals using a similar 
analysis method as the primary endpoints.
5.2.2. Analyses for Continuous Endpoints
For continuous endpoint, (ie, viral titers measured via RT-PCR in nasal swabs over time), an 
ANCOVA model will be used to analyze change from baseline (Day 1) to Day 5. 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.
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. Analyes for Count Endpoints
For count endpoints (ie. number of COVID-19 related medical visits  and number of 
hospitalizations/ICU visits), a negative binomial regression model analysis, using the 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
For time-to-event endpoints (ie, time (days) to sustained alleviation/resolution of all targeted 
signs/symptoms through Day 28 and duration of each targeted COVID-19 sign/symptom),
2 analyses may be provided: (1) a Cox proportional hazard regression model where the 
estimate of the hazard ratio for treatment (PF-07321332 vs Placebo), its confidence interval 
and p-value will be provided; and (2) Kaplan-Meier analysis where tabular summaries of the 
Kaplan-Meier curves providing the median and quartiles, will be provided for each treatment 
group. In addition, the KM curves will be presented graphically.
5.3. Methods to Manage Missing Data
For missing efficacy data other than time to event endpoints, a mixed baseline observation 
carried forward (BOCF)/ last observation carried forward (LOCF) approach will be used. See 
below:

For efficacy endpoints related to COVID-19 targeted sign/symptoms, missing data at 
baseline will be treated as mild. If participant discontinues study due to AE or 
discontinues study at same time of treatment discontinuation due to lack of efficacy,
missing data will use BOCF. Otherwise, missing data will use LOCF.
For safety data, missing and partial dates will be programmatically handled according to 
Pfizer standards. 


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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 proportion of participants with COVID-19 related hospitalization or 
death from any cause through Day 28 in the mITT population. 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 losses to follow-up and summarized graphically for each treatment group. 
The estimand is then the difference of the proportions in the 2 treatment groups and its 
95% confidence interval will be presented, as well as, the associated two-sample proportion 
test. For the 95% CI, the corresponding estimate of the standard error is computed using 
Greenwood’s formula (Kalbfleisch and Prentice; 1980). 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) we will use the log-log approach to CI. The 
95% CI will be computed for the estimate of L(t)= log(-log(S(t))), the log hazard function. 
ܸܽݎ൫ܮ෠ሺݐሻ൯ൌܸܽݎቂ݈݋݃൬െ݈݋݃ቀܵመሺݐሻቁ൰ቃ
The CI will be in right range when we transform back to S(t) = exp (-exp (L(t)). Antilogging 
this confidence interval will give a 95% confidence interval for the difference itself.
The above primary analysis will be conducted for the planned interim analyses as well. 
Two-sided 95% CI (adjusted for the planned interim analyses) and associated p-value 
(two-sample proportion test) for the null hypothesis of no difference between treatment 
groups will be presented. Significance level will be determined using the O’Brien-Fleming 
approach at the interim analysis and the final analysis. The overall significance level is set at 
5% (2 sided).
For participants who complete Day 28 efficacy assessment (Day 34 visit), they will be 
censored at their last visits. For participants who discontinue before Day 28 assessment or are 
lost to follow-up, they will be censored at the last known date in the study.
Participants will be analysed under the mAb stratum assigned at randomization/baseline.
The proportion of participants with COVID-19 related hospitalization or death from any 
cause through Day 28 will be summarized graphically using Kaplan-Meier plots for each of 
the treatment groups, the analyses will be done using mITT, mITT1, and mITT2 populations.
The sensitivity analysis associated with primary endpoint will be conducted using the mITT2 
population set. Four addditional sensitivity analysis for the primary endpoint will be 
performed:


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
a sensitivity analysis excluding all data from India sites for the mITT population;

a sensitivity analysis excluding all participants from Site 1470 for the mITT, mITT1 
and mITT2 populations;

a sensitivity analysis excluding participants from the sentinel cohort of the study 
treated with active treatment (3 doses of 100 mg) for the mITT population;

An additional sensitivity analysis for participants with missing data (i.e., participant 
who was without any COVID-19 related hospitalization or death of any cause but 
discontinued from study due to lost to follow up and their last observations are <28
days) will be performed for the mITT population. The sensitivity analysis will 
implement the following event imputation methodology for those with missing data 
for primary endpoint:

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 participant remains censored at day of last observed data.
6.1.1.2. Supplementary Analyses
Supplemental analyses will be performed to the primary efficacy endpoint. See below:
1. An analysis in the mITT analysis set of the primary endpoint where participants who 
received a therapeutic COVID-19 mAb treatment postbaseline will be considered as
an event for the endpoint (in addition to COVID-19 related hospitalization and death 
due to any cause) with mAb treatment date as the time of event.
2. A logistic regression model will be fitted to the primary endpoint of 
hospitalization/death and will include treatment and region effect as independent 
variables. In addition the stratification variables specified in Section 3.5 will be added 
to the model analyses depending on the analysis population. Odds ratios, 95% CI and 
p-values will be summarized (p-values will be reported from main model likelihood 
ratio test). Additional analyses may be performed adjusting for baseline covariates 
(such as age, gender, etc.) as additive terms to the primary model, if necessary. For 
the primary endpoint, a model including main terms and interaction term for 
treatment and region will be fitted and p-value from the interaction term will be 
summarized. 
3. A completers only analysis similar to the primary efficacy analysis will be conducted.
Completers are mITT participants who have been in the study for at least 28 days, or 
any participant with COVID-19 related hospitalization or Death from any cause 
through Day 28.


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4. An analysis associated with primary endpoint will be conducted using the per-
protocol (PP) population set.
6.2. Secondary Endpoint(s)
6.2.1. Proportion of Participants with COVID-19 Related Hospitalization or Death due 
to All Cause through Day 28 in mITT1 Analysis Set
The proportion of participants with COVID-19 related hospitalization or death due to any 
cause through Day 28 in the mITT1 analysis set will be similar to the primary endpoint 
analysis. 
6.2.2. Incidence of Treatment Emergent Adverse Events (TEAEs)
The incidence of TEAEs will be summarized by treatment group, by system organ class 
(SOC) and preferred term (PT) using the SAS population.  
6.2.3. 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.
6.2.4. Time (days) to Sustained Alleviation and Time to Resolution of Targeted 
COVID-19 Sign/Symptoms through Day 28
The time (days) to sustained alleviation and time to resolution will be defined for all targeted 
COVID-19 associated symptoms based on self-assessment.
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.
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.
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:


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
For a participant with sustained symptom alleviation/resolution (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 decision to require 4 consecutive days with all targeted symptoms absent 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/resolution and will be censored at day 25.
Cox proportional hazard model analyses will be used for time to sustained symptom
alleviation/resolution. Cox proportional hazard model will include treatment and region 
effect as independent variables. In addition, the stratification variables specified in 
Section 3.5 will be added to the model analyses depending of the analysis population.
Time to sustained symptom alleviation/resolution will be summarized graphically using
Kaplan-Meier plots for each of the treatment groups, the analyses will be done using the 
mITT population only.
In the mITT populations, the analysis will be repeated in subgroups based on baseline 
serology status (positive, negative), by baseline viral load (<104 copies/mL, ≥104 copies/mL),
and (<107 copies/mL, ≥107 copies/mL). 
6.2.5. Proportion of Participants with Severe Signs/Symptoms Attributed to COVID-19 
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 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. A participant with 
severe score for any targeted symptoms post-baseline will be counted as severe. Proportions 
for each targeted signs and symptom with severe category only will be plotted over time 
through Day 28. Additionally, the proportion of participants reporting the presence of each 
targeted sign and symptom that is mild, moderate or severe categories will also be presented.
In addition, to understand the severity of signs/symptoms attributed to COVId-19, the 
following analysis will be performed:  
1. Proportion of participants with any severe targeted signs/symptoms attributed to 
COVID-19 at DAY 1 (baseline).
2. Proportion of participants with any severe targeted signs/symptoms attributed to 
COVID-19 Day 2 to Day 6 (during treatment).
3. Proportion of participants with any severe targeted signs/symptoms attributed to 
COVID-19 Day 7 to Day 28 (post treatment).
Treatment comparison between the group will be presented as odds ratio and 95% CI using 
logistic regression with a similar analysis model as specified in Section 6.1.1.2. The analyses 
will be done using mITT, mITT1, and mITT2 populations.
In the mITT population, the analysis will be repeated in subgroups based on baseline 
serology status (positive, negative), by baseline viral load (<104 copies/mL, ≥104 copies/mL) 
and (<107 copies/mL, ≥107 copies/mL). 
An additional follow-up analysis for signs/symptoms data will be conducted at Week 12 and 
Week 24 for all signs/symptoms (not just targeted signs/symptoms, See Appendix 5). The 
Week 12 and Week 24 signs/symptoms data is collected from a long-term FU telemedicine 
interview performed by the site to participant and collected in CRF (diary data is not colected 
after Day 34).
The observed proportion of participants with any mild, moderate, and severe of all 
signs/symptoms attributed to COVID-19 at Week 12 and Week 24 will be summarized by 
treatment group and overall. Observed proportion of participants reporting the presence of 
each sign and symptom that is mild, moderate, or severe categories will also be summarized 
by treatment group and overall. 
The analyses will be done using mITT, mITT1, and mITT2 populations.
6.2.6. Duration of Each Targeted COVID-19 Sign/Symptom through Day 28
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. 


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Duration of each targeted COVID-19 sign/symptom with a mild or worse severity will be 
summarized for each group within mITT, mITT1, and mITT2 populations.
For duration of each targeted COVID19 sign/symptom, a Kaplan-Meier analysis providing 
the median and quartiles will be provided for each treatment group for mITT population set.
Two additional figures (Number of Participants and Median Time to Sustained Alleviation of 
Each Targeted Sign/Symptom by Treatment Group [mITT) will be included for the endpoint 
of Duration of Each Targeted COVID-19 Sign/Symptom.
6.2.7. 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 symptoms 
worsen 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% confidence intervals and P-value based on logistic 
regression model as specified in Section 6.1.1.2. The analyses will be done using mITT, 
mITT1, and mITT2  population. Missing severity at baseline will be treated as mild.
6.2.8. 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 the following table:
Oxygen saturation (Yes/No)
≥95%
Yes
<95%
No


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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 table will 
be presented for both Day1 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 mITT, mITT1, and mITT2 populations. Missing data at Day 1 or Day 5 will be 
excluded from the analysis. 
6.2.9. Proportion of Participants with Death (all-cause) Through Week 24
The proportion of participants with death (all-cause) through Week 24 will be summarized 
by treatment group. Treatment comparison between the group will be presented as odds ratio 
and its 95% CI using logistic regression with a similar analysis model as specified in 
Section 6.1.1.2. The analyses will be done using mITT, mITT1, and mITT2 populations.
If zero counts are observed in either treatment group, the Fishers Exact test will be performed 
(instead of logistic regression) and pvalue provided.
As mortality is the most important of the efficacy at Week 24, this pertains specifically to 
that endpoint. If the impact s minimal (defined below), then no sensitivity analysis is 
required.
6.2.10. PF-07321332 Plasma PK in Plasma and Whole Blood (if feasible)
The PK analyses will be performed and summarized by the PK/PD group.
6.2.11. Viral Titers Measured via RT-PCR in Nasal Swabs Over Time
The viral load data measured in Day 1 and Day 5 are nasopharyngeal samples. These are the 
samples that will be used on the POC analysis. POC analysis of viral load data will occur 
when approximately 200 participants in the mITT population with evaluable data complete 
the Day 5 assessments.
Descriptive statistics by treatment group for the change from baseline will be provided. An 
analysis of covariance (ANCOVA) model will be used to analyze the change from baseline 
in Log10 transformed viral load (copies/mL) data. The ANCOVA model will include 
treatment group, baseline viral load and baseline serology status. The mAb treatment (yes/no) 
as well as symptom onset to first dose date (≤3 days, >3 days) will be used in the model 
dependent of population. Participants are excluded from the analysis for reasons of Not 
Detected, Zero or Missing baseline viral load result, and local (nonvalidated) swabs use. 
Results from samples collected at non-nasopharyngeal site (like nostril, other or missing) are 
also excluded. As well as exclusions due to non-validated swab use (only viral load data 
based on samples collected through validated swab will be used for analyses). In addition, a 
sensitivity analysis summaries will be performed excluding all data from India sites.


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The viral load measured in nasal or nasopharyngeal samples over time will be evaluated. The 
change from baseline to each visit (Day 3, Day 5, Day 10, Day 14) in viral load will be 
analyzed using an MMRM method. Viral load, including change from baseline, will be 
summarized by treatment group. Change from baseline to Day 3/Day 5/Day 10/Day 14 in 
viral load in the log base 10 scale will be statistically analyzed using a linear mixed-effect 
model. The model will contain log base 10 transformed baseline as a covariate, baseline 
serology status, treatment, day, treatment-by-day as fixed effects. Sampling site 
(Nasopharyngeal or not) will be included as covariate in the model if applicable. The mAb 
treatment (yes/no) as well as symptom onset to first dose date (≤3 days, >3 days) will be used 
in the model dependent of population. The LS means and treatment difference will be 
calculated and presented with their corresponding 95% CIs. The analyses will be done using 
mITT, mITT1 and mITT2 populations.  
In the mITT and mITT1 populations, the analysis will be repeated in subgroups based on 
baseline serology status (positive, negative), by baseline viral load (<104 copies/mL, 
≥104 copies/mL) and (<107 copies/mL, ≥107 copies/mL). 
To assess the association between baseline viral strain and primary endpoint, the proportion 
of participants with primary endpoint events will be summarized according to COVID-19 
variants of concern and variants of interests.
6.2.12. Number of COVID-19 Related Medical Visits 
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 show the difference in estimated rate of medical 
visits between treatment groups. The analyses will be done using mITT, mITT1, and mITT2 
populations. 
6.2.13. Number of Days in Hospital and ICU Stay in Participants with COVID-19 
Related Hospitalization
Health resource utilization data will be summarized by treatment group. This will include 
number (days) of hospital stay and number (days) of ICU stay. The analyses will be done 
using mITT, mITT1 ,and mITT2 populations. Descriptive statistics (ie, mean, median, range) 
will be used to summarize this endpoint. 
6.4. Subset Analyses
For the primary endpoint, forest plots for the following subgroups on mITT, mITT1 and 
mITT2) will be presented.
CCI


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Subgroup analyses of the primary endpoint will include:
•
age group (<65, >=65);
•
Gender;
•
Race;
•
BMI category ( <25, 25-29, ൒30);
•
Baseline viral load (<104 copies/mL, ≥104 copies/mL) and (<107 copies/mL, 
≥107 copies/mL);
•
Baseline serology status (positive, negative);
•
Number of baseline comorbidities present (0-1, 2-3, >=4);
•
Viral strain/linage at Day 1 if appropriate;
•
Present of any of these baseline comorbidities/risk factors: 
•
Smoking (yes, no);
•
Diabetes mellitus;
•
Immunosuppression disorders (including use of corticosteroids, biologics or those 
undergoing chemotherapy);
•
Chronic lung disease requiring medication;
•
Hypertension (taking medications for hypertension);
•
Cardiovacular disorders;
•
Chronic kidney disease;
•
HIV Infection;
•
Sickle Cell Disease;
•
Neurodevelopmental Disorder;
•
Cancer;
•
Device Dependence.


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For a particular risk factor to be summarized, a minimum of 100 subjects in risk group is 
required. The sub-group analysis will be performed for mITT and mITT1 populations.
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, 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 PPanalysis 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.
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 4. 


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6.6.2. Laboratory Data
Descriptive statistics will be summarized by treatment group as well as mean change from 
baseline for laboratory parameters within SAS population.
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.
6.6.3. Vital Signs
The measurement taken immediately prior to start of study drug will be used as the baseline 
for calculating changes in vital signs.
All vital sign data will be descriptively summarized by treatment group within SAS 
population and reported in accordance with the Pfizer Data Standards for safety reporting.
6.6.4. Electrocardiograms
Central reader will provide the reading of all ECG parameters. Descriptive statistics will be 
provided for change from baseline to each measurement time for heart rate, PR interval, QRS 
width, QT interval and QTcF (Fridericia correction) values. Baseline will be defined as the 
mean of the pre-dose triplicates at the Baseline Visit. Additionally, the incidence of 
categorical increases in QTc intervals will be provided. Categories for QTcF are ≥450 msec, 
≥480 msec, and ≥500 msec. Categories for QTcF as change from baseline are ≥30 msec 
increase and ≥60 msec increase. QTcF is considered the primary QTc value for 
measurements of change and for clinical decision making as this correction is more accurate 
with changes in heart rate. 
7. INTERIM ANALYSES
7.1. Interim Analyses and Summaries
A planned interim analysis for efficacy and futility with a sample size-re-estimation will be
conducted and reviewed by an independent E-DMC after approximately 45% overall
participants have completed the Day 28 assessments in the mITT analysis set(ie, 28 days
after randomization). 
At the time of planning the Phase 2/3 study, there was uncertainty about the rate of
COVID-19-related hospitalization or death in the primary analysis population, and about the
treatment effect of PF-07321332. Hence, a sample size re-estimation will be conducted
during the first interim analysis based on conditional power. The sample size can be adjusted
one time and the increase will be capped at 30%. A well-established method described by


Protocol C4671005 (PF-07321332) Statistical Analysis Plan
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Cui, Hung, and Wang (1999)1 (implemented in EAST 6.5) will be used to control the Type I
error probability.2
The nominal significance level for theplanned interim and final proportion of
hospitalization/death 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. The final p-value for rejecting H0 
will be ≤0.049 (2-sided) or reject H1 with 2-sided p-value >0.049. The actual stopping 
boundaries will depend on the exact timing of the interim analysis. If the efficacy boundary is 
crossed at the interim analysis, a final analysis will be conducted as a supportive 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 the interim analysis SAP.
7.2. Data Monitoring Committee
This study will use a E-DMC. The E-DMC is independent of the study team and includes 
only external members. The E-DMC charter describes the role of the DMC in more detail.
The E-DMC will be responsible for ongoing monitoring of the efficacy and safety of 
participants in the study according to the charter. The recommendations made by the E-DMC 
will be forwarded to the appropriate authorized Pfizer personnel for review and final 
decision. Pfizer will communicate such decisions, which may include summaries of 
aggregate analyses of safety data to regulatory authorities, investigators, as appropriate. 
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. However, a blinded study team will manage 
the completion of the study until all participants have completed the Week 24 visit (or ET 
prior to the Week 24 visit). The blinded team will be separate from the unblinded team.
Details of the unblinded sponsor staff supporting the E-DMC and the timing of unblinding 
will be outlined in the Unblinding Plan.


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8. REFERENCES
1.
Cui L, Hung HM, Wang SJ. Modification of sample size in group sequential 
clinicaltrials. Biometrics. 1999;55(3):853-7.
2.
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-guidance documents/ assessing-
covid-19-related-symptoms- outpatient-adult-and-adolescent subjects-clinical-trials-
drugs. Accessed on: 16 June 2021.


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9. APPENDICES
Appendix 1. Summary of Efficacy Analyses
Endpoint
Analysis Type
Population
Data Inclusion and Rules for 
Handling Intercurrent Events 
and Missing Data 
Analysis Model
Proportion of 
participants with 
COVID-19 related 
hospitalization or 
death from any cause 
through Day 28.
Primary Efficacy 
analysis 
mITT
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 primary 
endpoint
mITT2
All data collected will be 
included regardless of 
intercurrent events. 
Kaplan-Meier method to take 
account of losses to follow-up.
Kaplan-Meier 
Proportion of 
participants with 
COVID-19 related 
hospitalization or 
death from any cause 
through Day 28.
Sensitivity analysis 
for primary 
analysis
mITT
Analysis excluding all data 
from India sites and 
participants from Site 1470.
Kaplan-Meier 
method
Proportion of 
participants with 
COVID-19 related 
hospitalization or 
death from any cause 
through Day 28.
Sensitivity analysis 
for primary 
analysis
mITT
Analysis excluding all 
participants from Site 1470.
Kaplan-Meier
method
Proportion of 
participants with 
COVID-19 related 
hospitalization or 
death from any cause 
through Day 28.
Sensitivity analysis 
for primary 
analysis
mITT
Analysis excluding participants 
from the sentinel cohort of the 
study treated with active 
treatment (3 doses of 100 mg).
Kaplan-Meier 
method
Proportion of 
participants with 
COVID-19 related 
hospitalization or 
death from any cause 
through Day 28.
Sensitivity analysis 
for primary 
analysis
mITT
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 
participant remains censored at 
day of last observed data
Kaplan-Meier 
method
Proportion of 
participants with 
COVID-19 related 
Supplemental 
analysis for 
primary analysis
mITT
All data collected will be 
included regardless of 
intercurrent events. 
logistic 
regression 
model


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Endpoint
Analysis Type
Population
Data Inclusion and Rules for 
Handling Intercurrent Events 
and Missing Data 
Analysis Model
hospitalization or 
death from any cause 
through Day 28. 
Use stratification variables as in 
Section 3.5.
Proportion of 
participants with 
COVID-19 related 
hospitalization or 
death from any cause 
through Day 28. 
Supplemental 
analysis for 
primary analysis 
Completers 
Analysis 
Only data collected are 
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. 
Supplemental 
analysis for 
primary analysis
mITT
In the mITT population, 
participants that received a 
therapeutic COVID-19 mAb 
treatment post-baseline will be 
considered as an event for the 
endpoint (in addition to 
hospitalization and death due to 
any with mAb treatment date as 
the time of event). 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.
Primary Efficacy 
analysis 
mITT 
including 
only data with 
first 
randomization 
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 primary 
endpoint
mITT2
including 
only data with 
first 
randomization
All data collected will be 
included regardless of 
intercurrent events. 
Kaplan-Meier method to take 
account of losses to follow-up.
Kaplan-Meier 
Proportion of 
participants with 
COVID-19 related 
hospitalization or 
death from any cause 
through Day 28.
Sensitivity analysis 
for primary 
analysis
mITT 
including 
only data with 
first 
randomization
Analysis excluding all data 
from India sites and 
participants from Site 1470.
Kaplan-Meier 
method
Proportion of 
participants with 
COVID-19 related 
hospitalization or 
death from any cause 
through Day 28.
Sensitivity analysis 
for primary 
analysis
mITT 
including 
only data with 
first 
randomization
Analysis excluding all 
participants from Site 1470.
Kaplan-Meier
method


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Endpoint
Analysis Type
Population
Data Inclusion and Rules for 
Handling Intercurrent Events 
and Missing Data 
Analysis Model
Proportion of 
participants with 
COVID-19 related 
hospitalization or 
death from any cause 
through Day 28.
Sensitivity analysis 
for primary 
analysis
mITT 
including 
only data with 
first 
randomization
Analysis excluding participants 
from the sentinel cohort of the 
study treated with active 
treatment (3 doses of 100 mg).
Kaplan-Meier 
method
Proportion of 
participants with 
COVID-19 related 
hospitalization or 
death from any cause 
through Day 28.
Sensitivity analysis 
for primary 
analysis
mITT 
including 
only data with 
first 
randomization
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 participant remains 
censored at day of last observed 
data.
Kaplan-Meier 
method
Proportion of 
participants with 
COVID-19 related 
hospitalization or 
death from any cause 
through Day 28. 
Supplemental 
analysis for 
primary analysis
mITT 
including 
only data with 
first 
randomization
All data collected will be 
included regardless of 
intercurrent events. 
Use stratification variables as in 
Section 3.5.
logistic 
regression 
model
Proportion of 
participants with 
COVID-19 related 
hospitalization or 
death from any cause 
through Day 28. 
Supplemental 
analysis for 
primary analysis 
Completers 
Analysis 
including 
only data with 
first 
randomization
Only data collected are 
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. 
Supplemental 
analysis for 
primary analysis
mITT 
including 
only data with 
first 
randomization
In the mITT population, 
participants that received a 
therapeutic COVID-19 mAb 
treatment post-baseline will be 
considered as an event for the 
endpoint (in addition to 
hospitalization and death due to 
any with mAb treatment date as 
the time of event). 
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.
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


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Endpoint
Analysis Type
Population
Data Inclusion and Rules for 
Handling Intercurrent Events 
and Missing Data 
Analysis Model
Proportion of 
participants with 
COVID-19 related 
hospitalization or 
death from any cause 
through Day 28.
Subgroup Analysis 
for primary 
endpoint
mITT
Subset analysis identified in 
Section 6.4.
Kaplan-Meier 
method
Time to sustained 
alleviation and time 
to sustained 
resolution of all 
targeted 
signs/symptoms 
through Day 28.
Secondary analysis
mITT & 
mITT1 & 
mITT2
All data collected will be 
included regardless of 
intercurrent events. Missing 
severity at baseline will be 
treated as mild.
Use stratification variables as in 
Section 3.5.
Cox 
proportional 
hazard model 
Time to sustained 
alleviation of all 
targeted 
signs/symptoms 
through Day 28.
Subgroup Analysis 
of secondary 
endpoint
mITT
All data collected will be 
included regardless of 
intercurrent events. Missing 
severity at baseline will be 
treated as mild. Use 
stratification variables as in 
Section 3.5.
Subset analysis by baseline 
serology status and baseline 
viral load. 
Cox 
proportional 
hazard model
Time to sustained 
resolution of all 
targeted 
signs/symptoms 
through Day 28.
Subgroup Analysis 
of secondary 
endpoint
mITT
All data collected will be 
included regardless of 
intercurrent events. Missing 
severity at baseline will be 
treated as mild. Use 
stratification variables as in 
Section 3.5.
Subset analysis by baseline 
serology status and baseline 
viral load. 
Cox 
proportional 
hazard model
Proportion of 
participants with 
severe 
signs/symptoms 
attributed to 
COVID-19 through 
Day 28.
Secondary analysis
mITT, mITT1
& mTT2
All data collected will be 
included regardless of 
intercurrent events. Use 
BOCF/LOCF for missing data.
Use stratification variables as in 
Section 3.5.
Kaplan-Meier 
method Logistic 
regression


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Endpoint
Analysis Type
Population
Data Inclusion and Rules for 
Handling Intercurrent Events 
and Missing Data 
Analysis Model
Proportion of 
participants with 
severe 
signs/symptoms 
attributed to 
COVID-19 through 
Day 28.
Subgroup Analysis 
of secondary 
endpoint
mITT
All data collected will be 
included regardless of 
intercurrent events. Use 
BOCF/LOCF for missing data.
Use stratification variables as in 
Section 3.5.
Subset analysis by baseline 
serology status and baseline 
viral load. 
Logistic 
regression
Duration of each 
targeted COVID-19 
sign/symptom.
Secondary analysis 
mITT, 
mITT1 & 
mTT2
All data collected will be 
included regardless of 
intercurrent events. Missing 
data will not be imputed.
Descriptive 
statistics
Progression to a 
worsening status in 1 
or more self-reported 
COVID-19-
associated symptoms 
through Day 28.
Secondary analysis
mITT, mITT1
& mTT2
All data collected will be 
included regardless of 
intercurrent events. Use 
BOCF/LOCF for missing data.
Use stratification variables as in 
Section 3.5.
Logistic 
regression
Proportion of 
participants with a 
resting peripheral 
oxygen saturation 
≥95% at Days 1 
and 5.
Secondary analysis
mITT, mITT1 
& mTT2
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
Proportion of 
participants with any 
signs/symptoms 
attributed to 
COVID-19 through 
Week 12 & Week 24.
Additional 
follow-up analysis
mITT, mITT1 
& mITT2
All data collected will be 
included regardless of 
intercurrent events. Missing 
data will not be imputed.
Descriptive 
Statistics
Proportion of 
participants with 
death (all cause) 
through Week 24.
Secondary analysis
mITT, mITT1 
& mTT2
All data collected will be 
included regardless of 
intercurrent events.  Missing 
data will not be imputed.
Use stratification variables as in 
Section 3.5.
Logistic 
regression or 
Fisher Exact test 
(if appropriate)
Viral titers measured 
via RTPCR in 
nasopharyngeal 
samples at Day 1 and 
Day 5.
Sensitivity analysis 
(POC)
mITT, mITT1 
& mTT2
All data collected will be 
included regardless of 
intercurrent events. 
Use baseline viral load 
(continuous).
ANCOVA 
analysis 


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Endpoint
Analysis Type
Population
Data Inclusion and Rules for 
Handling Intercurrent Events 
and Missing Data 
Analysis Model
Viral titers measured 
via RT-PCR in nasal 
swabs over time.
Secondary analysis
mITT, mITT1 
& mTT2
All data collected will be 
included regardless of 
intercurrent events. 
Use baseline viral load 
(continuous).
MMRM 
analysis 
Number of 
COVID-19 related 
medical visits.
Secondary analysis
mITT, mITT1 
& mTT2
All data collected will be 
included regardless of 
intercurrent events. Missing 
data will not be imputed.
Descriptive 
statistics (based 
on negative 
Binomial 
Distribution)
Number of days in 
hospital and ICU stay 
in participants with 
COVID-19 related 
hospitalization.
Secondary analysis
mITT, mITT1
& mTT2
All data collected will be 
included regardless of 
intercurrent events. Missing 
data will not be imputed.
Descriptive 
statistics


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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 days, 
(ie, days 2 to 4)
4
Day 5
= Day 5, with a window of ±1 days, 
(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 and ECG: 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.

Sign and symptom data at Week 12 & Week 24: No visit windowing will be applied. 
The nominal visits will be used.


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Appendix 3. List of Abbreviations
Abbreviation
Term
AE
adverse event
AESI
adverse events of special interest
ANCOVA
analysis of covariance
BOCF
baseline observation carried forward
CDARS
Clinical Data Analysis and Reporting System
CI
confidence interval
ECG
electrocardiogram
E-DMC
external data monitoring committee 
ET
early termination
FAS
full analysis set
FDA
Food and Drug Administration (United States)
LOCF
last observation carried forward
MedDRA
Medical Dictionary for Regulatory Activities
ITT
intent-to-treat
MMRM
mixed-effects model with repeated measures
PD
pharmacodynamic(s)
PK
pharmacokinetic(s)
PP
per-protocol
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. List of pre-specified AESIs


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Appendix 5. COVID-19 Signs/Symptoms
Daily Sign and Symptom 
Collection
Entry Criterion #3 
Targeted (used for 
study entry)
Daily Signs 
and Symptoms 
Collection
Targeted 
Symptom 
Analysis
Long Term 
Follow-Up
Cough
X
X
X
X
Shortness of Breath or 
difficulty breathing
X
X
X
X
Fever
X
X
Feeling Feverish
X
X
Chills or shivering
X
X
X
X
Fatigue (low energy or
tiredness)
X
X
X
Malaise
X
Muscle or Body Aches
X
X
X
X
Diarrhea (loose or watery 
stools) 
X
X
X
X
Nausea (feeling like you 
wanted to throw up)
X
X
X
X
Vomiting (throw up)
X
X
X
X
Headache
X
X
X
X
Sore Throat
X
X
X
X
Stuffy or runny nose 
(Rhinorrhea)
X
X
X
X
Loss of smell
X
X
Loss of taste
X
X
Difficulty with concentration
X
Sleep disturbances
X
Heart palpitations
X
Other Symptoms
X