Clinical trial NCT05567952
Conditions: COVID-19
Keywords: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Coronavirus disease 2019 (COVID-19) COVID-19 rebound Paxlovid Nirmatrelvir
Sponsor: Pfizer
Start date: 2022-10-19; Completion date: 2024-02-09
Enrollment: 436 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study is to learn about the safety and effects of nirmatrelvir/ritonavir for the potential treatment of COVID-19 rebound.

The study is seeking participants who:

* Have completed treatment with nirmatrelvir/ritonavir
* Have a rebound in COVID-19 symptoms
* Are SARS-CoV-2 (COVID-19) positive

All study medications will be taken 2 times a day by mouth for 5 days. The first dose of study medication is taken at the study clinic and the rest at home.

We will examine the experiences of people receiving the study medicines to those who do not. This will help us determine if the study medicines are safe and effective.

People taking part will be in this study for about 24 weeks. Enrolled participants will need to visit the study clinic at least 8 times during the study.

Detailed description:

Arms: arm 1: Nirmatrelvir (2 tablets) plus ritonavir (1 capsule) will be given by mouth every 12 hours for 5 days arm 2: placebo (2 tablets) plus ritonavir (1 capsule) will be given by mouth every 12 hours for 5 days
Interventions: intervention 1: nirmatrelvir intervention 2: ritonavir intervention 3: placebo for nirmatrelvir
Intervention descriptions: intervention 1: Participants will receive 2 tablets of nirmatrelvir every 12 hours intervention 2: Participants will receive 1 capsule of ritonavir every 12 hours intervention 3: Participants will receive 2 tablets of placebo for nirmatrelvir every 12 hours. A placebo does not have any medicine in it but looks just like the medicine being studied.

Protocol documents:
Prot_000.pdf: 
Nirmatrelvir/ritonavir
Protocol C4671042 
Final Protocol Amendment 4, 29 June 2023
PFIZER CONFIDENTIAL
CT02-GSOP Clinical Protocol Template Phase 1 2 3 4 (14 April 2023)
Page 1
Title Page
AN INTERVENTIONAL, EFFICACY AND SAFETY, PHASE 2, RANDOMIZED,
DOUBLE-BLIND, 2-ARM STUDY TO INVESTIGATE A REPEAT 5-DAY COURSE 
OF NIRMATRELVIR/RITONAVIR COMPARED TO PLACEBO/RITONAVIR IN
PARTICIPANTS AT LEAST 12 YEARS OF AGE WITH REBOUND OF COVID-19 
SYMPTOMS AND RAPID ANTIGEN TEST POSITIVITY
Study Intervention Number:
PF-07321332
Study Intervention Name:
nirmatrelvir
US IND Number:
153517
EudraCT/EU CT Number:
2022-002827-36
ClinicalTrials.gov ID:  
NCT05567952
Pediatric Investigational Plan Number:
not available
Protocol Number:
C4671042
Phase:
2
Sponsor Legal Address:
Pfizer Inc.
66 Hudson Boulevard East
New York, NY 10001
Brief Title:
A Study to Learn About a Repeat 5-Day Treatment with Nirmatrelvir/Ritonavir in 
People with Return of COVID-19 Symptoms and SARS-CoV-2 Positivity After 
Finishing Treatment with Nirmatrelvir/Ritonavir
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.


Nirmatrelvir/ritonavir
Protocol C4671042 
Final Protocol Amendment 4, 29 June 2023
PFIZER CONFIDENTIAL
CT02-GSOP Clinical Protocol Template Phase 1 2 3 4 (14 April 2023)
Page 2
Document History
Document 
Version Date
Amendment 4
29 June 2023
Amendment 3
12 May 2023
Amendment 2
01 February 2023
Amendment 1
16 September 2022
Original protocol
05 August 2022
This amendment incorporates all revisions to date, including amendments made at the 
request of country health authorities and IRBs/ECs and any protocol administrative change 
letter(s).


Nirmatrelvir/ritonavir
Protocol C4671042 
Final Protocol Amendment 4, 29 June 2023
PFIZER CONFIDENTIAL
CT02-GSOP Clinical Protocol Template Phase 1 2 3 4 (14 April 2023)
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Protocol Amendment Summary of Changes Table
Amendment 4 (29 June 2023)
Overall Rationale for the Amendment: The protocol was primarily amended to add secondary analyses for the primary and 
secondary efficacy endpoints using the new analysis set (mITT1). Additional revisions are noted in the table below.
Description of Change
Brief Rationale
Section # and Name
Substantial Modification(s)
Additional secondary analyses for 
primary and secondary efficacy endpoints 
using the new analysis set (mITT1).  
Update the multiplicity adjustment 
accordingly.
Based on regulatory feedback on the definition of the study analysis 
set.
Section 9.1.2 Multiplicity Adjustment
Section 9.2 Analysis Sets
Section 9.3.2.2 Main Analytical Approach
Section 9.3.3.1 Time to 2 consecutive negative rapid 
antigen test results obtained at least 24(-2)h apart 
through Day 28
Section 9.3.3.2 Time (days) to sustained alleviation of 
all targeted signs and symptoms through Day 28
Non-substantial Modification(s)
Minor editorial updates.
To correct grammatical and formatting errors, and to maintain 
consistency.
Throughout the protocol


Nirmatrelvir/ritonavir
Protocol C4671042 
Final Protocol Amendment 4, 29 June 2023
PFIZER CONFIDENTIAL
CT02-GSOP Clinical Protocol Template Phase 1 2 3 4 (14 April 2023)
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TABLE OF CONTENTS
LIST OF TABLES...................................................................................................................10
1. PROTOCOL SUMMARY...................................................................................................11
1.1. Synopsis ..................................................................................................................11
1.2. Schema ....................................................................................................................18
1.3. Schedule of Activities .............................................................................................19
2. INTRODUCTION ...............................................................................................................31
2.1. Study Rationale .......................................................................................................31
2.2. Background .............................................................................................................32
2.2.1. Clinical Overview.......................................................................................32
2.3. Benefit/Risk Assessment.........................................................................................33
2.3.1. Risk Assessment.........................................................................................34
2.3.2. Benefit Assessment.....................................................................................36
2.3.3. Overall Benefit/Risk Conclusion................................................................36
3. OBJECTIVES, ENDPOINTS, AND ESTIMANDS ...........................................................36
4. STUDY DESIGN.................................................................................................................39
4.1. Overall Design.........................................................................................................39
4.2. Scientific Rationale for Study Design.....................................................................40
4.2.1. Choice of Contraception/Barrier Requirements .........................................41
4.2.2. Collection of Retained Research Samples..................................................41
4.2.3. Inclusion of Pediatric Participants..............................................................41
4.3. Justification for Dose ..............................................................................................41
4.4. End of Study Definition ..........................................................................................41
5. STUDY POPULATION......................................................................................................42
5.1. Inclusion Criteria.....................................................................................................42
5.2. Exclusion Criteria....................................................................................................43
5.3. Lifestyle Considerations..........................................................................................44
5.3.1. Contraception..............................................................................................44
5.4. Screen Failures ........................................................................................................45
5.5. Criteria for Temporarily Delaying 
Enrollment/Randomization/Administration of Study Intervention...........................45
6. STUDY INTERVENTION(S) AND CONCOMITANT THERAPY.................................45
6.1. Study Intervention(s) Administered........................................................................45


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Final Protocol Amendment 4, 29 June 2023
PFIZER CONFIDENTIAL
CT02-GSOP Clinical Protocol Template Phase 1 2 3 4 (14 April 2023)
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6.1.1. Administration............................................................................................47
6.2. Preparation, Handling, Storage, and Accountability...............................................48
6.2.1. Preparation and Dispensing........................................................................49
6.3. Assignment to Study Intervention...........................................................................49
6.4. Blinding...................................................................................................................49
6.4.1. Blinding of Participants..............................................................................49
6.4.2. Blinding of Site Personnel..........................................................................49
6.4.3. Blinding of the Sponsor..............................................................................50
6.4.4. Breaking the Blind......................................................................................50
6.5. Study Intervention Compliance...............................................................................50
6.6. Dose Modification...................................................................................................51
6.7. Continued Access to Study Intervention After the End of the Study......................51
6.8. Treatment of Overdose............................................................................................51
6.9. Prior and Concomitant Therapy..............................................................................52
7. DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL...........................................................................53
7.1. Discontinuation of Study Intervention ....................................................................53
7.1.1. Pregnancy ...................................................................................................54
7.2. Participant Discontinuation/Withdrawal From the Study.......................................54
7.2.1. Withdrawal of Consent...............................................................................54
7.3. Lost to Follow-Up ...................................................................................................55
8. STUDY ASSESSMENTS AND PROCEDURES...............................................................55
8.1. Administrative and Baseline Procedures.................................................................55
8.1.1. Baseline Procedures....................................................................................56
8.1.1.1. Medical History.........................................................................56
8.1.1.2. Secondary Contacts...................................................................56
8.1.2. Household Characteristics ..........................................................................57
8.1.3. Telehealth Visits.........................................................................................57
8.1.4. Home Health Visits.....................................................................................57
8.2. Efficacy Assessments..............................................................................................58
8.2.1. Participant Diary.........................................................................................58
8.2.2. COVID-19-Related Medical Details ..........................................................59
8.2.3. PRO Assessments.......................................................................................59


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8.2.3.1. Global Impression Questions ....................................................59
8.2.3.2. SF-36 v2® Health Survey (Acute Form)[18].............................59
8.2.3.3. WPAI.........................................................................................59
8.2.3.4. EQ-5D-5L Scale........................................................................60
8.2.3.5. COVID-19 Signs and Symptoms ..............................................60
8.3. Safety Assessments .................................................................................................61
8.3.1. Targeted Physical Examination, Height and Weight..................................61
8.3.2. Vital Signs ..................................................................................................61
8.3.2.1. Blood Pressure and Pulse Rate..................................................61
8.3.2.2. Temperature and Respiratory Rate............................................62
8.3.2.3. Oxygen Saturation Level...........................................................62
8.3.2.4. Point-of-Care Serum Creatinine Assessments ..........................62
8.3.3. Clinical Safety Laboratory Assessments ....................................................62
8.3.3.1. Alternative Facilities for Clinical Safety Laboratory 
Assessment ........................................................................................62
8.3.4. Pregnancy Testing ......................................................................................63
8.3.4.1. At Home Pregnancy Testing .....................................................63
8.4. Adverse Events, Serious Adverse Events, and Other Safety Reporting .................63
8.4.1. Time Period and Frequency for Collecting AE and SAE Information.......64
8.4.1.1. Reporting SAEs to Pfizer Safety...............................................64
8.4.1.2. Recording Nonserious AEs and SAEs on the CRF...................64
8.4.2. Method of Detecting AEs and SAEs ..........................................................65
8.4.3. Follow-Up of AEs and SAEs......................................................................65
8.4.4. Regulatory Reporting Requirements for SAEs...........................................65
8.4.5. Environmental Exposure, Exposure During Pregnancy or 
Breastfeeding, and Occupational Exposure.....................................................66
8.4.5.1. Exposure During Pregnancy......................................................66
8.4.5.2. Exposure During Breastfeeding ................................................67
8.4.5.3. Occupational Exposure .............................................................68
8.4.6. Cardiovascular and Death Events...............................................................68
8.4.7. Disease-Related Events and/or Disease-Related Outcomes Not 
Qualifying as AEs or SAEs..............................................................................68
8.4.8. Adverse Events of Special Interest.............................................................68


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8.4.8.1. Lack of Efficacy........................................................................68
8.4.9. Medical Device Deficiencies......................................................................68
8.4.10. Medication Errors.....................................................................................68
8.5. Pharmacokinetics ....................................................................................................69
8.6. Genetics...................................................................................................................70
8.6.1. Specified Genetics ......................................................................................70
8.6.2. Retained Research Samples for Genetics ...................................................70
8.7. Biomarkers ..............................................................................................................70
8.7.1. Viral RNA Assessment (NP Swab)............................................................70
8.7.2. Viral RNA Assessment (Plasma)................................................................71
8.7.3. Rapid Antigen Assessments .......................................................................71
8.7.4. Viral Sequencing Assessments (OP Swab) ................................................71
8.7.5. Specified Gene Expression (RNA) Research .............................................71
8.7.6. Specified Protein Research.........................................................................71
8.7.6.1. Plasma for Protein Analysis ......................................................71
8.7.7. Specified Metabolomic Research ...............................................................72
8.7.8. Retained Research Samples for Biomarkers...............................................72
8.8. Immunogenicity Assessments.................................................................................72
8.9. Health Economics ...................................................................................................72
9. STATISTICAL CONSIDERATIONS ................................................................................72
9.1. Statistical Hypothesis ..............................................................................................72
9.1.1. Estimands....................................................................................................73
9.1.1.1. Primary Estimand......................................................................73
9.1.1.2. Secondary Estimands ................................................................73
9.1.2. Multiplicity Adjustment..............................................................................73
9.2. Analysis Sets ...........................................................................................................74
9.3. Statistical Analyses .................................................................................................74
9.3.1. General Considerations...............................................................................74
9.3.2. Primary Endpoint(s)/Estimand(s) Analysis ................................................75
9.3.2.1. Definition of Endpoint(s) ..........................................................75
9.3.2.2. Main Analytical Approach........................................................75
9.3.3. Secondary Endpoints ..................................................................................75


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Final Protocol Amendment 4, 29 June 2023
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9.3.3.1. Time to 2 consecutive negative rapid antigen test results 
obtained at least 24(-2)h apart through Day 28.................................75
9.3.3.2. Time (days) to sustained alleviation of all targeted signs 
and symptoms through Day 28..........................................................76
9.3.4. Tertiary/Exploratory Endpoint(s) Analysis ................................................77
9.3.5. Safety Analyses ..........................................................................................77
9.3.6. Other Analyses............................................................................................77
9.4. Interim Analyses .....................................................................................................77
9.5. Sample Size Determination.....................................................................................77
10. SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS..........................................................................................................79
10.1. Appendix 1: Regulatory, Ethical, and Study Oversight Considerations...............79
10.1.1. Regulatory and Ethical Considerations ....................................................79
10.1.1.1. Reporting of Safety Issues and Serious Breaches of the 
Protocol or ICH GCP.........................................................................79
10.1.2. Financial Disclosure .................................................................................80
10.1.3. Informed Consent/Assent Process ............................................................80
10.1.3.1. Informed Consent Process.......................................................80
10.1.3.2. Informed Assent Process.........................................................81
10.1.4. Data Protection .........................................................................................82
10.1.5. Committees Structure ...............................................................................83
10.1.5.1. Data Monitoring Committee ...................................................83
10.1.6. Dissemination of Clinical Study Data ......................................................83
10.1.7. Data Quality Assurance ............................................................................84
10.1.8. Source Documents....................................................................................85
10.1.9. Study and Site Start and Closure ..............................................................86
10.1.10. Publication Policy...................................................................................86
10.1.11. Sponsor’s Medically Qualified Individual..............................................87
10.2. Appendix 2: Clinical Laboratory Tests .................................................................88
10.3. Appendix 3: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-Up, and Reporting .....................................................................89
10.3.1. Definition of AE .......................................................................................89
10.3.2. Definition of an SAE ................................................................................90


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10.3.3. Recording/Reporting and Follow-Up of AEs and/or SAEs During 
the Active Collection Period............................................................................91
10.3.4. Reporting of SAEs....................................................................................95
10.4. Appendix 4: Contraceptive and Barrier Guidance ................................................96
10.4.1. Female Participant Reproductive Inclusion Criteria.................................96
10.4.2. Woman of Childbearing Potential ............................................................96
10.4.3. Contraception Methods.............................................................................97
10.5. Appendix 5: Genetics............................................................................................99
10.6. Appendix 6: Liver Safety: Suggested Actions and Follow-Up Assessments 
and Study Intervention Rechallenge Guidelines .....................................................100
10.7. Appendix 7: Age-Specific Kidney Function Calculation Recommendations.....102
10.7.1. Adults (18 Years and Above)—2021 CKD-EPI Equations ...................102
10.7.1.1. Adolescents (12 Years to <18 Years)—Cockcroft-Gault 
Formula............................................................................................102
10.7.2. Adverse Event Grading for Kidney Safety Laboratory 
Abnormalities.................................................................................................102
10.8. Appendix 8: Prohibited and Precautionary Concomitant Medications That 
May Result in DDI ..................................................................................................103
10.9. Appendix 9: Country-Specific Requirements .....................................................115
10.9.1. France .....................................................................................................115
10.9.2. Germany .................................................................................................115
10.10. Appendix 10: Eligibility Criteria.......................................................................116
10.10.1. Age and Sex..........................................................................................116
10.10.2. Rebound of COVID-19 Signs/Symptoms ............................................116
10.10.3. SARS-CoV-2 Infection.........................................................................116
10.10.4. Risk of Developing Severe Illness from COVID-19............................116
10.10.5. Prior/Concomitant Therapy ..................................................................117
10.10.6. Other Treatments for COVID-19..........................................................118
10.10.7. Immunocompromised Criteria Details .................................................118
10.11. Appendix 11: Participant-Reported COVID-19-Related Signs and 
Symptoms................................................................................................................119
10.12. Appendix 12: Protocol Amendment History.....................................................120
10.13. Appendix 13: Abbreviations .............................................................................125
11. REFERENCES ................................................................................................................128


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Final Protocol Amendment 4, 29 June 2023
PFIZER CONFIDENTIAL
CT02-GSOP Clinical Protocol Template Phase 1 2 3 4 (14 April 2023)
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LIST OF TABLES
Table 1.
Study Schedule of Assessment.................................................................19
Table 2.
Protocol-Required Safety Laboratory Assessments .................................88
Table 3.
Drugs That are Contraindicated With Nirmatrelvir/Ritonavir................103
Table 4.
Established and Other Potentially Significant Drug Interactions...........106


Nirmatrelvir/ritonavir
Protocol C4671042 
Final Protocol Amendment 4, 29 June 2023
PFIZER CONFIDENTIAL
CT02-GSOP Clinical Protocol Template Phase 1 2 3 4 (14 April 2023)
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1. PROTOCOL SUMMARY 
1.1. Synopsis 
Protocol Title: 
An Interventional, Efficacy and Safety, Phase 2, Randomized, Double-Blind, 2-Arm Study to 
Investigate a Repeat 5-Day Course of Nirmatrelvir/Ritonavir Compared to Placebo/Ritonavir 
in Participants at Least 12 Years of Age with Rebound of COVID-19 Symptoms and Rapid 
Antigen Test Positivity
Brief Title: 
A Study to Learn About a Repeat 5-Day Treatment with Nirmatrelvir/Ritonavir in People 
with Return of COVID-19 Symptoms and SARS-CoV-2 Positivity After Finishing Treatment 
with Nirmatrelvir/Ritonavir
Regulatory Agency Identification Number(s):
US IND Number:
153517
EudraCT/EU CT Number:
2022-002827-36
ClinicalTrials.gov ID:  
NCT05567952
Pediatric Investigational Plan Number:
not available
Protocol Number:
C4671042
Phase:
2
Rationale:
Case reports in the literature describe individuals who have experienced symptomatic 
relapses of SARS-CoV-2 infection following completion of a 5-day course of 
nirmatrelvir/ritonavir. In the available cases, patients are described as experiencing rapid 
improvement in systemic symptoms following initiation of treatment but then experience a 
rebound in COVID-19 symptoms after completing therapy. The time course of symptom 
rebound suggests that symptom recurrence is likely not related to re-exposure and it does not 
reflect a potential re-infection event. In one case report, symptom relapse was accompanied 
by fluctuating RT-PCR cycle thresholds and antigen testing suggesting the potential for a 
rebound in viral replication. In a separate case series of 7 patients with recurrent symptoms, 
median SARS-CoV-2 RNA at baseline was 6.1 log10 copies/mL (range 4.2-7.3) and 
enrollment viral cultures were positive in 3 of 7 individuals. Several of the published case 
reports on symptom recurrence included viral sequencing and these reports to date have not 
identified resistance mutations to nirmatrelvir.
A retrospective review of 483 high-risk patients treated with nirmatrelvir/ritonavir reported 
4 (0.8%) patients who experienced rebound of symptoms. Median time to rebound in this 
study was 9 days and rebound symptoms were characterized as mild and resolving without 
additional COVID-19 therapy with no patient requiring hospitalization.


Nirmatrelvir/ritonavir
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Post-treatment increases in SARS-CoV-2 RNA levels (ie, viral RNA rebound) in 
nasopharyngeal samples were observed on Day 10 or Day 14 in a subset of 
nirmatrelvir/ritonavir and placebo recipients in the EPIC-HR study. The frequency of 
detection of post-treatment viral RNA rebound varied according to analysis parameters but 
was generally similar among nirmatrelvir/ritonavir and placebo recipients, regardless of the 
rebound definition used. A similar or smaller percentage of placebo recipients compared to 
nirmatrelvir/ritonavir recipients had nasopharyngeal viral RNA results <LLOQ at all study 
timepoints in both the treatment and post-treatment periods. Post-treatment viral RNA 
rebound was not associated with the primary clinical outcome of COVID-19-related 
hospitalization or death from any cause through Day 28 following the single 5-day course of 
nirmatrelvir/ritonavir treatment. Post-treatment viral RNA rebound also was not associated 
with drug resistance as measured by mPro sequencing. The clinical relevance of 
post-treatment increases in viral RNA following nirmatrelvir/ritonavir or placebo treatment is 
unknown.
At present, there are no controlled efficacy and safety data of a repeat 5-day course of 
nirmatrelvir/ritonavir in participants with acute rebound in symptoms and SARS-CoV-2 
infection. Recurrence in symptoms along with a positive rapid antigen test following the 
completion of a 5-day course of nirmatrelvir/ritonavir may indicate that these patients may 
require additional therapy to achieve sustained viral clearance. Such patients may benefit 
from an additional 5-day treatment duration. The purpose of this study is to evaluate the 
efficacy, safety and tolerability of a second 5-day treatment course of nirmatrelvir/ritonavir 
in participants with a rebound in COVID-19 symptoms and a positive rapid antigen test 
within 2 weeks (14 days) following completion of an initial 5-day treatment course.
Objectives, Endpoints, and Estimands:
Objectives
Endpoints
Estimands
Primary: 
Primary:
Primary: 
To compare the effect of 
nirmatrelvir/ritonavir to 
placebo/ritonavir on viral RNA level 
in NP swabs in participants with mild-
to-moderate COVID-19.
The change in viral SARS-CoV-2 RNA 
level as measured in NP swabs from 
baseline to Day 5.
The difference in mean change of 
SARS-CoV-2 RNA level in NP swabs 
from baseline to Day 5 between 
nirmatrelvir/ritonavir and 
placebo/ritonavir group in patients 
with a rebound in COVID-19 
symptoms and a positive rapid antigen 
test within 2 weeks following 
completion of an initial 5-day 
treatment course ,who have a positive 
viral RNA NP swab test result at 
baseline. This will be estimated 
without regard to study treatment 
discontinuation and without regard to 
prohibited therapies.


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Objectives
Endpoints
Estimands
Secondary: 
Secondary:
Secondary: 
To compare the effect of 
nirmatrelvir/ritonavir to 
placebo/ritonavir on the duration of 
viral shedding.
Time to 2 consecutive negative rapid 
antigen test results obtained at least 24 (-
2) h apart through Day 28.
The hazard ratio for time to 2 
consecutive negative rapid antigen test 
results obtained at least 24 (-2) h apart 
through Day 28 between 
nirmatrelvir/ritonavir and 
placebo/ritonavir group in patients 
with rebound in COVID-19 symptoms 
and a positive rapid antigen test within 
2 weeks following completion of an 
initial 5-day treatment course, who 
have a positive viral RNA NP swab
test result at baseline. This will be 
estimated without regard to study 
treatment discontinuation and without 
regard to prohibited therapies.
To compare the effect of 
nirmatrelvir/ritonavir to 
placebo/ritonavir on the duration and 
severity of signs and symptoms in 
participants with mild-to-moderate 
COVID-19. 
Time (days) to sustained alleviation of 
all targeted signs and symptoms through 
Day 28 where sustained alleviation is 
defined as the first of 2 consecutive days 
when any symptoms scored as moderate 
or severe at baseline are scored as mild 
or absent and any symptoms scored as 
mild or absent at baseline are scored as 
absent.
The hazard ratio for time to sustained 
alleviation of all targeted signs and 
symptoms through Day 28 between 
nirmatrelvir/ritonavir and 
placebo/ritonavir group in patients  
with rebound in COVID-19 symptoms 
and a positive rapid antigen test within 
2 weeks following completion of an 
initial 5-day treatment course, who 
have a positive viral RNA NP swab 
test result at baseline. This will be 
estimated without regard to study 
treatment discontinuation and without 
regard to prohibited therapies.
To describe the safety and tolerability 
of nirmatrelvir/ritonavir in participants 
with mild-to-moderate COVID-19.
Incidence of TEAEs. Incidence of SAEs 
and AEs leading to discontinuation.
Not applicable.
Overall Design:
This Phase 2, randomized, double-blind, placebo-controlled study will evaluate the efficacy 
and safety of a repeat 5-day treatment course of nirmatrelvir/ritonavir or placebo/ritonavir for 
the treatment of mild-to-moderate COVID-19. Participants must have written documentation, 
such as an electronic health record, medical record, or prescription receipt of treatment with 
nirmatrelvir/ritonavir (verbal assertion of treatment is not acceptable) with patient-reported 
100% compliance (ie, completed a 5 day course of nirmatrelvir/ritonavir). They must have 
experienced alleviation or resolution in COVID-19 signs/symptoms followed by a worsening 
(rebound) of signs/symptoms along with a positive rapid antigen test after completing an 
initial 5-day course of nirmatrelvir/ritonavir. 
The onset of rebound in COVID-19 symptoms along with evidence of SARS-CoV-2 
infection must occur within 2 weeks (14 days) after completion of an initial 5-day course of 
nirmatrelvir/ritonavir. A 2-week time-period for rebound symptoms and SARS-CoV-2 
infection was selected to enroll a population that has a presumptive recurrence of the same 


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viral illness and not a new SARS-CoV-2 infection. Symptom burden including alleviation, 
resolution and worsening (rebound) to qualify for the study is based on the judgment of both
the participant along with investigator judgment.
Eligible participants for this study will be randomly assigned (2:1 allocation of active to 
placebo) to receive:

nirmatrelvir plus ritonavir orally q12h for 5 days; or

placebo plus ritonavir orally q12h for 5 days.
Randomization will be stratified by geographic region. 
Participants will be screened within 24 hours before randomization.  
Participants must be randomized within 48 hours from the onset of the rebound COVID-19 
symptoms and must be randomized within 24 hours of a positive baseline rapid antigen test. 
The total study duration is up to 24 weeks, including study intervention administration 
through Day 5 or Day 6, efficacy and safety assessments through Day 34, and long-term 
follow up at Weeks 12 and 24.
Participants are eligible if they are at least 12 years of age (and weigh ≥40 kg at screening) 
and they must have at least 1 characteristic or underlying medical condition associated with 
an increased risk of developing severe illness from COVID-19. However, participants who 
are immunocompromised are excluded from this study as they may have prolonged viral 
shedding due to their immunocompromised state. Participants will be eligible for enrollment 
irrespective of COVID-19 vaccination/boosted status (except for time course restrictions 
listed in the exclusion criteria).
An independent E-DMC will review unblinded data to ensure the safety of participants on an 
ongoing basis throughout the duration of the study.
Number of Participants:
Approximately 411 participants will be enrolled in the study. 
Note: "Enrolled" means a participant's, or their legally authorized representative’s, agreement 
to participate in a clinical study following completion of the informed consent process and 
randomization. A participant will be considered enrolled if the informed consent is not 
withdrawn prior to participating in any study activity. Potential participants who are screened 
for the purpose of determining eligibility for the study, but do not participate in the study, are 
not considered enrolled. 


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Study Population: 
Inclusion and exclusion criteria are listed below:
Inclusion Criteria 
Participants must meet the following inclusion criteria to be eligible for enrollment into the 
study:
1. Participants aged 12 years or older and weighing ≥40 kg at screening.
2. Participants must have written documentation with patient-reported 100% 
compliance (ie, completed a 5 day course of nirmatrelvir/ritonavir). They must 
have symptom alleviation or resolution in COVID-19 signs/symptoms followed 
by a worsening (rebound) of signs/symptoms after completing an initial 5-day 
course of nirmatrelvir/ritonavir based on the judgement of both the participant and 
investigator.
3. The onset of rebound in COVID-19 symptoms must occur within 2 weeks (14 
days) after the completion of the initial 5-day course of nirmatrelvir/ritonavir.
4. Onset of rebound in signs/symptoms attributable to COVID-19 within 48 hours 
prior to randomization and ≥1 sign/symptom attributable to COVID-19 present on 
the day of randomization.
5. SARS-CoV-2 infection as determined by rapid antigen testing in any specimen 
collected within 24 hours prior to randomization and collected within 2 weeks (14 
days) after the completion of the initial 5-day treatment course of 
nirmatrelvir/ritonavir.
6. Has at least 1 characteristic or underlying medical condition associated with an 
increased risk of developing severe illness from COVID-19.
Exclusion Criteria
Participants with any of the following characteristics/conditions will be excluded:
1. Current need for hospitalization, hospitalized for the index COVID-19 infection, 
or anticipated need for hospitalization within 24 h after randomization in the 
clinical opinion of the site investigator.
2. History of severe chronic liver disease (eg, jaundice, ascites, hepatic 
encephalopathy, history of bleeding esophageal or gastric varices). No laboratory 
testing is needed.
3. History of hypersensitivity or other contraindication to any of the components of 
the study interventions, as determined by the investigator.


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4. Suspected or confirmed concurrent active systemic infection other than COVID-
19 that may interfere with the evaluation of response to the study intervention.
5. Receiving dialysis or eGFR <30 mL/min/1.73 m2 (for adults) or eCrCl <30 
mL/min (for adolescents) at screening using creatinine point of care device.
6. Oxygen saturation of <92% on room air obtained at rest within 24 hours prior to 
randomization.
7. Immunocompromised.
8. 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.
9. Current use of any prohibited concomitant medication(s).
10. COVID-19 vaccination within 14 days prior to study entry or anticipated COVID-
19 vaccination through Day 34.
11. Receiving other COVID-19 specific treatments within 30 days of randomization 
and through Day 34, excluding the initial course of nirmatrelvir/ritonavir as well 
as blinded study medication.
12. Prior participation in this trial.
13. Current or previous administration with an investigational product (drug or 
vaccine) within 30 days (or as determined by the local requirement) or 5 half-lives 
preceding the first dose of study intervention used in this study (whichever is 
longer).
14. Females who are pregnant up to 14 weeks gestation. Pregnancy ≥14 weeks is not 
exclusionary.
15. Investigator site staff directly involved in the conduct of the study and their 
family members, site staff otherwise supervised by the investigator, and sponsor 
and sponsor delegate employees directly involved in the conduct of the study and 
their family members.
Study Arms and Duration:
Eligible participants for this study will be randomly assigned (2:1) to receive nirmatrelvir 
plus ritonavir orally q12h or placebo/ritonavir as specified in the tables below.


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Study Intervention(s)
Intervention Name
Nirmatrelvir
Placebo for nirmatrelvir
Ritonavir
Arm Name
(group of participants 
receiving a specific treatment 
or no treatment)
nirmatrelvir/ritonavir
placebo
ritonavir
Unit Dose Strength(s)
150 mg
0 mg
100 mg
Route of Administration
Oral
Oral
Oral
Use
Experimental
Placebo
Experimental
IMP or NIMP/AxMP
IMP
IMP
IMP
Study Arm(s)
Arm Title
Nirmatrelvir/ritonavir
Placebo/ritonavir
Arm Type
Experimental
Other
Arm 
Description
Participants will receive nirmatrelvir/ritonavir 
300 mg/100 mg (or 150 mg/100 mg for participants 
with eGFR ≥30 to <60 mL/min/1.73 m2 or eCrCl ≥30 
to <60 mL/min) q12h from Day 1 through Day 5.
Participants will receive placebo 
0 mg/ritonavir 100 mg q12h for 5 days.
Statistical Methods:
The study will randomize approximately 411 participants in a 2:1 randomization ratio to 
nirmatrelvir/ritonavir or placebo/ritonavir.
The primary efficacy endpoint is the change in viral SARS-CoV-2 RNA level from baseline 
to Day 5 as measured in NP swabs. This will be estimated without regard to study treatment 
discontinuation and without regard to prohibited therapies. 
With respect to the primary endpoint of change in SARS-CoV-2 RNA level from baseline to 
Day 5 as measured in NP swab in the mITT analysis set, and assuming a SD of 1.8 (based on 
Study C4671005 [EPIC-HR, NCT04960202]), a sample size of approximately 315 evaluable 
participants (210 participants in the nirmatrelvir/ritonavir group and 105 participants in the 
placebo/ritonavir group) is expected to provide 90% power to detect a difference of 0.7 log10
copies/mL in viral RNA between groups using a 2-sided 0.05 alpha level test. Assuming 
approximately 10% of participants will have a negative viral RNA result at baseline, and 
assuming a non-evaluable rate of 15%, approximately 411 participants will be randomized in 
the study to achieve approximately 315 participants evaluable for the primary efficacy 
endpoint.
No formal interim analysis is planned for this study. However, the sponsor may conduct 
unblinded reviews of the data during the course of the study if requested by regulatory 


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authorities including in the support of regulatory submissions.  Should an unblinded review 
be requested, details of the unblinding plan will be described in the SAP and a separate data 
unblinding document.
Ethical Considerations:
Previous studies have demonstrated efficacy, safety, and tolerability of nirmatrelvir/ritonavir 
in adults at increased risk of progressing to severe COVID-19 illness. The FDA has granted 
EUA for nirmatrelvir/ritonavir for the treatment of mild-to-moderate COVID-19 in adults 
and pediatric patients (12 years of age and older and weighing at least 40 kg) with positive 
results of direct SARS-CoV-2 testing, and who are at high risk for progression to severe 
COVID-19, including hospitalization or death. The most common adverse events described 
with nirmatrelvir/ritonavir treatment are allergic reactions, change in taste, diarrhea, 
headache, and vomiting. At present, there are no controlled efficacy and safety data of a 
repeat 5-day course of nirmatrelvir/ritonavir in participants with acute rebound in symptoms 
and SARS-CoV-2 infection. People who have rebound in mild-to-moderate COVID-19 may 
benefit from a repeat 5-day treatment course of nirmatrelvir/ritonavir. Considering the 
measures to minimize risk to study participants, the potential risks identified in association 
with nirmatrelvir/ritonavir are justified by the anticipated benefits that may be afforded to 
participants eligible for enrollment in this study. 
Participants will be expected to commit time and may experience some discomfort while 
undergoing study assessments. In addition, participants must avoid use of a non-study 
COVID-19 antiviral (excluding a single 5-day treatment course of nirmatrelvir/ritonavir for 
eligibility), monoclonal antibody therapy for COVID-19, or COVID-19 vaccination within 
14 days prior to randomization and through completion of Day 34. Participants who progress 
to severe or critical COVID-19 will however be permitted to receive specific COVID-19 
treatment(s) such as antiviral therapy or use of other treatments considered standard of care. 
Female participants who are not pregnant and are of childbearing potential must agree to use 
appropriate contraception methods.
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. 
Table 1.
Study Schedule of Assessment
Visit Identifier
Screen
Treatment Period
Efficacy and Safety Follow-up Period
LTFU
Notes
Abbreviations used 
in this table may 
be found in 
Appendix 12.
Baseline 
(Day 1)
Day 3 Day 5 Day 10Day 15 Day 21 Day 28 Day 34 Week 
12
Week 
24
ET 
(prior 
to Day 
34)
Day relative to start of study intervention 
(Day 1).
Baseline (Day 1) visit is a mandatory visit.
Assessments indicated in brackets [X] are only 
to be conducted if indicated as described in the 
“Notes”.
Visit Window 
Day -1 to 
Day 1 
0 days ±1 day
±1 
day
±1 day
±2 
days
±2 
days
±2 days ±3 days
±7 
days
±7 
days
±5 days Screening procedures may be done from Day -
1 to Day 1 and may be completed on the same 
calendar day as Baseline/Day 1 procedures. If 
screening and baseline visits are conducted on 
the same calendar day, assessments and 
procedure that are listed to occur at both visits 
only need to be completed once.
Study Visit 
Location
S
S
S/P
S/P
S/P
S/P
S/P
S/P
S/P
T
T
S/P
Site staff should, in discussion with 
participants, determine the most appropriate 
location to conduct study visits. Visits should 
take place at the investigational site (S). If this 
is not feasible, then alternate venues may 
include the participant’s location (P).
If an in-person visit is held at a location other 
than S, the HCP performing the visit may be 
unable to complete all assessments. In these 
cases, a telemedicine/telehealth visit should 
also occur to perform the remaining 
assessments.
ELIGIBILITY


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Table 1.
Study Schedule of Assessment
Visit Identifier
Screen
Treatment Period
Efficacy and Safety Follow-up Period
LTFU
Notes
Abbreviations used 
in this table may 
be found in 
Appendix 12.
Baseline 
(Day 1)
Day 3 Day 5 Day 10Day 15 Day 21 Day 28 Day 34 Week 
12
Week 
24
ET 
(prior 
to Day 
34)
Day relative to start of study intervention 
(Day 1).
Baseline (Day 1) visit is a mandatory visit.
Assessments indicated in brackets [X] are only 
to be conducted if indicated as described in the 
“Notes”.
Visit Window 
Day -1 to 
Day 1 
0 days ±1 day
±1 
day
±1 day
±2 
days
±2 
days
±2 days ±3 days
±7 
days
±7 
days
±5 days Screening procedures may be done from Day -
1 to Day 1 and may be completed on the same 
calendar day as Baseline/Day 1 procedures. If 
screening and baseline visits are conducted on 
the same calendar day, assessments and 
procedure that are listed to occur at both visits 
only need to be completed once.
Informed 
consent/assent 
X
Informed consent/assent should be obtained 
prior to undergoing any study-specific 
procedures.
See Section 10.1.3 for additional information.
Verify 
inclusion/exclusion 
criteria
X
See Section 5.1 and Section 5.2.
Screening visit: A serum creatinine point-of-
care device assessment for calculating eGFR 
for adults 18 years and older, and eCrCl for 
adolescents 12 years to <18 years is required 
for eligibility (Appendix 7).
Demographics and 
medical history
X
See Section 8.1.1.1.
Includes history of confirmed/presumed prior 
COVID-19 infections, including most recent 
infection, SARS-CoV-2 test results, if 
available, and COVID-19 vaccinations.
Physical 
Examination and 
Vital Signs
Targeted physical 
examination
X
See Section 8.3.1 for additional information.
Weight, height
X
Height may be self-reported for participants 
≥18 years of age.
See Section 8.3.1 for additional information.
Vital signs
X
X
X
X
X
X
X
See Section 8.3.2 for additional information.


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Table 1.
Study Schedule of Assessment
Visit Identifier
Screen
Treatment Period
Efficacy and Safety Follow-up Period
LTFU
Notes
Abbreviations used 
in this table may 
be found in 
Appendix 12.
Baseline 
(Day 1)
Day 3 Day 5 Day 10Day 15 Day 21 Day 28 Day 34 Week 
12
Week 
24
ET 
(prior 
to Day 
34)
Day relative to start of study intervention 
(Day 1).
Baseline (Day 1) visit is a mandatory visit.
Assessments indicated in brackets [X] are only 
to be conducted if indicated as described in the 
“Notes”.
Visit Window 
Day -1 to 
Day 1 
0 days ±1 day
±1 
day
±1 day
±2 
days
±2 
days
±2 days ±3 days
±7 
days
±7 
days
±5 days Screening procedures may be done from Day -
1 to Day 1 and may be completed on the same 
calendar day as Baseline/Day 1 procedures. If 
screening and baseline visits are conducted on 
the same calendar day, assessments and 
procedure that are listed to occur at both visits 
only need to be completed once.
Laboratory 
Assessments
See Section 8.3.3 for additional information.
See Appendix 2 for a list of Clinical 
Laboratory tests to be done.
For laboratory collection volumes, see the 
laboratory manual.
Hematology
X
X
X
X
Baseline laboratory assessments should be 
collected prior to first dose of study 
intervention.
If deemed necessary to confirm eligibility, 
laboratory assessments at screening may be 
performed at the local laboratory at the 
investigator’s discretion.
Abnormal laboratory valued related to AEs 
should be followed until resolution.
Blood chemistry
X
X
X
X
Point-of-care 
serum creatinine 
assessment
X
[X]
Screening visit: A serum creatinine point-of-
care device assessment for determining 
estimation of kidney function (eGFR for adults 
18 years and older, and eCrCl for adolescents 
12 years to <18 years) is required for 
eligibility. See Section 10.7 for age specific 
kidney function calculations.  
Baseline visit assessment expected only if 
screening and baseline visits are held on 
different days. If a serum creatinine point-of-
care device assessment is performed at 


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Table 1.
Study Schedule of Assessment
Visit Identifier
Screen
Treatment Period
Efficacy and Safety Follow-up Period
LTFU
Notes
Abbreviations used 
in this table may 
be found in 
Appendix 12.
Baseline 
(Day 1)
Day 3 Day 5 Day 10Day 15 Day 21 Day 28 Day 34 Week 
12
Week 
24
ET 
(prior 
to Day 
34)
Day relative to start of study intervention 
(Day 1).
Baseline (Day 1) visit is a mandatory visit.
Assessments indicated in brackets [X] are only 
to be conducted if indicated as described in the 
“Notes”.
Visit Window 
Day -1 to 
Day 1 
0 days ±1 day
±1 
day
±1 day
±2 
days
±2 
days
±2 days ±3 days
±7 
days
±7 
days
±5 days Screening procedures may be done from Day -
1 to Day 1 and may be completed on the same 
calendar day as Baseline/Day 1 procedures. If 
screening and baseline visits are conducted on 
the same calendar day, assessments and 
procedure that are listed to occur at both visits 
only need to be completed once.
screening and baseline, the baseline estimate 
of kidney function will determine eligibility.
See Section 8.3.2.4.
FSH
X
FSH is to be performed locally to confirm 
postmenopausal status in female participants 
<60 years of age at screening who are not 
using hormonal contraception or hormonal 
replacement therapy. Female participants aged 
50 to 60 years with no menses for 12 months 
do not need FSH testing to be performed to 
confirm postmenopausal status.
See Appendix 2.
HIV test (Germany 
only)
X
Local HIV testing at screening will be 
performed for participants in Germany as 
required by the German HA
See Appendix 2
Pregnancy Test
X
X
X
See Section 8.3.4.
SARS-CoV-2 
Serology
X
X
X
X
Biomarker 
Assessments
NP swab collection 
for SARS-CoV-2 
RNA level
X
X
X
X
X
X
X
X
X
All NP swabs of both nares, will be collected 
by HCP at visits indicated. Samples will be 
shipped to central lab for quantitative SARS-
CoV-2 RNA concentration. 


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Table 1.
Study Schedule of Assessment
Visit Identifier
Screen
Treatment Period
Efficacy and Safety Follow-up Period
LTFU
Notes
Abbreviations used 
in this table may 
be found in 
Appendix 12.
Baseline 
(Day 1)
Day 3 Day 5 Day 10Day 15 Day 21 Day 28 Day 34 Week 
12
Week 
24
ET 
(prior 
to Day 
34)
Day relative to start of study intervention 
(Day 1).
Baseline (Day 1) visit is a mandatory visit.
Assessments indicated in brackets [X] are only 
to be conducted if indicated as described in the 
“Notes”.
Visit Window 
Day -1 to 
Day 1 
0 days ±1 day
±1 
day
±1 day
±2 
days
±2 
days
±2 days ±3 days
±7 
days
±7 
days
±5 days Screening procedures may be done from Day -
1 to Day 1 and may be completed on the same 
calendar day as Baseline/Day 1 procedures. If 
screening and baseline visits are conducted on 
the same calendar day, assessments and 
procedure that are listed to occur at both visits 
only need to be completed once.
At Screening and Baseline (Day 1) only, rapid 
antigen testing can be done before NP swab 
collection.
At all other time points, NP swab collection 
will be collected PRIOR to the sample for 
rapid antigen testing.
See Section 8.7.1.
Rapid antigen 
testing (on site)
X
X
X
X
X
X
X
X
X
X
Investigative sites will use test kits provided 
by the sponsor and perform sample collection 
and testing according to manufacturer’s 
instructions.
At Screening and Baseline (Day 1) only, rapid 
antigen testing can be done before NP swab 
collection.
At all other time points rapid antigen testing 
must occur after NP swab collection.
Screening assessment performed locally, at 
site. If rapid antigen testing is performed at  
screening and baseline, the baseline result will 
determine eligibility.
Site staff should train participants/caregiver at 
the screening/baseline visit to ensure 
participants can perform the rapid antigen test 
appropriately. The participant should perform 
the baseline rapid antigen testing assessment 


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Table 1.
Study Schedule of Assessment
Visit Identifier
Screen
Treatment Period
Efficacy and Safety Follow-up Period
LTFU
Notes
Abbreviations used 
in this table may 
be found in 
Appendix 12.
Baseline 
(Day 1)
Day 3 Day 5 Day 10Day 15 Day 21 Day 28 Day 34 Week 
12
Week 
24
ET 
(prior 
to Day 
34)
Day relative to start of study intervention 
(Day 1).
Baseline (Day 1) visit is a mandatory visit.
Assessments indicated in brackets [X] are only 
to be conducted if indicated as described in the 
“Notes”.
Visit Window 
Day -1 to 
Day 1 
0 days ±1 day
±1 
day
±1 day
±2 
days
±2 
days
±2 days ±3 days
±7 
days
±7 
days
±5 days Screening procedures may be done from Day -
1 to Day 1 and may be completed on the same 
calendar day as Baseline/Day 1 procedures. If 
screening and baseline visits are conducted on 
the same calendar day, assessments and 
procedure that are listed to occur at both visits 
only need to be completed once.
during the visit to ensure proper sample 
collection under observation by site staff.
Will be self-collected by the participant.
See Section 8.1.3.
See Section 8.7.3.
Participant 
self-collected rapid 
antigen testing
Collected daily and witnessed by the site staff.*

Site staff should train participants/caregiver at 
the screening/baseline visit to ensure 
participants can perform the rapid antigen test 
appropriately. The participant should perform 
the baseline rapid antigen testing assessment 
during the visit to ensure proper sample 
collection.
Only 1 rapid antigen test is expected to be 
performed daily. When onsite, rapid antigen 
testing will be done at the site and no self-
collected rapid antigen testing at home will be 
done.
Site staff will observe the participant 
performing the rapid antigen test (ie, via video 
or videoconferencing software if the procedure 
is conducted remotely), confirm testing, and 
record the test result in the CRF.
*Daily testing will stop once the participant 
has 2 consecutive negative tests separated by 
at least 24[-2]h. Thereafter, rapid antigen 


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Table 1.
Study Schedule of Assessment
Visit Identifier
Screen
Treatment Period
Efficacy and Safety Follow-up Period
LTFU
Notes
Abbreviations used 
in this table may 
be found in 
Appendix 12.
Baseline 
(Day 1)
Day 3 Day 5 Day 10Day 15 Day 21 Day 28 Day 34 Week 
12
Week 
24
ET 
(prior 
to Day 
34)
Day relative to start of study intervention 
(Day 1).
Baseline (Day 1) visit is a mandatory visit.
Assessments indicated in brackets [X] are only 
to be conducted if indicated as described in the 
“Notes”.
Visit Window 
Day -1 to 
Day 1 
0 days ±1 day
±1 
day
±1 day
±2 
days
±2 
days
±2 days ±3 days
±7 
days
±7 
days
±5 days Screening procedures may be done from Day -
1 to Day 1 and may be completed on the same 
calendar day as Baseline/Day 1 procedures. If 
screening and baseline visits are conducted on 
the same calendar day, assessments and 
procedure that are listed to occur at both visits 
only need to be completed once.
testing will be done at regularly scheduled 
onsite visits.
See Section 8.1.3
Oropharyngeal 
samples for SARS-
CoV-2 RNA level
X
X
X
X
X
X
See Section 8.7.4.  
Plasma collection 
for SARS-CoV-2 
RNA level 
X
X
X
X
X
X
X
X
X
See Section 8.7.2.
Plasma collection 
specific for 
biomarkers
X
X
X
X
X
X
See Section 8.7.6.1 .
Retained research 
samples for 
genetics (Prep D1) 
X
X
X
X
X
If not collected on the designated collection 
day, collect at the next available time point 
when biospecimens are being collected in 
conjunction with a participant visit.
See Section 8.6.2.
Retained research 
samples for 
biomarkers (Prep 
B2.5, Prep R1), 
M3 (urine)
X
X
X
X
X
See Section 8.7.8
Study 
Intervention 
Randomization
X


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Table 1.
Study Schedule of Assessment
Visit Identifier
Screen
Treatment Period
Efficacy and Safety Follow-up Period
LTFU
Notes
Abbreviations used 
in this table may 
be found in 
Appendix 12.
Baseline 
(Day 1)
Day 3 Day 5 Day 10Day 15 Day 21 Day 28 Day 34 Week 
12
Week 
24
ET 
(prior 
to Day 
34)
Day relative to start of study intervention 
(Day 1).
Baseline (Day 1) visit is a mandatory visit.
Assessments indicated in brackets [X] are only 
to be conducted if indicated as described in the 
“Notes”.
Visit Window 
Day -1 to 
Day 1 
0 days ±1 day
±1 
day
±1 day
±2 
days
±2 
days
±2 days ±3 days
±7 
days
±7 
days
±5 days Screening procedures may be done from Day -
1 to Day 1 and may be completed on the same 
calendar day as Baseline/Day 1 procedures. If 
screening and baseline visits are conducted on 
the same calendar day, assessments and 
procedure that are listed to occur at both visits 
only need to be completed once.
Study intervention 
dispensation
X
Study intervention will be dispensed on Day 1. 
(See Section 6.1.1)
See Appendix 7 for age-specific kidney 
function calculations to determine nirmatrelvir 
dosing.
Study intervention 
administration 
Days 1 through 5
Baseline assessments should be performed 
before administration of the first study 
intervention.
The first dose of study intervention will be 
administered to all participants on Day 1 
during the in-person visit. All subsequent 
doses of study intervention will be self-
administered (or administered to the 
participant by a legal guardian or caregiver). If 
only 1 dose of study intervention is 
administered on Day 1, study intervention 
should end on Day 6.
See Section 6.1.
Participant-
completed study 
intervention log
Daily on Days 1 through 
5
Participants will use a participant-completed 
electronic dosing diary to record the date and 
time of their study intervention dosing.
Study intervention log should be completed 
daily on Days 1 through 6 if only 1 dose was 
administered on Day 1.
See Section 6.5.


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Table 1.
Study Schedule of Assessment
Visit Identifier
Screen
Treatment Period
Efficacy and Safety Follow-up Period
LTFU
Notes
Abbreviations used 
in this table may 
be found in 
Appendix 12.
Baseline 
(Day 1)
Day 3 Day 5 Day 10Day 15 Day 21 Day 28 Day 34 Week 
12
Week 
24
ET 
(prior 
to Day 
34)
Day relative to start of study intervention 
(Day 1).
Baseline (Day 1) visit is a mandatory visit.
Assessments indicated in brackets [X] are only 
to be conducted if indicated as described in the 
“Notes”.
Visit Window 
Day -1 to 
Day 1 
0 days ±1 day
±1 
day
±1 day
±2 
days
±2 
days
±2 days ±3 days
±7 
days
±7 
days
±5 days Screening procedures may be done from Day -
1 to Day 1 and may be completed on the same 
calendar day as Baseline/Day 1 procedures. If 
screening and baseline visits are conducted on 
the same calendar day, assessments and 
procedure that are listed to occur at both visits 
only need to be completed once.
Staff review of 
study intervention 
log
Daily on Days 1 through 
5
Staff review of the study intervention log 
should be completed daily on Days 1 through 
6 if only 1 dose was administered on Day 1.
See Section 6.
Study 
Intervention 
Accountability
Retrieval of 
unused study 
intervention and 
empty study 
intervention 
containers
X
If the last dose of study intervention is taken 
on Day 6, collect at next visit.
Study intervention 
accountability
X
Study intervention accountability is only 
performed at the Day 10 visit if the last dose 
of study intervention is taken on Day 6.
Patient Reported 
Outcomes
Participant-
completed study 
diary (COVID-19 
signs and 
symptoms)
Collected daily from Days 1 through 28.
See Section 8.2.3.5.


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Table 1.
Study Schedule of Assessment
Visit Identifier
Screen
Treatment Period
Efficacy and Safety Follow-up Period
LTFU
Notes
Abbreviations used 
in this table may 
be found in 
Appendix 12.
Baseline 
(Day 1)
Day 3 Day 5 Day 10Day 15 Day 21 Day 28 Day 34 Week 
12
Week 
24
ET 
(prior 
to Day 
34)
Day relative to start of study intervention 
(Day 1).
Baseline (Day 1) visit is a mandatory visit.
Assessments indicated in brackets [X] are only 
to be conducted if indicated as described in the 
“Notes”.
Visit Window 
Day -1 to 
Day 1 
0 days ±1 day
±1 
day
±1 day
±2 
days
±2 
days
±2 days ±3 days
±7 
days
±7 
days
±5 days Screening procedures may be done from Day -
1 to Day 1 and may be completed on the same 
calendar day as Baseline/Day 1 procedures. If 
screening and baseline visits are conducted on 
the same calendar day, assessments and 
procedure that are listed to occur at both visits 
only need to be completed once.
Collection of 
global impression 
questions
Collected daily from Days 1 through 28.
Participants will answer 3 global impression 
questions. The global impression questions 
will be answered after the completion of the 
COVID-19 signs and symptoms diary is 
completed.
See Section 8.2.3.1.
SF-36 v2 Health 
Survey (Acute 
Form)
X
X
X
X
Only adult participants (≥18 years of age at the 
time of screening) will be asked to complete 
the SF-36. See Section 8.2.3.2.
WPAI
X
X
X
X
Only adult participants (≥18 years of age at the 
time of screening) will be asked to complete 
the WPAI. See Section 8.2.3.3
EQ-5D-5L 
X
X
X
X
X
X
Only adult participants (≥18 years of age at the 
time of screening) will be asked to complete 
the EQ-5D-5L. See Section 8.2.3.4. 
Study Procedures 
and Assessments
Provide 
participants with 
study emergency 
contact card
X
See Section 10.1.11.
Collect/update 
secondary contacts
X
X
See Section 8.1.1.2.


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Table 1.
Study Schedule of Assessment
Visit Identifier
Screen
Treatment Period
Efficacy and Safety Follow-up Period
LTFU
Notes
Abbreviations used 
in this table may 
be found in 
Appendix 12.
Baseline 
(Day 1)
Day 3 Day 5 Day 10Day 15 Day 21 Day 28 Day 34 Week 
12
Week 
24
ET 
(prior 
to Day 
34)
Day relative to start of study intervention 
(Day 1).
Baseline (Day 1) visit is a mandatory visit.
Assessments indicated in brackets [X] are only 
to be conducted if indicated as described in the 
“Notes”.
Visit Window 
Day -1 to 
Day 1 
0 days ±1 day
±1 
day
±1 day
±2 
days
±2 
days
±2 days ±3 days
±7 
days
±7 
days
±5 days Screening procedures may be done from Day -
1 to Day 1 and may be completed on the same 
calendar day as Baseline/Day 1 procedures. If 
screening and baseline visits are conducted on 
the same calendar day, assessments and 
procedure that are listed to occur at both visits 
only need to be completed once.
Record/update 
household 
characteristics
X
X
X
X
X
X
X
X
See Section 8.1.2.
Record COVID-
19-related medical 
visits
X
X
X
X
X
X
X
X
COVID-19-related medical visits a participant 
has attended since the last assessment will be 
collected.
See Section 8.2.2.
Contraception 
check
X
X
X
X
X
X
X
X
X
X
See Section 5.3.1 and Appendix 4. 
Prior/concomitant 
therapy
X
X
X
X
X
X
X
X
X
X
All prescription and over-the-counter 
medications including vaccines taken by the 
participant within 30 days before study entry 
(considered prior treatment) will be recorded. 
Includes documentation along with start/stop 
dates of recent nirmatrelvir/ritonavir.
See Section 6.9.
COVID-19 
adjunctive 
therapeutic 
procedures
X
X
X
X
X
X
X
X
X
X
Nondrug treatments will be collected through 
the Day 34 visit or at the ET visit.
COVID-19 signs 
and symptoms
X
X
See Section 8.2.3.5.
Vital Status Check
X
X
Verify mortality status of participants.


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Table 1.
Study Schedule of Assessment
Visit Identifier
Screen
Treatment Period
Efficacy and Safety Follow-up Period
LTFU
Notes
Abbreviations used 
in this table may 
be found in 
Appendix 12.
Baseline 
(Day 1)
Day 3 Day 5 Day 10Day 15 Day 21 Day 28 Day 34 Week 
12
Week 
24
ET 
(prior 
to Day 
34)
Day relative to start of study intervention 
(Day 1).
Baseline (Day 1) visit is a mandatory visit.
Assessments indicated in brackets [X] are only 
to be conducted if indicated as described in the 
“Notes”.
Visit Window 
Day -1 to 
Day 1 
0 days ±1 day
±1 
day
±1 day
±2 
days
±2 
days
±2 days ±3 days
±7 
days
±7 
days
±5 days Screening procedures may be done from Day -
1 to Day 1 and may be completed on the same 
calendar day as Baseline/Day 1 procedures. If 
screening and baseline visits are conducted on 
the same calendar day, assessments and 
procedure that are listed to occur at both visits 
only need to be completed once.
Serious and 
nonserious AE 
monitoring
X
X
X
X
X
X
X
X
X
X
AEs should be assessed by means of a 
telemedicine visit if an in-person visit is not 
feasible.
Previously identified AEs (either by interview, 
physical exam, or other assessment) should be 
monitored to the extent possible if 
telemedicine is used.
See Section 8.4.3 for follow-up AE and SAE 
assessments.


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2. INTRODUCTION
Nirmatrelvir, a potent and selective SARS-CoV-2 3CL orally administered protease inhibitor, 
is being investigated in participants with rebound of COVID-19 symptoms and rapid antigen 
test positivity.
2.1. Study Rationale 
Case reports in the literature describe individuals who have experienced symptomatic 
relapses of SARS-CoV-2 infection following completion of a 5-day course of 
nirmatrelvir/ritonavir[1-3]. In the available cases, patients are described as experiencing rapid 
improvement in systemic symptoms following initiation of treatment but then experience a 
rebound in COVID-19 symptoms after completing therapy. The time course of symptom 
rebound suggests that symptom recurrence is likely not related to re-exposure and that it does 
not reflect a potential re-infection event. In one case report, symptom relapse was 
accompanied by fluctuating RT-PCR cycle thresholds and antigen testing suggesting the 
potential for a rebound in viral replication. In a separate case series of 7 patients with 
recurrent symptoms, median SARS-CoV-2 RNA at baseline was 6.1 log10 copies/mL (range 
4.2-7.3) and enrollment viral cultures were positive in 3 of 7 individuals[4]. Several of the 
published case reports on symptom recurrence included viral sequencing and these reports to 
date have not identified resistance mutations to nirmatrelvir.
A retrospective review of 483 high-risk patients treated with nirmatrelvir/ritonavir reported 
4 (0.8%) of patients experienced rebound of symptoms. Median time to rebound was 
reported as 9 days. Rebound symptoms were characterized as mild and resolving without 
additional COVID-19 therapy with no patient requiring hospitalization[5].
Post-treatment increases in SARS-CoV-2 RNA levels (ie, viral RNA rebound) in 
nasopharyngeal samples were observed on Day 10 or Day 14 in a subset of 
nirmatrelvir/ritonavir and placebo recipients in the EPIC-HR study. The frequency of
detection of post-treatment viral RNA rebound varied according to analysis parameters but 
was generally similar among nirmatrelvir/ritonavir and placebo recipients, regardless of the 
rebound definition used. For participants who showed a half-log10 or greater increase relative 
to end of treatment and whose viral load was persistent through follow-up, the occurrence 
was 1.73% placebo and 2.32% nirmatrelvir/ritonavir. In addition to these, some participants 
had transient half-log10 or greater increases relative to end of treatment, the occurrence was 
2.35% in placebo vs 4.65% nirmatrelvir/ritonavir. A similar or smaller percentage of placebo 
recipients compared to nirmatrelvir/ritonavir recipients had nasopharyngeal viral RNA 
results <LLOQ at all study timepoints in both the treatment and post-treatment periods. Post-
treatment viral RNA rebound was not associated with the primary clinical outcome of 
COVID-19-related hospitalization or death from any cause through Day 28 following the 
single 5-day course of nirmatrelvir/ritonavir treatment. Post-treatment viral RNA rebound 
also was not associated with drug resistance as measured by mPro sequencing. The clinical 
relevance of post-treatment increases in viral RNA following nirmatrelvir/ritonavir or 
placebo treatment is unknown. 
At present, there are no controlled efficacy and safety data of a repeat 5-day course of 
nirmatrelvir/ritonavir in participants with acute rebound in symptoms and SARS-CoV-2 


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infection. Recurrence in symptoms along with a positive rapid antigen test following the 
completion of a 5-day course of nirmatrelvir/ritonavir may indicate that these patients require 
additional therapy to achieve sustained viral clearance. Such patients may benefit from an 
additional 5-day treatment duration. The purpose of this study is to evaluate the efficacy, 
safety and tolerability of a second 5-day treatment course of nirmatrelvir/ritonavir in 
participants with a rebound in COVID-19 symptoms and a positive rapid antigen test within 
2 weeks (14 days) following completion of an initial 5-day treatment course.
2.2. Background 
COVID-19, caused by the SARS-CoV-2 coronavirus, was declared a global pandemic by the 
WHO on 11 March 2020[6], and continues to be a serious global threat to public health and 
to health care systems. As of 07 March 2022, COVID-19 has infected at least 446 million 
people, and has led to at least 6 million deaths worldwide[7]. 
In order to prevent SARS-CoV-2 infection, several COVID-19 vaccines have been approved 
or authorized for emergency use by Health Authorities and are being administered 
globally[8]. 
In December 2021, the FDA granted EUA for a 5 day course of treatment for 2 separate oral 
antiviral agents, nirmatrelvir/ritonavir[9] and molnupiravir[10], for the treatment of COVID-
19 in adult and pediatric patients 12 years of age and older who weigh at least 40 kg, with 
mild to moderate COVID-19 who are at high risk for progressing to severe illness. In January 
2022, remdesivir received approval for this same population[11]. This treatment is 
administered by IV infusion over 3 days for nonhospitalized patients with mild to moderate 
COVID-19 who are at high risk for progressing to severe illness.
In this study of participants with rebound of COVID-19 symptoms and rapid antigen test 
positivity, nirmatrelvir/ritonavir will be administered for 5 days.
2.2.1. Clinical Overview
The safety and efficacy of a 5-day treatment with nirmatrelvir/ritonavir in adults was 
demonstrated in Study C4671005, which enrolled nonhospitalized symptomatic adults with 
laboratory-confirmed diagnosis of SARS-CoV-2 infection with at least 1 risk factor for 
progression to severe disease and with a COVID-19 symptom onset of ≤5 days. In the 
analysis of the primary endpoint from all participants enrolled in Study C4671005, an 89% 
reduction in COVID-19-related hospitalization or death from any cause compared with 
placebo in participants treated within 3 days of symptom onset was observed. 0.72% of 
participants who received nirmatrelvir/ritonavir were hospitalized through Day 28 following 
randomization (5 of 697 hospitalized with no deaths), compared to 6.45% of participants who 
received placebo and were hospitalized or died (44 of 682 hospitalized with 9 subsequent 
deaths) (p<0.001). In the final analysis of participants who initiated treatment ≤5 days from 
symptom onset and did not receive or were not expected to receive COVID-19 therapeutic 
mAbs treatment at time of randomization (mITT1 population), nirmatrelvir/ritonavir 
significantly reduced COVID-19‒related hospitalization or death from 66/1046 (6.31%) to 
9/1039 (0.87%) compared with placebo at Day 28 (p<0.0001), corresponding to an 86.3% 
relative risk reduction.


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Refer to the IB[12] for more details on studies, including clinical efficacy, safety, and PK 
results for completed and ongoing studies.
2.3. Benefit/Risk Assessment
More detailed information about the known and expected benefits and risks and reasonably 
expected AEs of nirmatrelvir/ritonavir may be found in the IB, which is the SRSD for this 
study.


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2.3.1. Risk Assessment
Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
Study Intervention(s) Nirmatrelvir
Emesis
In Study C4671005, vomiting occurred at a 
greater frequency in the nirmatrelvir/ritonavir 
group (1.1%) than in the placebo group (0.8%).
AEs will be monitored and participants may 
receive antiemetics if needed.
Hypertension
Transient increases in systolic, diastolic, and 
mean blood pressure were observed in the 
preclinical studies. In Study C4671005 (adults at 
high risk for severe disease), a small imbalance 
in hypertension AEs (1% vs <1%) was reported.
Vital signs and all AEs will be monitored in the 
study.
Reduced maternal and fetal weight
In rabbit embryo-fetal development toxicity 
studies, nirmatrelvir-related lower maternal body 
weight change and food consumption were 
observed at 1000 mg/kg/day but were not 
considered adverse based on low magnitude of 
difference from control and lack of impact on 
absolute body weights. Nirmatrelvir -related, 
adverse, lower fetal weight (0.91x control) was 
observed at 1000 mg/kg/day.
Lower dose of 300 mg q12h (or 150 mg q12h in 
moderate renal impairment) is used in this study.
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.
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.
Rash (most commonly reported as erythematous 
and maculopapular, followed by pruritic)
Frequently reported adverse reaction in patients 
who are HIV-positive at 600 mg BID.
Lower dose used in this study. There will be close 
observation of AEs and monitoring through 


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Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
targeted physical exams. If needed, therapeutic 
interventions per SoC may be provided.
Fatigue/Asthenia
Frequently reported adverse reaction in patients 
who are HIV-positive at 600 mg BID.
Lower dose used in this study. There will be close 
observation of AEs.


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2.3.2. Benefit Assessment 
Nirmatrelvir/ritonavir has been shown to have SARS-CoV-2 antiviral activity in vitro. 
Efficacy, safety and tolerability of nirmatrelvir/ritonavir was demonstrated in adults at 
increased risk of progressing to severe COVID-19 illness. The EMA has granted marketing 
authorisation approval for nirmatrelvir/ritonavir for the treatment COVID-19 in adults who 
do not require supplemental oxygen and who are at increased risk for progressing to severe 
COVID-19[13]. The FDA has granted EUA for nirmatrelvir/ritonavir for the treatment of 
mild to moderate COVID-19 in adults and pediatric patients (12 years of age and older and 
weighing ≥40 kg) with positive results of direct SARS-CoV-2 testing, and who are at high 
risk for progression to severe COVID-19, including hospitalization or death.
2.3.3. Overall Benefit/Risk Conclusion
Considering the current COVID-19 global pandemic, the high burden of both mortality and 
morbidity, the potential for future epidemic outbreaks, the lack of readily available outpatient 
treatment options, and the measures taken to minimize risk to study participants, the potential 
risks identified in association with nirmatrelvir/ritonavir are justified by the anticipated 
benefits that may be afforded to participants with rebound of COVID-19 symptoms and rapid 
antigen test positivity. Rebound in symptoms along with a positive rapid antigen test 
following the completion of a 5-day course of nirmatrelvir/ritonavir may indicate that these 
patients may require additional therapy to achieve sustained viral clearance. Such patients 
may benefit from an additional 5-day treatment duration.
3. OBJECTIVES, ENDPOINTS, AND ESTIMANDS 
Objectives
Endpoints
Estimands
Primary: 
Primary:
Primary: 
To compare the effect of 
nirmatrelvir/ritonavir to 
placebo/ritonavir on viral RNA level 
in NP swabs in participants with 
mild-to-moderate COVID-19.
The change in viral SARS-CoV-2 
RNA level as measured in NP swabs 
from baseline to Day 5.
The difference in mean change of 
SARS-CoV-2 RNA level in NP 
swabs from baseline to Day 5 
between nirmatrelvir/ritonavir and 
placebo/ritonavir group in patients 
with a rebound in COVID-19 
symptoms and a positive rapid 
antigen test within 2 weeks 
following completion of an initial 
5-day treatment course ,who have a 
positive viral RNA NP swab test 
result at baseline. This will be 
estimated without regard to study 
treatment discontinuation and
without regard to prohibited 
therapies.


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Objectives
Endpoints
Estimands
Secondary: 
Secondary:
Secondary: 
To compare the effect of 
nirmatrelvir/ritonavir to 
placebo/ritonavir on the duration of 
viral shedding.
Time to 2 consecutive negative rapid 
antigen test results obtained at least 
24 (-2) h apart through Day 28.
The hazard ratio for time to 2 
consecutive negative rapid antigen 
test results obtained at least 24 (-2) h 
apart through Day 28 between 
nirmatrelvir/ritonavir and 
placebo/ritonavir group in patients 
with rebound in COVID-19 
symptoms and a positive rapid 
antigen test within 2 weeks following 
completion of an initial 5-day 
treatment course, who have a positive 
viral RNA NP swab test result at 
baseline. This will be estimated 
without regard to study treatment 
discontinuation and without regard to 
prohibited therapies.
To compare the effect of 
nirmatrelvir/ritonavir to 
placebo/ritonavir on the duration and 
severity of signs and symptoms in 
participants with mild-to-moderate 
COVID-19. 
Time (days) to sustained alleviation of
all targeted signs and symptoms 
through Day 28 where sustained 
alleviation is defined as the first of 
2 consecutive days when any 
symptoms scored as moderate or 
severe at baseline are scored as mild or 
absent and any symptoms scored as 
mild or absent at baseline are scored as 
absent.
The hazard ratio for time to sustained 
alleviation of all targeted signs and 
symptoms through Day 28 between 
nirmatrelvir/ritonavir and 
placebo/ritonavir group in patients 
with rebound in COVID-19 
symptoms and a positive rapid
antigen test within 2 weeks following 
completion of an initial 5-day 
treatment course, who have a positive 
viral RNA NP swab test result at 
baseline. This will be estimated 
without regard to study treatment 
discontinuation and without regard to 
prohibited therapies.
To describe the safety and 
tolerability of nirmatrelvir/ritonavir 
in participants with mild-to-
moderate COVID-19.
Incidence of TEAEs. Incidence of 
SAEs and AEs leading to 
discontinuation.
Not applicable.
Tertiary/Exploratory:
Tertiary/Exploratory:
Tertiary/Exploratory:
To compare the effect of 
nirmatrelvir/ritonavir to 
placebo/ritonavir on viral RNA level 
in NP swabs in participants with 
mild-to-moderate COVID-19.
Proportion of participants with SARS-
CoV-2 RNA in NP swab below the 
LLOQ on Days 3, 5, 10, 15, 21, 28, 
and 34.
Proportion of participants with 
sustained NP swab SARS-CoV-2 RNA 
below the LLOQ (defined as 
<2.0 log10 copies/mL) from Day 5 
through Day 34.
Proportion of participants with 
SARS-CoV-2 RNA in NP swabs below 
the LLOQ (defined as <2.0 log10 
copies/mL) on both Days 5 and 10.
The change in SARS-CoV-2 RNA 
level in NP swabs from baseline to 
Days 3, 10, 15, 21, 28, and 34.
Time to sustained NP swab 
SARS-CoV-2 RNA below the LLOQ 
(defined as <2.0 log10 copies/mL) and 

Not applicable.


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Objectives
Endpoints
Estimands
remains below the LLOQ through Day 
34 for participants with NP swab 
SARS-CoV-2 RNA greater than or 
equal to the LLOQ at baseline.
Rebound in SARS-CoV-2 RNA level 
in NP swabs at follow-up (ie, any study 
visit from Day 10 to through Day 34, 
defined as a half (0.5) log10 copies/mL 
increase or greater in SARS-CoV-2 
RNA level relative to SARS-CoV-2 
RNA level on Day 5 and with a 
follow-up viral RNA level 
≥2.5 log10 copies/mL.
To compare the effect of 
nirmatrelvir/ritonavir on the rate of 
cell culture infectious virus over 
time in participants with mild-to-
moderate COVID-19
In participants with detectable viral titers 
at baseline by TCID50:
Time to negative infectious titer by 
TCID50.
Change in TCID50 from baseline to 
Days 3, 5, 10, 15, 21, 28, and 34.
Proportion of participants with 
negative infectious titer by TCID50 
on Days 3, 5, 10, 15, 21, 28, and 34.
In participants with positive viral titers at 
baseline by virus recovery:

Time to negative infectious titer by 
virus recovery.

Proportion of participants with 
negative infectious titer by virus 
recovery on Days 3, 5, 10, 15, 21, 
28, and 34.

Not applicable
To compare the effect of 
nirmatrelvir/ritonavir to 
placebo/ritonavir on viral 
concentration in plasma in 
participants with mild-to-moderate 
COVID-19.
Change from baseline in SARS-CoV-2 
viral RNA level in plasma, over time.

Not applicable.
To compare the effect of 
nirmatrelvir/ritonavir to 
placebo/ritonavir on COVID-19-
related hospitalization and all-cause 
mortality in participants with mild-
to-moderate COVID-19.
Proportion of participants with 
COVID-19-related hospitalization >24 
h or death from any cause through 
Day 28.

Not applicable.
To compare the effect of 
nirmatrelvir/ritonavir to 
placebo/ritonavir on COVID-19-
related healthcare resource 
utilization in participants with mild-
to-moderate COVID-19.
Number of COVID-19-related medical 
visits through Day 34.

Not applicable.
To compare the effect of 
nirmatrelvir/ritonavir to 
placebo/ritonavir on the duration and 
severity of signs and symptoms in 
participants with mild-to-moderate 
COVID-19.
Time (days) to sustained resolution of 
all targeted signs and symptoms 
through Day 28 where sustained 
resolution is defined as the first of two 
consecutive days when all targeted 
COVID-19 symptoms are scored as 
absent.  

Not applicable


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4. STUDY DESIGN
4.1. Overall Design
This Phase 2, randomized, double-blind, placebo-controlled study will evaluate the efficacy 
and safety of a repeat 5-day treatment course of nirmatrelvir/ritonavir or placebo/ritonavir for 
the treatment of mild-to-moderate COVID-19. Participants must have written documentation, 
such as an electronic health record, medical record, or prescription receipt of treatment with 
nirmatrelvir/ritonavir (verbal assertion of treatment is not acceptable) with patient-reported 
100% compliance (ie, completed a 5 day course of nirmatrelvir/ritonavir). They must have 
experienced alleviation or resolution in COVID-19 signs/symptoms followed by a worsening 
(rebound) of signs/symptoms along with a positive rapid antigen test after completing an 
initial 5-day course of nirmatrelvir/ritonavir. The onset of rebound in COVID-19 symptoms 
along with evidence of SARS-CoV-2 infection must occur within 2 weeks (14 days) after
completion of an initial 5-day course of nirmatrelvir/ritonavir. 
Eligible participants for this study will be randomly assigned (2:1 allocation of active to 
placebo) to receive:

nirmatrelvir plus ritonavir orally q12h for 5 days; or

placebo plus ritonavir orally q12h for 5 days.
Randomization will be stratified by geographic region. 
Participants will be screened within 24 hours before randomization. 
Participants must be randomized within 48 hours from the onset of the rebound COVID-19 
symptoms and must be randomized within 24 hours of a positive baseline rapid antigen test. 
The total study duration is up to 24 weeks, including study intervention administration 
through Day 5 or Day 6, efficacy and safety assessments through Day 34, and long-term 
follow up at Weeks 12 and 24.   
Participants are eligible if they are at least 12 years of age (and weigh ≥40 kg at screening) 
and have at least 1 characteristic or underlying medical condition associated with an 
increased risk of developing severe illness from COVID-19. However, participants who are 
immunocompromised are excluded from this study as they may have prolonged viral 
shedding due to their immunocompromised state[14,15]. Participants will be eligible for 
enrollment irrespective of COVID-19 vaccination/boosted status (except for time course 
restrictions listed in the exclusion criteria).
An independent E-DMC will review unblinded data to ensure the safety of participants on an 
ongoing basis throughout the duration of the 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.


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4.2. Scientific Rationale for Study Design
Case reports in the literature describe individuals who have experienced symptomatic 
relapses of SARS-CoV-2 infection following completion of a 5-day course of 
nirmatrelvir/ritonavir[1-3]. In the available cases, patients are described as experiencing rapid 
improvement in systemic symptoms following initiation of treatment but then experience a 
rebound in COVID-19 symptoms after completing therapy. The time course of symptom 
rebound suggests that symptom recurrence is likely not related to re-exposure and it does not 
reflect a potential re-infection event.  
In Study C4671005 (EPIC-HR; NCT04960202), post-treatment increases in SARS-CoV-2 
RNA shedding levels (ie, viral RNA rebound) in nasopharyngeal samples were observed on 
Day 10 and/or Day 14 in a subset of nirmatrelvir/ritonavir and placebo recipients, 
irrespective of COVID-19 symptoms. The frequency of detection of post-treatment viral 
RNA rebound varied according to analysis parameters but was generally similar among 
nirmatrelvir/ritonavir and placebo recipients, regardless of the rebound definition used. A 
similar or smaller percentage of placebo recipients compared to nirmatrelvir/ritonavir 
recipients had nasopharyngeal viral RNA results <LLOQ at all study timepoints in both the 
treatment and post-treatment periods[9].
Post-treatment viral RNA rebound was not associated with the primary clinical outcome of 
COVID-19-related hospitalization or death from any cause through Day 28 following the 
single 5-day course of nirmatrelvir/ritonavir treatment. Post-treatment viral RNA rebound 
also was not associated with drug resistance as measured by Mpro sequencing. The clinical 
relevance of post-treatment increases in viral RNA following nirmatrelvir or placebo 
treatment is unknown[9].
At present, there are no controlled efficacy and safety data of a repeat 5-day course of 
nirmatrelvir/ritonavir in participants with acute rebound in symptoms and SARS-CoV-2 
infection. Rapid rebound in symptoms along with a positive rapid antigen test following the 
completion of a 5-day course of nirmatrelvir/ritonavir may indicate that these patients require 
additional therapy to achieve sustained viral clearance. Such patients may benefit from an 
additional 5-day treatment duration. The purpose of this study is to evaluate the efficacy, 
safety and tolerability of a second 5-day treatment course of nirmatrelvir/ritonavir in
participants with a rebound in COVID-19 symptoms and a positive rapid antigen test within 
2 weeks following completion of an initial 5-day treatment course that a participant received 
as part of routine clinical care.
A 2-week time-period for rebound symptoms and SARS-CoV-2 infection was selected to 
enroll a population that has a presumptive recurrence of the same viral illness and not a new 
SARS-CoV-2 infection. Symptom burden including alleviation, resolution and worsening 
(rebound) to qualify for the study is based on the judgment of both the participant along with 
investigator judgment.
In order to avoid potential unblinding given the characteristic taste disturbance AEs 
associated with ritonavir, all participants in this study will receive ritonavir and be randomly 
assigned to either nirmatrelvir or placebo. 100 mg ritonavir will be administered in the 
nirmatrelvir placebo group to match the 100 mg ritonavir in the active treatment group.


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Ritonavir is an inhibitor of CYP3A4 and may increase plasma concentrations of drugs that 
are primarily metabolized by CYP3A4. In order to avoid potential unblinding due to the 
magnitude of drug-drug interactions, all participants in this trial will receive ritonavir, and be 
randomly assigned to either nirmatrelvir or placebo.   
4.2.1. Choice of Contraception/Barrier Requirements
Human reproductive safety data are limited for nirmatrelvir/ritonavir, but there is no 
suspicion of human teratogenicity based on the intended pharmacology of the 
compound. Therefore, the use of a highly effective method of contraception is required for 
female participants who are not pregnant on study entry (see Appendix 4).
4.2.2. 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.
4.2.3. Inclusion of Pediatric Participants
This study includes participants of 12 years of age and older and weighing ≥40 kg, which is 
consistent with the Fact Sheet for nirmatrelvir/ritonavir where FDA has granted EUA for the 
treatment of mild-to-moderate COVID-19 in adults and pediatric patients (12 years of age 
and older and weighing ≥40 kg)[16].
4.3. Justification for Dose
On 22 December 2021, the US FDA granted EUA to nirmatrelvir/ritonavir for the treatment 
of mild-to-moderate COVID-19 in adults and pediatric patients (12 years of age or older 
weighing at least 40 kg) who are at risk for progression to severe disease. The recommended 
dose is 300 mg nirmatrelvir co-administered with 100 mg ritonavir q12h for 5 days for 
subjects with normal renal function or mild renal impairment. This dose was well tolerated in 
Study C4671005 and reduced the rate of hospitalization or death by 89% compared with 
placebo in symptomatic adult participants with COVID-19 who were at increased risk of 
progression to severe disease. 
Results from the renal impairment study showed that the adjusted geometric mean (90% CI) 
test/reference ratios comparing moderate renal impairment (test) to normal renal function 
(reference) for nirmatrelvir AUCinf and Cmax was 187.40% (148.52%, 236.46) and 138.12% 
(113.18%, 168.55%), respectively. Due to the increase in in exposures of nirmatrelvir in 
those with moderate renal impairment, and verified by modeling and simulation, the 
nirmatrelvir/ritonavir dose in patients with moderate renal impairment was reduced to 150 
mg/100 mg q12h. 
4.4. End of Study Definition
The end of the study is defined as the date of the last visit of the last participant in the study.
A participant is considered to have completed the study if they have completed all periods of 
the study, including the last visit.


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5. STUDY POPULATION
This study can fulfill its objectives only if appropriate participants are enrolled, including 
participants across diverse and representative racial and ethnic backgrounds. If a 
prescreening tool is utilized for study recruitment purposes, it will include collection of 
information that reflects the enrollment of a diverse participant population including, where 
permitted under local regulations, age, sex, race, and ethnicity. The following eligibility 
criteria are designed to select participants for whom participation in the study is considered 
appropriate. All relevant medical and nonmedical conditions should be taken into 
consideration when deciding whether a particular participant is suitable for this protocol. 
Prospective approval of protocol deviations to recruitment and enrollment criteria, also 
known as protocol waivers or exemptions, is not permitted.
5.1. Inclusion Criteria
Participants are eligible to be included in the study only if all of the following criteria apply:
Age and Sex:
1. Participants aged 12 years or older and weighing ≥40 kg at screening (Section 10.10.1).  

Refer to Appendix 4 for reproductive criteria for female (Section 10.4.1) 
participants.
Disease Characteristics:
2. Participants must have written documentation with patient-reported 100% compliance (ie, 
completed a 5 day course of nirmatrelvir/ritonavir). They must have symptom alleviation 
or resolution in COVID-19 signs/symptoms followed by a worsening (rebound) of 
signs/symptoms after completing an initial 5-day course of nirmatrelvir/ritonavir based 
on the judgement of both the participant and investigator (Section 10.10.2).
3. The onset of rebound in COVID-19 symptoms must occur within 2 weeks (14 days) after 
the completion of the initial 5-day course of nirmatrelvir/ritonavir.
4. Onset of rebound in signs/symptoms attributable to COVID-19 within 48 hours prior to 
randomization and ≥1 sign/symptom attributable to COVID-19 present on the day of 
randomization (Section 10.10.2).
5. SARS-CoV-2 infection as determined by rapid antigen testing in any specimen collected 
within 24 hours prior to randomization and collected within 2 weeks (14 days) after the 
completion of the initial 5-day treatment course of nirmatrelvir/ritonavir.
6. Has at least 1 characteristic or underlying medical condition associated with an increased 
risk of developing severe illness from COVID-19 (Section 10.10.4).


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5.2. Exclusion Criteria
Participants are excluded from the study if any of the following criteria apply:
Medical Conditions:
1. Current need for hospitalization, hospitalized for the index COVID-19 infection, or 
anticipated need for hospitalization within 24 h after randomization in the clinical opinion 
of the site investigator.
2. History of severe chronic liver disease (eg, jaundice, ascites, hepatic encephalopathy, 
history of bleeding esophageal or gastric varices). No laboratory testing is needed.
3. History of hypersensitivity or other contraindication to any of the components of the 
study interventions, as determined by the investigator.
4. Suspected or confirmed concurrent active systemic infection other than COVID-19 that 
may interfere with the evaluation of response to the study intervention.
5. Receiving dialysis or eGFR <30 mL/min/1.73 m2 (for adults) or eCrCl <30 mL/min (for 
adolescents) at screening using creatinine point of care device (see Section 10.7.1 for 
age-specific kidney function calculation).
6. Oxygen saturation of <92% on room air obtained at rest within 24 hours prior to 
randomization (Section 10.10.4).
7. Immunocompromised (Section 10.10.7).
8. 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:
9. Current use of any prohibited concomitant medication(s) (see Section 6.9; Appendix 8,
and Section 10.10.6).
10. COVID-19 vaccination within 14 days prior to study entry or anticipated COVID-19 
vaccination through Day 34.
11. Receiving other COVID-19 specific treatments within 30 days of randomization and 
through Day 34, excluding a single 5-day treatment course of nirmatrelvir/ritonavir as 
well as blinded study medication (Section 10.10.6).
Prior/Concurrent Clinical Study Experience:
12. Prior participation in this trial.


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13. Current or previous administration with an investigational product (drug or vaccine) 
within 30 days (or as determined by the local requirement) or 5 half-lives preceding the 
first dose of study intervention used in this study (whichever is longer). 
Other Exclusion Criteria:
14. Females who are pregnant up to 14 weeks gestation. Pregnancy ≥14 weeks is not 
exclusionary.
15. Investigator site staff directly involved in the conduct of the study and their family 
members, site staff otherwise supervised by the investigator, and sponsor and sponsor 
delegate employees directly involved in the conduct of the study and their family 
members.
5.3. Lifestyle Considerations
5.3.1. Contraception
All female participants who are not pregnant at study entry, and who in the opinion of the 
investigator, are biologically capable of having children must agree to use a highly effective 
method of contraception consistently and correctly for at least 28 days after the last study 
intervention.
Note: If the childbearing potential changes after start of the study (eg, a premenarchal female 
participant experiences menarche) or the risk of pregnancy changes (eg, a female participant 
who was not heterosexually active becomes active), the participant must discuss this with the 
investigator, who should determine if a female participant must begin a highly effective 
method of contraception. If reproductive status is questionable, additional evaluation should 
be considered.
The investigator or their designee, in consultation with the participant, will confirm that the 
participant is utilizing an appropriate method of contraception for the individual participant 
and their partner(s) from the permitted list of contraception methods (see Section 10.4.3) and 
will confirm that the participant has been instructed in its consistent and correct use. At time 
points indicated in the SoA, the investigator or designee will inform the participant of the 
need to use highly effective contraception consistently and correctly and document the 
conversation and the participant’s affirmation in the participant’s chart. Participants need to 
affirm their consistent and correct use of at least 1 of the selected methods of contraception, 
considering that their risk for pregnancy may have changed since the last visit. 
In addition, the investigator or designee will instruct the participant to call immediately if the 
selected contraception method is discontinued and document the requirement to use an 
alternate protocol-specified method, including if the participant will no longer use abstinence 
as the selected contraception method, or if pregnancy is known or suspected in the participant 
or partner.


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5.4. Screen Failures
Screen failures are defined as participants who consent to participate in the clinical study but 
are not subsequently enrolled in the study. 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, and any SAE.
Individuals who do not meet the criteria for participation in this study (screen failure) may 
not be rescreened.  
To assist in further understanding rebound, the following screen failure information will be 
captured in the eCRF and included in the study report.

Number (%) of participants with rebound symptoms at time of screening but who 
are negative by rapid antigen testing at screening and therefore screen fail for the 
study.
5.5. Criteria for Temporarily Delaying Enrollment/Randomization/Administration of 
Study Intervention
Not applicable.
6. STUDY INTERVENTION(S) AND CONCOMITANT THERAPY
Study interventions are all prespecified investigational and noninvestigational medicinal 
products/auxiliary medicinal products, medical devices, and other interventions (eg, surgical 
and behavioral) intended to be administered to the study participants during the study 
conduct.
For the purposes of this protocol, study intervention refers to nirmatrelvir 150 mg tablets and 
matching placebo and ritonavir 100 mg capsules.
6.1. Study Intervention(s) Administered
Study intervention will be self-administered by the participant OR administered to the 
participant by a legal guardian or caregiver.
A legal guardian or caregiver may administer study medication. Study personnel should 
review dose administration requirements with the participant, and, as appropriate, with the 
delegated caregiver(s) (may include school nurse) before administration and throughout the 
study as necessary.
Study Intervention(s)
Intervention Name
Nirmatrelvir
Placebo for nirmatrelvir
Ritonavir
Arm Name
(group of participants 
receiving a specific 
nirmatrelvir/ritonavir
placebo
ritonavir


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Study Intervention(s)
treatment or no 
treatment)
Type
drug
placebo
drug
Dose Formulation
tablet
tablet
capsule
Unit Dose Strength(s)
150 mg
0 mg
100 mg 
Dosage Level(s)
300 mg q12h for 5 days
150 mg q12h for 5 days 
(for participants with 
eGFR ≥30 to <60 
mL/min/1.73 m2 (or 
eCrCl ≥30 to 
<60 mL/min) at 
screening)
0 mg q12h for 5 days
100 mg q12h for 5 days
Route of 
Administration
Oral
Oral
Oral
Use
Experimental
Placebo
Experimental
IMP or NIMP/AxMP
IMP
IMP
IMP
Sourcing
Provided centrally by 
the sponsor.
Refer to the IPM.
Provided centrally by 
the sponsor.
Refer to the IPM.
Provided centrally by the 
sponsor.
Refer to the IPM.
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. 
Products will be 
provided with blinded 
labels.
Study intervention will 
be provided in HDPE 
bottles. Each bottle will 
be labeled as required per 
country requirement. 
Products will be provided 
with open labels.
Current/Former 
Name(s) or Alias(es)
PF-07321332
NA
ritonavir
Study Arm(s)
Arm Title
Nirmatrelvir/ritonavir
Placebo/ritonavir
Arm Type
Experimental
Other
Arm 
Description
Participants will receive 
nirmatrelvir/ritonavir 300 mg/100 mg (or 
150 mg/100 mg for participants with 
Participants will receive placebo 0 mg/ritonavir 
100 mg q12h for 5 days.


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eGFR ≥30 to <60 mL/min/1.73 m2 or 
eCrCl ≥30 to <60 mL/min) q12h from 
Day 1 through Day 5.
Associated 
Intervention 
Labels
Nirmatrelvir/ritonavir
Placebo/ritonavir
6.1.1. Administration
The first dose of study intervention will be administered at the site. 
Nirmatrelvir 150 mg tablets or placebo for nirmatrelvir will be administered with ritonavir 
100 mg for 5 days. Participants will be dispensed 1 blister wallet card of nirmatrelvir 150 mg 
tablets and 1 bottle of ritonavir capsules at the Day 1 site visit. Participants will be instructed 
to take:

2 tablets of nirmatrelvir 150 mg or placebo for nirmatrelvir q12h;

1 capsule of ritonavir 100 mg q12h.
o
Participants with moderate renal impairment (eGFR ≥30 to <60 mL/min/1.73 
m2 [or eCrCl ≥30 to <60 mL/min] at screening) will receive either 1 tablet of 
nirmatrelvir 150 mg and placebo for nirmatrelvir or 2 tablets of placebo for 
nirmatrelvir. The dose for ritonavir remains unchanged (ie, participants will 
receive 1 capsule of ritonavir 100 mg q12h).
Participants should take the first dose of study intervention on Day 1, during the in-person 
visit; that is, participants should take nirmatrelvir/placebo and ritonavir at the same time (no 
more than 15 minutes apart). The study intervention should be taken every 12 hours 
(±4 hours), and not more than twice in a calendar day. Depending on the time of first dose, 
the timing of the second dose may be adjusted slightly to allow the participant/caregiver to 
select a convenient 12 hour dosing schedule as long as the next dose is taken at least 4 hours, 
but no later than 16 hours, after the first dose. Once the dosing schedule is adjusted, all 
subsequent doses should be taken every 12 hours (±4 hours).
If a dose is delayed, it should be taken as soon as possible (but no later than 8 hours after the 
scheduled 12-hourly dose time), then resume the normal dosing schedule. If the participant 
misses a dose by more than 8 hours, the participant should not take the missed dose and 
instead take the next dose at the regularly scheduled time. The participant should not double 
the dose to make up for a missed dose. Dosing should be stopped at the end of the treatment 
period (Day 5 or 6). Any remaining tablets and/or capsules at the Day 5 visit should be 
returned. If the Day 5 visit is conducted prior to the last dose of study intervention (ie. 
Day 6), any remaining tablets or capsules should be collected at the next visit.
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 
IPM for additional dosing and administration instructions.


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6.2. Preparation, Handling, Storage, and Accountability
The excipients used in the nirmatrelvir tablets/ritonavir capsules are safe for administration to 
pediatric participants.
Study intervention will be self-administered or administered to the participant by the 
caregiver. 
1. The investigator or designee must confirm that appropriate conditions (eg, temperature) 
have been maintained during transit for all study interventions received and any 
discrepancies are reported and resolved before use of the study intervention. 
2. Only participants enrolled in the study may receive study intervention and only 
authorized site staff may supply, prepare, and/or administer study intervention. 
3. All study interventions must be stored in a secure, environmentally controlled, and 
monitored (manual or automated recording) area in accordance with the labeled storage 
conditions with access limited to the investigator and authorized site staff. At a minimum, 
daily minimum and maximum temperatures for all site storage locations must be 
documented and available upon request. Data for nonworking days must indicate the 
minimum and maximum temperatures since previously documented upon return to 
business.
4. Any excursions from the study intervention label storage conditions should be reported to 
Pfizer upon discovery along with actions taken. The site should actively pursue options 
for returning the study intervention to labeled storage conditions, as soon as possible. 
Once an excursion is identified, the study intervention must be quarantined and not used 
until Pfizer provides permission to use the study intervention. Specific details regarding 
the excursion definition and information to report for each excursion will be provided to 
the site in the IPM.
5. Any storage conditions stated in the SRSD will be superseded by the storage conditions 
stated on the label. Site staff will instruct participants on the proper storage requirements 
for take-home study intervention.
6. Study interventions should be stored in their original containers.
7. The investigator, institution, head of the medical institution (where applicable), or 
authorized site staff is responsible for study intervention accountability, reconciliation, 
and record maintenance (ie, receipt, reconciliation, and final disposition records), such as 
the IPAL or sponsor-approved equivalent. All study interventions will be accounted for 
using a study intervention accountability form/record. All study intervention containers
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 IPM. All destruction must be adequately documented. If destruction is 


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authorized to take place at the investigator site, the investigator must ensure that the 
materials are destroyed in compliance with applicable environmental regulations, 
institutional policy, and any special instructions provided by Pfizer.
Upon identification of a product complaint, notify the sponsor within 1 business day of 
discovery as described in the IPM.
6.2.1. Preparation and Dispensing
A qualified staff member will dispense nirmatrelvir/ritonavir using unique container numbers 
via an IRT system in the bottles and blister cards provided, according to the SoA. A second 
staff member will verify the dispensing. The participant/caregiver 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.
6.3. Assignment to Study Intervention
Allocation of participants to treatment groups will proceed through the use of an IRT system. 
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 randomization 
number corresponding to the assigned treatment group, and DU or container number(s) 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. 
The study-specific IRT reference manual and IPM will provide the contact information and 
further details on the use of the IRT system.
6.4. Blinding
This is a double-blind study. 
6.4.1. Blinding of Participants
Participants and their caregivers will be blinded to their assigned study intervention.
6.4.2. Blinding of Site Personnel
Investigators and other site staff will be blinded to participants’ assigned study intervention. 
Participants will be assigned to receive study intervention according to the assigned treatment 
group from the randomization scheme. Investigators will remain blinded to each participant’s 
assigned study intervention throughout the course of the study. 
In the event of a Quality Assurance audit, the auditor(s) will be allowed access to unblinded 
study intervention records at the site(s) to verify that randomization/dispensing has been done 
accurately.


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6.4.3. Blinding of the Sponsor
Sponsor staff will be blinded to participants’ assigned study intervention, except for 
designated individuals who may conduct unblinded reviews of the data if requested by 
regulatory authorities. An unblinded submissions team may be assembled to prepare 
unblinded analyses and documents to support regulatory activities that may be required while 
the study is ongoing.
Sponsor staff who are not directly involved with the conduct of this study will prepare 
analyses and documentation containing unblinded data while the study is ongoing to support 
interactions with the E-DMC.
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 data review(s) described above and the 
timing of unblinding will be outlined in the Unblinding Plan.
6.4.4. 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 study medical monitor 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 IPM will provide the contact information and 
further details on the use of the IRT system.
6.5. Study Intervention Compliance
Participants will use a participant-completed electronic dosing diary to record the date and 
time of their study intervention dosing, and will be educated at the time of first dose.
Site personnel will review the participant-completed electronic dosing diary daily during the 
study intervention period, preferably after the participant has self-administered the morning 
dose of nirmatrelvir/ritonavir. If any noncompliance with dosing is suspected, site personnel 
will promptly contact the participant by phone, to remind them of the relevant study 
procedures and/or entering the information in the electronic diary as applicable.
When participants are dosed at the site, they will receive study intervention directly from the 
investigator or designee, under medical supervision. The dose of study intervention and study 
participant identification will be confirmed at the time of dosing by a member of the study 
site staff other than the person administering the study intervention. 


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When participants self-administer study intervention(s) at home, compliance with study 
intervention will be assessed at each visit. Compliance will be assessed by delegated study 
personnel upon return of study intervention through counting returned tablets/capsules and 
direct questioning, if applicable during the site visits and documented in the source 
documents. 
A record of the number of nirmatrelvir tablets/ritonavir capsules dispensed to and taken by 
each participant must be maintained and reconciled with study intervention and compliance 
records.
The following noncompliance cases will be considered medication errors (see Section 6.5):

Participants interrupting study intervention for 2 consecutive doses;

Participants taking either nirmatrelvir or ritonavir alone for 2 consecutive doses;

Participants who have an overall study intervention compliance <80% or >115%.
In addition to the above listed-medication errors, any deviation from protocol-specified 
dosing (eg, missed single dose or partial dose) should be recorded as a protocol deviation and 
the investigator or designee is to counsel the participant/guardian and ensure steps are taken 
to improve compliance.
6.6. Dose Modification 
Not applicable.
6.7. Continued Access to Study Intervention After the End of the Study
No study intervention will be provided to participants at the end of their study participation. 
It is expected that participants will be treated as required with standard-of-care treatments, as 
advised by their usual care physician.
6.8. Treatment of Overdose
Study sites should warn parents/caregivers to store the study intervention out of reach of 
children and to provide close supervision when intervention will be self-administered by the 
child.
For this study, any dose of nirmatrelvir greater than 900 mg (or any dose greater than 450 mg 
for participants on the reduced nirmatrelvir dose for moderate renal impairment) or ritonavir 
greater than 300 mg within a 24-hour time period will be considered an overdose.
There is no specific treatment for an overdose.
In the event of an overdose, the investigator should:
1. Contact the study medical monitor within 24 hours.


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Closely monitor the participant for any AEs/SAEs and laboratory abnormalities as 
medically appropriate and at least until the next scheduled follow-up. 
2. Document the quantity of the excess dose as well as the duration of the overdose in 
the CRF.
3. Overdose is reportable to Pfizer Safety only when associated with an SAE.
Decisions regarding dose interruptions or modifications will be made by the investigator in 
consultation with the study medical monitor as needed based on the clinical evaluation of the 
participant.  
6.9. Prior and Concomitant Therapy 
Permitted During the Study
Concomitant medications are permitted unless specifically listed as prohibited medication 
(see Appendix 8) or as defined in Section 5.2. However, as described below, use of other 
specific COVID-19 treatments (eg, antivirals or monoclonal antibodies) are prohibited during 
the study.
Sites should consult with the sponsor if a new SoC option for COVID-19 becomes available 
after study initiation. The Investigator should ensure that any concomitant therapy is not a 
strong inducer of CYP3A4 or highly dependent on CYP3A4 for clearance. The Pfizer 
medical monitor should be consulted to review for potential drug-drug interactions (see 
Appendix 8).
Ritonavir is an inhibitor of CYP3A4 and may increase plasma concentrations of drugs that 
are primarily metabolized by CYP3A4. Participants will receive ritonavir for 5 days but as 
treatment is blinded, some concomitant medications (Appendix 8, Table 4) may require 
monitoring of drug levels, consideration of temporary withdrawal of the concomitant 
medication, or dose adjustment throughout the study treatment period and following 
completion of the blinded treatment duration period.
Prohibited During the Study
Participants are prohibited from receiving a non-study COVID-19 antiviral or monoclonal 
antibody therapy for COVID-19 within 14 days prior to randomization (excluding qualifying 
treatment with nirmatrelvir/ritonavir) and through completion of Day 34. Vaccination for 
COVID-19 is also prohibited within 14 days prior to randomization and through completion 
of Day 34. 
As an exception, participants who progress to severe or critical COVID-19 will, however, be 
permitted to receive specific COVID-19 treatment(s) such as antiviral therapy or use of other 
treatments considered standard of care and the above restriction would not apply.
Nirmatrelvir and ritonavir are both primarily metabolized by CYP3A4. In addition, ritonavir 
is a strong inhibitor of CYP3A4. Therefore, concomitant use of medications that are strong 


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inducers of CYP3A4 and which are contraindicated in combination with 
nirmatrelvir/ritonavir (see Appendix 8 Table 3) are prohibited during study treatment. Some 
medications that are highly dependent on CYP3A4 for clearance are also contraindicated 
with nirmatrelvir/ritonavir (see Appendix 8, Table 3).
Some other medications that are not contraindicated but are highly dependent on CYP3A4 
for clearance may require dose adjustment or additional monitoring. Refer to Appendix 8
Table 4 for a nonexhaustive list of these medications and consult the Pfizer medical monitor 
for guidance on coadministration with nirmatrelvir/ritonavir.
Medications or substances that are strong inducers of CYP3A4 and that are contraindicated 
in combination with nirmatrelvir/ritonavir must be discontinued for an appropriate washout 
period prior to the first dose of nirmatrelvir/ritonavir and are prohibited for the duration of 
the study treatment period and for 4 days after the last dose of nirmatrelvir/ritonavir 
(Appendix 8). The appropriate washout period for CYP3A4 inducers should be determined 
based on the prescribing information for the concomitant medication and in consultation with 
the medical monitor.
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;

Study terminated by sponsor;

Withdrawal by participant or legally authorized representative;

If postscreening eGFR is <30 mL/min/1.73 m2 (adult participants) or eCrCl is 
<30 mL/min (adolescent participants), the participant will be instructed to 
discontinue any remaining study intervention doses as soon as study staff become 
aware of the eGFR results.
In the event that a participant is hospitalized, study intervention may continue to be 
administered, as feasible, and based on medical judgment of the investigator.
Note that discontinuation of study intervention does not represent withdrawal from the study. 
If study intervention is permanently discontinued, the participant should remain in the study 
to be evaluated for all subsequent scheduled assessments. See the SoA for data to be 


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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. Pregnancy 
For further details, refer to Section 8.4.5.1.
7.2. Participant Discontinuation/Withdrawal From the Study 
A participant may withdraw from the study at any time at their own request. Reasons for 
discontinuation from the study include the following: 

Refused further study procedures;

Lost to follow up; 

Study terminated by sponsor;

Withdrawal of consent/assent by parent/legal guardian or by a child who has provided 
assent during any phase of the study.
At the time of discontinuing from the study (if prior to Day 34), 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, they may request destruction of any remaining 
samples taken and not tested, and the investigator must document any such requests in the 
site study records and notify the sponsor accordingly.
If the participant withdraws from the study and also withdraws consent (see Section 7.2.1) 
for disclosure of future information, no further evaluations will be performed and no 
additional data will be collected. The sponsor may retain and continue to use any data 
collected before such withdrawal of consent.
7.2.1. Withdrawal of Consent 
Participants who request to discontinue receipt of study intervention will remain in the study 
and must continue to be followed for protocol-specified follow-up procedures. The only 
exception to this is when a participant specifically withdraws consent/assent for any further 


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contact with them or persons previously authorized by the participant to provide this 
information. Participants should notify the investigator in writing of the decision to withdraw 
consent from future follow-up, whenever possible. The withdrawal of consent should be 
explained in detail in the medical records by the investigator, as to whether the withdrawal is 
only from further receipt of study intervention or also from study procedures and/or 
posttreatment study follow-up, and entered on the appropriate CRF page. In the event that 
vital status (whether the participant is alive or dead) is being measured, publicly available 
information should be used to determine vital status only as appropriately directed in 
accordance with local law.
7.3. Lost to Follow-Up 
A participant will be considered lost to follow-up if the participant repeatedly fails to return 
for scheduled visits and is unable to be contacted by the study site.
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, the participant will be considered 
to have withdrawn from the study. 

In the event the participant is deemed unreachable, the investigator should utilize the 
contact information collected for the 2 individuals who can be contacted if the 
participant cannot be reached after multiple attempts.
8. STUDY ASSESSMENTS AND PROCEDURES
8.1. Administrative and Baseline Procedures
The investigator (or an appropriate delegate at the investigator site) must obtain a signed and 
dated ICD before performing any study-specific procedures.  
Study procedures and their timing are summarized in the SoA. Protocol waivers or 
exemptions are not allowed.
Adherence to the study design requirements, including those specified in the SoA, is essential 
and required for study conduct.


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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.
Every effort should be made to ensure that protocol-required tests and procedures are 
completed as described. However, it is anticipated that from time to time there may be 
circumstances outside the control of the investigator that make it unfeasible to perform the 
test. In these cases, the investigator must take all steps necessary to ensure the safety and 
well-being of the participant. When a protocol-required test cannot be performed, the 
investigator will document the reason for the missed test and any corrective and preventive 
actions that they have taken to ensure that required processes are adhered to as soon as 
possible. The study team must be informed of these incidents in a timely manner.
In the event a participant is hospitalized, study assessments should be performed as feasible. 
Procedures not performed due to hospitalizations will not be considered protocol deviations.
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 
160 mL. The actual collection times of blood sampling may change. Additional blood 
samples may be taken for safety assessments at times specified by Pfizer, provided the total 
volume taken during the study does not exceed 550 mL during any period of 56 consecutive 
days. For pediatric participants, every effort will be made to ensure that blood volume 
collections do not exceed 1% of the total blood volume at any single time and 3% of the total 
blood volume during any period of 4 weeks.
8.1.1. Baseline Procedures
8.1.1.1. Medical History
Medical history, COVID-19 disease history and SARS-CoV-2 tests results if available, 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. COVID-19 vaccinations, antiviral and monoclonal antibody treatment for the 
treatment of COVID-19 at any time prior to the planned first dose will also be collected.
Risk factors for the participant developing severe COVID-19 illness will be recorded.
8.1.1.2. Secondary Contacts
At baseline and as noted in the SoA, the investigator will collect contact information for at 
least 2 individuals who can be contacted if the participant cannot be reached after multiple 
attempts. Secondary contacts may be used to determine if a participant is lost to follow-up or 
vital status check.


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8.1.2. Household Characteristics
Household characteristics will be determined through interview with the study participant 
and will be updated during the study. The household characteristics include:

Number of people living in household;

Number of additional confirmed SARS-CoV-2 positive or suspected (ie, 
symptomatic) household members and date of confirmed or suspected SARS-CoV-2.
8.1.3. Telehealth Visits
Telehealth visits may be used to assess participant safety and collect data points. Telehealth 
includes the exchange of healthcare information and services via telecommunication 
technologies (eg, audio, video, videoconferencing software) remotely, allowing the 
participant and the investigator to communicate on aspects of clinical care, including medical 
advice, reminders, education, and safety monitoring. The following assessments must be 
performed during a telehealth visit (see the SoA):

Review and record study intervention(s), including compliance and missed doses.

Review and record any AEs and SAEs since the last contact. Refer to Section 8.4.

Review and record any new concomitant medications or changes in concomitant 
medications since the last contact.

Review and record contraceptive method and results of pregnancy testing. Confirm 
that the participant is adhering to the contraception method(s) required in the 
protocol. Refer to Appendix 4.
Study participants must be reminded to promptly notify site staff about any change in their 
health status.
Observe (ie, video, videoconferencing software) the participant performing the rapid antigen 
test (participant self collected rapid antigen test), if the procedure is conducted remotely, and 
record the results for offsite visits in accordance with the SoA.
8.1.4. Home Health Visits 
A home health visit may be utilized to facilitate scheduled visits. Home health visits include 
a healthcare provider conducting an in-person study visit at the participant’s location, rather 
than an in-person study visit at the site. The following may be performed during a home 
health visit (see the SoA):

Review and record study intervention(s), including compliance and missed doses.

Review and record any AEs and SAEs since the last contact. Refer to Section 8.4.


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
Review and record any new concomitant medications or changes in concomitant 
medications since the last contact.

Review and record contraceptive method and results of pregnancy testing. Confirm 
that the participant is adhering to the contraception method(s) required in the 
protocol. Refer to Appendix 4.

Collect clinical laboratory and biomarker samples.

Observe rapid antigen testing, record result, and collect NP/OP swab samples.

Collect vital signs.

Confirm the participant has completed the PRO assessments.

Retrieve unused study intervention and empty study intervention containers

Collect/update secondary contacts

Collect/update household characteristics

Collect COVID-19-related medical visits

Collect COVID-19 adjunctive therapeutic procedures

If the HCP is unable to collect AEs, concomitant medications, the site should contact
the participant via a follow-up telephone call to collect the additional information.
It is recommended that the investigator discuss temporary or permanent discontinuation of 
study intervention with the study medical monitor.
8.2. Efficacy Assessments
8.2.1. Participant Diary
Participants will be provided an electronic handheld device or will use their own device to 
record study intervention administration, signs and symptoms of COVID-19, 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 (next 
calendar day), 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 


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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.
8.2.2. COVID-19-Related Medical Details
Details of participants’ COVID-19-related medical visits will be collected. These are 
hospitalization of any duration, urgent care, emergency room ≤24h, practitioner’s office, 
telemedicine, home health care services or extended care facility stay and will be collected 
during study visits, including level of care (ICU status) and dates of utilization, including 
admission and discharge, as applicable. 
Hospitalization >24 hours is defined as >24h of acute care in a hospital or similar acute care 
facility, including Emergency Rooms or temporary facilities instituted to address medical 
needs of those with severe COVID-19. 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.
8.2.3. PRO Assessments
PRO assessments will be recorded in the study eDiary.
8.2.3.1. 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[17]. For participants who report COVID-19 symptoms in the diary, the global 
impression questions will be answered after the completion of the COVID-19 signs and 
symptoms diary is completed.
8.2.3.2. SF-36 v2® Health Survey (Acute Form)[18]
Only adult study participants ≥18 years of age at the time of screening will be asked to 
complete the SF-36 at the timepoints indicated in the SoA. 
SF-36 v2® Health Survey (the acute form) is a 36-item questionnaire that measures 
functional health and well-being from a patient’s perspective over a 1-week recall period. It 
is a generic questionnaire and can be used across age (adults), disease, and treatment groups. 
The questionnaire consists of 8 health domain scales: physical functioning (10 items), role 
physical (4 items), bodily pain (2 items), general health (5 items), vitality (4 items), social 
functioning (2 items), role-emotional (3 items), mental health (5 items), reported health 
transition (1 item) and 2, physical and mental component summary scores. Each health 
domain scale raw score is transformed to 0-100 scale which can then be converted to norm 
based T-scores (Mean=50, SD=10). SF-36 v2® Health Survey will be completed as specified 
in the SoA.
8.2.3.3. WPAI
Only adult study participants ≥18 years of age at the time of screening will be asked to 
complete the WPAI at the timepoints indicated in the SoA.


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COVID-19 impacts manual and office-based work, and results in missed work due to illness 
or quarantine and loss of productivity [19]. The WPAI-GH is being implemented for COVID 
19 (ie, WPAI-COVID-19) in order to evaluate change from baseline in work burdens. The 
WPAI-GH has demonstrated validity, reliability and sufficient predictive value to measure 
the impact of disease on absenteeism, presenteeism, and overall productivity in a manner that 
can also be monetized [20].
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 for 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 [20]. The WPAI-COVID-19 will be completed as specified in the SoA.
8.2.3.4. EQ-5D-5L Scale
Only adult study participants ≥18 years of age at the time of screening will be asked to 
complete the EQ-5D-5L at the timepoints indicated in the SoA.
The EQ-5D is a validated, standardized, generic instrument that is a preference-based health 
related quality of life questionnaire in cost effectiveness and HTA[21-23]. Recently, a 
version was developed called EQ-5D-5L with 5 response levels on each dimension compared 
to the 3 response levels in the EQ-5D-3L[21-27].
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[21,23,25,26]. 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[24,28]. 
The EQ-5D-5L should be completed as described in the SoA.
8.2.3.5. COVID-19 Signs and Symptoms
On Day 1, participants will complete the COVID-19 signs and symptoms (Appendix 11) in 
the study diary, before receiving study intervention. Participant assessment of COVID-19-
related symptoms should be recorded at approximately the same time each day as specified in 
the SoA and as described in Appendix 11.
COVID-19-related symptoms will be evaluated in accordance with FDA guidelines. 
Participants will record a 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. 


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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.
During the long-term follow-up period as noted in the SoA, site staff will ask participants if 
they have experienced pre-defined COVID-19 signs and symptoms or other symptoms 
believed to be related to COVID-19, over the past 7 days, including the day of the study visit. 
For each sign or symptom reported, the worst severity (mild, moderate or severe) during the 
past week should be recorded in the CRF.  
8.3. Safety Assessments
Planned time points for all safety assessments are provided in the SoA. Unscheduled safety 
measurements may be obtained at any time during the study to assess any perceived safety 
issues.
8.3.1. Targeted Physical Examination, Height and Weight
Physical examination is to be completed before administration of study intervention.
A targeted physical examination will include, at a minimum, cardiopulmonary assessments.  
Height and weight will also be measured and recorded at screening, though height may be 
self-reported for participants ≥18 years of age.
Physical examination findings collected during the study will be considered source data and 
will not be required to be reported, unless otherwise noted. Any untoward physical 
examination findings that are identified during the active collection period and meet the 
definition of an AE or SAE (Appendix 3) must be reported according to the processes in
Sections 8.4.1 to 8.4.3.
8.3.2. Vital Signs
Temperature, pulse rate, respiratory rate, oxygen saturation level, and blood pressure will be 
assessed as specified in the SoA.
Any untoward vital sign findings that are identified during the active collection period and 
meet the definition of an AE or SAE (Appendix 3) must be reported according to the 
processes in Sections 8.4.1 to 8.4.3.
8.3.2.1. Blood Pressure and Pulse Rate
BP and PR measurements will be assessed with the participant, preferably in the seated 
position with their feet on the floor when possible with a completely automated device[29]. 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.


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8.3.2.2. Temperature and Respiratory Rate
Temperature and respiratory rate will be assessed.
8.3.2.3. Oxygen Saturation Level
Oxygen saturation level will be assessed as part of the vital signs assessment.
8.3.2.4. Point-of-Care Serum Creatinine Assessments
A serum creatinine point-of-care device will be used to assess kidney function as described in 
the SoA and Appendix 7. If a serum creatinine point-of-care device assessment is performed 
at screening and baseline, the baseline estimate of kidney function will determine eligibility.
8.3.3. Clinical Safety Laboratory Assessments 
Laboratory safety parameters will be graded according to the DAIDS Table for Grading the 
Severity of Adult and Pediatric Adverse Events[30], version 2.1. See Appendix 2 for the list 
of clinical safety laboratory tests to be performed and the SoA for the timing and frequency. 
All protocol-required laboratory assessments, as defined in Appendix 2, must be conducted 
in accordance with the laboratory manual and the SoA. Unscheduled clinical laboratory 
measurements may be obtained at any time during the study to assess any perceived safety 
issues.  
The investigator must review the laboratory report, document this review, and record any 
clinically significant changes occurring during the study in the AE section of the CRF.
Clinically significant abnormal laboratory test findings are those that are not associated with 
the underlying disease, unless judged by the investigator to be more severe than expected for 
the participant's condition.
All laboratory tests with values considered clinically significant and abnormal during 
participation in the study or within 28 days after the last dose of study intervention should be 
repeated until the values return to normal or baseline or are no longer considered clinically 
significant by the investigator or study medical monitor.
If such values do not return to normal/baseline within a period of time judged reasonable by 
the investigator, the etiology should be identified and the sponsor notified.
See Appendix 6 for suggested actions and follow-up assessments in the event of potential 
DILI.
See Appendix 7 for instructions for laboratory testing to monitor kidney function and 
reporting laboratory test abnormalities.
8.3.3.1. Alternative Facilities for Clinical Safety Laboratory Assessment 
If a local laboratory is used, qualified study site personnel must order, receive, and review 
results. Site staff must collect the local laboratory reference ranges and certifications/
accreditations for filing at the site. Laboratory test results are to be provided to the site staff 
as soon as possible. The local laboratory reports should be filed in the participant’s source 


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documents/medical records. Relevant data from the local laboratory report should 
be recorded on the CRF.
8.3.4. Pregnancy Testing
A serum or urine pregnancy test is required at screening. Following screening, pregnancy 
tests may be urine or serum tests, and must have a sensitivity of at least 25 mIU/mL. 
Pregnancy tests will be performed in WOCBP at the times listed in the SoA. 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 the ET visit. Pregnancy 
tests may also be repeated if requested by IRBs/ECs or if required by local regulations. If a 
urine test cannot be confirmed as negative (eg, an ambiguous result), a serum pregnancy test 
is required. In such cases, the participant must be excluded if the serum pregnancy result is 
positive.
For a female pediatric participant who becomes pregnant, this information will be shared 
with the study participant’s parent/guardian if the participant’s age is within the specific 
range based on local/country regulations.
8.3.4.1. At Home Pregnancy Testing
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 
and relevant data recorded on the CRF. Confirm that the participant is adhering to the 
contraception method(s) required in the protocol.
8.4. Adverse Events, Serious Adverse Events, and Other Safety Reporting
The definitions of an AE and an SAE can be found in Appendix 3.
AEs may arise from symptoms or other complaints reported to the investigator by the 
participant (or, when appropriate, by a caregiver, surrogate, or the participant's legally 
authorized representative), or they may arise from clinical findings of the investigator or 
other healthcare providers (clinical signs, test results, etc).
The investigator and any qualified designees are responsible for detecting, documenting, and 
recording events that meet the definition of an AE or SAE and remain responsible to pursue 
and obtain adequate information both to determine the outcome and to assess whether the 
event meets the criteria for classification as an SAE or caused the participant to discontinue 
the study intervention (see Section 7.1). 
During the active collection period as described in Section 8.4.1, each 
participant/caregiver/parent/legal guardian/legally authorized representative will be 
questioned about the occurrence of AEs in a nonleading manner.
In addition, the investigator may be requested by Pfizer Safety to obtain specific follow-up 
information in an expedited fashion.


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8.4.1. Time Period and Frequency for Collecting AE and SAE Information
The time period for actively eliciting and collecting AEs and SAEs (“active collection 
period”) for each participant begins from the time the participant provides informed consent, 
which is obtained before undergoing any study-related procedure and/or receiving study 
intervention, through and including a minimum of 28 calendar days, except as indicated 
below, after the last administration of the study intervention. 
Follow-up by the investigator continues throughout the active collection period and until the 
AE or SAE or its sequelae resolve or stabilize at a level acceptable to the investigator.
When a clinically important AE remains ongoing at the end of the active collection period, 
follow-up by the investigator continues until the AE or SAE or its sequelae resolve or 
stabilize at a level acceptable to the investigator and Pfizer concurs with that assessment.
For participants who are screen failures, the active collection period ends when screen failure 
status is determined.
If the participant withdraws from the study and also withdraws consent for the collection of 
future information, the active collection period ends when consent is withdrawn.
If a participant permanently discontinues or temporarily discontinues study intervention 
because of an AE or SAE, the AE or SAE must be recorded on the CRF and the SAE 
reported using the PSSA. 
Investigators are not obligated to actively seek information on AEs or SAEs after the 
participant has concluded study participation. However, if the investigator learns of any SAE, 
including a death, at any time after a participant has completed the study, and they consider 
the event to be reasonably related to the study intervention, the investigator must promptly 
report the SAE to Pfizer using the PSSA.
8.4.1.1. Reporting SAEs to Pfizer Safety
All SAEs occurring in a participant during the active collection period as described in 
Section 8.4.1 are reported to Pfizer Safety using the PSSA immediately upon awareness and 
under no circumstance should this exceed 24 hours, as indicated in Appendix 3. The 
investigator will submit any updated SAE data to the sponsor within 24 hours of its being 
available.
8.4.1.2. Recording Nonserious AEs and SAEs on the CRF
All nonserious AEs and SAEs occurring in a participant during the active collection period, 
which begins after obtaining informed consent as described in Section 8.4.1, will be recorded 
on the AE section of the CRF.  
The investigator is to record on the CRF all directly observed and all spontaneously reported 
AEs and SAEs reported by the participant.


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As part of ongoing safety reviews conducted by the sponsor, any nonserious AE that is 
determined by the sponsor to be serious will be reported by the sponsor as an SAE. To assist 
in the determination of case seriousness, further information may be requested from the 
investigator to provide clarity and understanding of the event in the context of the clinical 
study.
Reporting of AEs and SAEs for participants who fail screening are subject to the CRF 
requirements as described in Section 5.4.
8.4.2. Method of Detecting AEs and SAEs
The method of recording, evaluating, and assessing causality of AEs and SAEs and the 
procedures for completing and transmitting SAE reports are provided in Appendix 3.
Care will be taken not to introduce bias when detecting AEs and/or SAEs. Open-ended and 
nonleading verbal questioning of the participant is the preferred method to inquire about 
AE occurrences.
8.4.3. Follow-Up of AEs and SAEs
After the initial AE or SAE report, the investigator is required to proactively follow each 
participant at subsequent visits/contacts. For each event, the investigator must pursue and 
obtain adequate information until resolution, stabilization, the event is otherwise explained, 
or the participant is lost to follow-up (as defined in Section 7.3).
In general, follow-up information will include a description of the event in sufficient detail to 
allow for a complete medical assessment of the case and independent determination of 
possible causality. Any information relevant to the event, such as concomitant medications 
and illnesses, must be provided. In the case of a participant death, a summary of available 
autopsy findings must be submitted as soon as possible to Pfizer Safety. 
Further information on follow-up procedures is provided in Appendix 3.
8.4.4. Regulatory Reporting Requirements for SAEs
Prompt notification by the investigator to the sponsor of an SAE is essential so that legal 
obligations and ethical responsibilities toward the safety of participants and the safety of a 
study intervention under clinical investigation are met.
The sponsor has a legal responsibility to notify both the local regulatory authority and other 
regulatory agencies about the safety of a study intervention under clinical investigation. The 
sponsor will comply with country-specific regulatory requirements relating to safety 
reporting to the regulatory authority, IRBs/ECs, and investigators.
Investigator safety reports must be prepared for SUSARs according to local regulatory 
requirements and sponsor policy and forwarded to investigators as necessary.


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An investigator who receives SUSARs or other specific safety information (eg, summary or 
listing of SAEs) from the sponsor will review and then file it along with the SRSD(s) for the 
study and will notify the IRB/EC, if appropriate according to local requirements.
8.4.5. Environmental Exposure, Exposure During Pregnancy or Breastfeeding, and 
Occupational Exposure
Environmental exposure occurs when a person not enrolled in the study as a participant 
receives unplanned direct contact with or exposure to the study intervention. Such exposure 
may or may not lead to the occurrence of an AE or SAE. Persons at risk for environmental 
exposure include healthcare providers, family members, and others who may be exposed. An 
environmental exposure may include EDP, EDB, and occupational exposure.
Any such exposures to the study intervention under study are reportable to Pfizer Safety 
within 24 hours of investigator awareness.
8.4.5.1. Exposure During Pregnancy
An EDP occurs if:

A female participant is found to be pregnant while receiving or after discontinuing 
study intervention. 

A male participant who is receiving or has discontinued study intervention 
inseminates a female partner. 

A female nonparticipant is found to be pregnant while being exposed or having been 
exposed to study intervention because of environmental exposure. Below are 
examples of environmental EDP:  

A female family member or healthcare provider reports that she is pregnant after 
having been exposed to the study intervention by ingestion.

A male family member or healthcare provider who has been exposed to the study 
intervention by ingestion then inseminates his female partner prior to or around 
the time of conception.
The investigator must report EDP to Pfizer Safety within 24 hours of the investigator’s 
awareness, irrespective of whether an SAE has occurred. The initial information submitted 
should include the anticipated date of delivery (see below for information related to 
termination of pregnancy). 

If EDP occurs in a participant/participant’s partner, the investigator must report this 
information to Pfizer Safety using the EDP Supplemental Form within PSSA, 
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. 


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
If EDP occurs in the setting of environmental exposure, the investigator must report 
information to Pfizer Safety using the PSSA. Since the exposure information does not 
pertain to the participant enrolled in the study, the information is not recorded on a 
CRF; however, a copy of the completed PSSA case 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 using PSSA. In the case of a live birth, the structural integrity of the neonate can 
be assessed at the time of birth. In the event of a termination, the reason(s) for termination 
should be specified and, if clinically possible, the structural integrity of the terminated fetus 
should be assessed by gross visual inspection (unless preprocedure test findings are 
conclusive for a congenital anomaly and the findings are reported).
Abnormal pregnancy outcomes are considered SAEs. If the outcome of the pregnancy meets 
the criteria for an SAE (ie, ectopic pregnancy, spontaneous abortion, intrauterine fetal 
demise, neonatal death, or congenital anomaly in a live-born baby, a terminated fetus, an 
intrauterine fetal demise, or a neonatal death), the investigator should follow the procedures 
for reporting SAEs. Additional information about pregnancy outcomes that are reported to 
Pfizer Safety as SAEs follows: 

Spontaneous abortion including miscarriage and missed abortion should be reported 
as an SAE;

Neonatal deaths that occur within 1 month of birth should be reported, without regard 
to causality, as SAEs. In addition, infant deaths after 1 month should be reported as 
SAEs when the investigator assesses the infant death as related or possibly related to
exposure to the study intervention. 
Additional information regarding the EDP may be requested by the sponsor. Further 
follow-up of birth outcomes will be handled on a case-by-case basis (eg, follow-up on 
preterm infants to identify developmental delays). In the case of paternal exposure, the 
investigator will provide the participant with the Pregnant Partner Release of Information 
Form to deliver to his partner. The investigator must document in the source documents that 
the participant was given the Pregnant Partner Release of Information Form to provide to his 
partner.
8.4.5.2. Exposure During Breastfeeding
An EDB occurs if:

A female participant is found to be breastfeeding while receiving or after 
discontinuing study intervention.

A female nonparticipant is found to be breastfeeding while being exposed or having 
been exposed to study intervention (ie, environmental exposure). An example of 
environmental EDB is a female family member or healthcare provider who reports 


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that she is breastfeeding after having been exposed to the study intervention by 
ingestion.  
The investigator must report EDB to Pfizer Safety within 24 hours of the investigator’s 
awareness, irrespective of whether an SAE has occurred. The information must be reported 
using the PSSA. When EDB occurs in the setting of environmental exposure, the exposure 
information does not pertain to the participant enrolled in the study, so the information is not 
recorded on a CRF. However, a copy of the completed SAE Case Report form from PSSA is 
maintained in the investigator site file.
An EDB report is not created when a Pfizer drug specifically approved for use in 
breastfeeding women (eg, vitamins) is administered in accordance with authorized use. 
However, if the infant experiences an SAE associated with such a drug, the SAE is reported 
together with the EDB.
8.4.5.3. Occupational Exposure
The investigator must report any instance of occupational exposure to Pfizer Safety within 24 
hours of the investigator’s awareness using the PSSA, regardless of whether there is an 
associated SAE. Since the information about the occupational exposure does not pertain to a 
participant enrolled in the study, the information is not recorded on a CRF; however, a copy 
of the completed SAE Case Report form from PSSA must be maintained in the investigator 
site file.
8.4.6. Cardiovascular and Death Events
Not applicable.
8.4.7. Disease-Related Events and/or Disease-Related Outcomes Not Qualifying as AEs 
or SAEs
Not applicable.
8.4.8. Adverse Events of Special Interest
Not applicable. 
8.4.8.1. 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.  
8.4.9. Medical Device Deficiencies
Not applicable.
8.4.10. Medication Errors
Medication errors may result from the administration or consumption of the study 
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Medication errors are recorded and reported as follows:
Recorded on the 
Medication Error Page 
of the CRF
Recorded on the 
Adverse Event Page 
of the CRF
Reported using the PSSA 
to Pfizer Safety Within 24 
Hours of Awareness
All (regardless of whether 
associated with an AE)
Any AE or SAE associated 
with the medication error
Only if associated with an 
SAE
Medication errors include:

Medication errors involving participant exposure to the study intervention;

Potential medication errors or uses outside of what is foreseen in the protocol that do 
or do not involve the study participant.

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 6.5.
Such medication errors occurring to a study participant are to be captured on the medication 
error page of the CRF, which is a specific version of the AE page.
Whether or not the medication error is accompanied by an AE, as determined by the 
investigator, the medication error is recorded on the medication error page of the CRF and, if 
applicable, any associated AE(s), serious and nonserious, are recorded on the AE page of the 
CRF.
In the event of a medication dosing error, the sponsor should be notified within 24 hours.
Medication errors should be reported to Pfizer Safety within 24 hours using PSSA only when
associated with an SAE.
8.5. Pharmacokinetics 
Pharmacokinetic parameters are not evaluated in this study. 


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8.6. Genetics
8.6.1. Specified Genetics
Specified genetic analyses are not evaluated in this study.
8.6.2. Retained Research Samples for Genetics
A 4-mL blood sample optimized for DNA isolation Prep D1 will be collected according to 
the SoA, as local regulations and IRBs/ECs allow.
Retained Research Samples may be used for research related to the study intervention(s) and 
COVID-19. Genes and other analytes (eg, proteins, RNA, nondrug metabolites) may be 
studied using the retained samples. 
See Appendix 5 for information regarding genetic research. Details on processes for 
collection and shipment of these samples can be found in the laboratory manual.
8.7. 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:

Nasopharyngeal swab will be collected to assess SARS-CoV-2 viral RNA level.

A plasma sample will be collected to assess SARS-CoV-2 viral RNA level.

Oropharyngeal swab will be collected to assess SARS-CoV-2 viral RNA level

A plasma sample will be collected and may be used for protein biomarker analysis.

Retained research samples.
8.7.1. Viral RNA Assessment (NP Swab)
An NP swab of both nares will be collected by HCP as per the SoA from participants and 
will be analyzed to measure SARS-CoV-2 RNA by RT-PCR. At Screening and Baseline 
(Day 1) only, rapid antigen testing can be done before NP swab collection. At all other 
timepoints, NP swab collection must occur prior to any Rapid Antigen Assessment. 
Residual samples may be used for viral sequencing to assess for signs of viral evolution and 
evaluation of potential genetic viral variants, infectivity, phenotypic assays, and additional 
molecular analysis. Host genetic analysis may also be performed. 
Residuals of all samples may be stored for future research. Storage and shipping instructions 
will be in accordance with the laboratory manual.


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8.7.2. Viral RNA Assessment (Plasma)
A 6-mL blood sample will be collected per the SoA from participants and may be analyzed to 
measure SARS-CoV-2 RNA by RT-PCR. Residual samples may be utilized for viral 
sequencing, infectivity and phenotypic assays and additional molecular analysis. Host genetic 
analysis may also be performed. 
Residuals of all samples may be stored for future research. Storage and shipping instructions 
will be in accordance with the laboratory manual.
8.7.3. Rapid Antigen Assessments
Rapid antigen testing for SARS-CoV-2 will be self-collected by the participant as described 
in the SoA. Sites will use test kits that are authorized for use in this study. At Screening and 
Baseline (Day 1) only, rapid antigen testing can be done before NP swab collection. At all 
other time points, rapid antigen testing must be done after NP swab collection. When 
participants have 2 consecutive negative rapid antigen tests separated by at least 24[-2]h, 
rapid antigen testing will revert to on site rapid antigen testing as noted in the SoA.
Site staff should train participants/caregiver at the screening/baseline visit to ensure 
participants can perform the rapid antigen test appropriately. The participant should perform 
the baseline rapid antigen testing assessment during the visit to ensure proper sample 
collection under observation by site staff.
8.7.4. Viral Sequencing Assessments (OP Swab)
An OP swab will be collected by the HCP as per the SoA from participants may be analyzed 
to measure SARS-CoV-2 RNA by RT-PCR. OP swabs should be obtained after NP swab 
collection and rapid antigen testing. Residual samples may be utilized for viral sequencing, 
infectivity and phenotypic assays and additional molecular analysis. Host genetic analysis 
may also be performed.
Residuals of all samples may be stored for future research.  Storage and shipping instructions 
will be in accordance with the laboratory manual.
8.7.5. Specified Gene Expression (RNA) Research
Specified gene expression (RNA) research is not included in this study.
8.7.6. Specified Protein Research 
8.7.6.1. Plasma for Protein Analysis
A 6-mL blood sample will be collected, as specified in the SoA, and isolated for plasma for 
biomarker analysis. Analysis may include but is not limited to proteomics and immunologic 
assessments. Residuals of all samples may be stored and used for additional analyses related 
to COVID-19 and/or the mechanism of action of nirmatrelvir/ritonavir.
Details on processes for collection and shipment of these sample(s) can be found in the 
laboratory manual.


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8.7.7. Specified Metabolomic Research 
Specified metabolomic research is not included in this study.
8.7.8. Retained Research Samples for Biomarkers
These Retained Research Samples will be collected in this study:

4-mL whole blood Prep B2.5 optimized for serum

2.5-mL whole blood Prep R1 optimized for RNA;

15-mL urine Prep M3.
Retained Research Samples will be collected as local regulations and IRB/ECs allow 
according to the SoA.  
Retained Research Samples may be used for research related to the study intervention(s) and 
COVID-19. Genes and other analytes (eg, proteins, RNA, nondrug metabolites) may be 
studied using the retained samples. 
8.8. Immunogenicity Assessments
Immunogenicity assessments are not included in this study.
8.9. Health Economics
Health economics/medical resource utilization and health economics parameters will be 
evaluated in this study (Section 8.2.2 and Section 8.2.3).
9. STATISTICAL CONSIDERATIONS 
Detailed methodology for summary and statistical analyses of the data collected in this study 
is outlined here and further detailed in the SAP, which will be maintained by the sponsor. 
The SAP may modify what is outlined in the protocol where appropriate; however, any major 
modifications of the primary endpoint definitions or their analyses will also be reflected in a 
protocol amendment.
9.1. Statistical Hypothesis
The primary hypothesis is to test whether or not there is a difference in mean change of viral 
RNA level in NP swabs from baseline to Day 5 between nirmatrelvir/ritonavir and the 
placebo/ritonavir group:
Null hypothesis:  H0    	
/
	 −/ = 0           
Alternative hypothesis: Ha    	
/
	 −/ ≠0          
Where µnirmatrelvir/ritonavir and µplacebo/ritonavir are mean change of viral RNA level in NP swabs 
from baseline to Day 5 for nirmatrelvir/ritonavir and placebo/ritonavir groups.


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9.1.1. Estimands
9.1.1.1. Primary Estimand
The primary estimand is the difference in mean change of SARS-CoV-2 RNA level in NP 
swabs from baseline to Day 5 between nirmatrelvir/ritonavir and placebo/ritonavir group in 
patients with a rebound in COVID-19 symptoms and a positive rapid antigen test within 
2 weeks following completion of an initial 5-day treatment course, who have a positive viral 
RNA NP swab test result at baseline. This will be estimated without regard to study treatment 
discontinuation and without regard to prohibited therapies.
9.1.1.2. Secondary Estimands
The secondary estimands are:

The hazard ratio for time to 2 consecutive negative rapid antigen test results obtained 
at least 24 (-2) h apart through Day 28 between nirmatrelvir/ritonavir and 
placebo/ritonavir group in patients with rebound in COVID-19 symptoms and a 
positive rapid antigen test within 2 weeks following completion of an initial 5-day 
treatment course, who have a positive viral RNA NP swab test result at baseline. This 
will be estimated without regard to study treatment discontinuation and without 
regard to prohibited therapies.

The hazard ratio for time to sustained alleviation of all targeted signs and symptoms 
through Day 28 between nirmatrelvir/ritonavir and placebo/ritonavir group in patients 
with rebound in COVID-19 symptoms and a positive rapid antigen test within 2 
weeks following completion of an initial 5-day treatment course, who have a positive 
viral RNA NP swab test result at baseline. This will be estimated without regard to 
study treatment discontinuation and without regard to prohibited therapies.
9.1.2. Multiplicity Adjustment
The overall Type I error rate across the primary and key secondary efficacy endpoints will be 
controlled at alpha = 0.05. Following the positive test of the primary efficacy endpoint in the 
primary analysis set (mITT), the secondary analysis for the primary efficacy endpoint using 
the mITT1 analysis set will be tested.  
Following the positive test of the secondary analysis, the following secondary efficacy 
endpoints will be tested using Hochberg method[31]:

Time to 2 consecutive negative rapid antigen test results obtained at least 24 (-2)h 
apart through Day 28 in the mITT analysis set.

Time (days) to sustained alleviation of all targeted signs and symptoms through 
Day 28 where sustained alleviation is defined as the first of two consecutive days 
when any symptoms scored as moderate or severe at baseline are scored as mild or 
absent and any symptoms scored as mild or absent at baseline are scored as absent in 
the mITT analysis set.


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9.2. Analysis Sets 
For purposes of analysis, the following analysis sets are defined:
Participant Analysis Set
Description
Full analysis set (FAS)
All participants randomly assigned to study intervention. 
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.
mITT
All participants randomly assigned to study intervention who 
take at least 1 dose of study intervention and who have a 
positive viral RNA NP swab test result (≥2.0 log10
copies/mL) at baseline.
Participants will be analyzed according to the study 
intervention they were randomized.
mITT1
All participants randomly assigned to study intervention who 
take at least 1 dose of study intervention and who have a 
positive rapid antigen test result at baseline.
Participants will be analyzed according to the study 
intervention they were randomized.
Per protocol(PP)
All participants in the mITT analysis set without important 
protocol deviations considered to impact the interpretation of 
the primary efficacy endpoint. Protocol deviations will be 
reviewed to generate the list of participants with significant 
deviations to be excluded from the PP analysis set. The PP 
exclusion criteria will be finalized prior to breaking the blind.
9.3. Statistical Analyses
The SAP will be developed and finalized before 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
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 and qualitative variables will be summarized by frequency tables with 
number and proportion in each category. 


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For continuous endpoints, an MMRM or ANCOVA model will be used to analyze change 
from baseline, whichever is appropriate. Estimated mean differences between treatments 
groups will be calculated.
For categorical endpoints, proportion of participants for each category will be summarized 
for each group.
For count endpoints, the total number of the events and average number of events will be 
summarized for each group.
Time to event will be summarized graphically using Kaplan-Meier plots for each treatment 
group. Treatment comparisons will be conducted using log-rank test or Cox proportional 
hazard model as appropriate.
9.3.2. Primary Endpoint(s)/Estimand(s) Analysis
9.3.2.1. Definition of Endpoint(s)
The primary efficacy endpoint is the change in viral SARS-CoV-2 RNA level from baseline 
to Day 5 as measured in NP swabs.
9.3.2.2. Main Analytical Approach
The primary analysis for mean change in SARS-CoV-2 RNA level from baseline will be 
performed using a MMRM. The analysis will include the fixed effects of treatment, 
geographic region, baseline viral RNA level, visit, and treatment-by-visit interaction. An 
unstructured (co)variance structure will be used to model the within-participant variability. 
The LS means and treatment difference for each visit will be calculated and presented with 
their corresponding 95% CIs. The primary comparison for treatment effect will be the 
difference in LS means and 95% CI at Day 5. The primary analysis will be performed using 
mITT analysis set.
The secondary analysis for primary endpoint will be performed using the mITT1 analysis set.
9.3.3. Secondary Endpoints
9.3.3.1. Time to 2 consecutive negative rapid antigen test results obtained at least 24(-
2)h apart through Day 28
For the event of 2 consecutive negative rapid antigen test results obtained at least 24(-2)h 
apart through Day 28, the date of the first negative rapid antigen test result will be considered 
the First Event Date.
Time to 2 consecutive negative rapid antigen test results obtained at least 24(-2)h apart for 
the purpose of this study is defined as:

For a participant achieving the event, time to event will be calculated as (First Event 
Date) – (First Dose Date) +1.

For a participant not achieving the event (censored), censoring date will be at the last 
date of rapid antigen test measurement, and time will be calculated as (Censoring 
Date) – (First Dose Date) +1 or Day 27 whichever occurs first (Day 27 is the last 


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possible day to achieve 2 consecutive negative rapid antigen test results obtained at 
least 24(-2)h apart through Day 28).
Cox proportional hazard model analyses will be used for time to 2 consecutive negative rapid 
antigen test results obtained at least 24(-2)h apart in mITT analysis set. Cox proportional 
hazard model will include treatment, geographic region and potential covariates as 
appropriate.  The treatment group comparison will be presented as the estimate of the hazard 
ratio, 95% CI and p-value. In addition, time to 2 consecutive negative rapid antigen test 
results obtained at least 24(-2)h apart will be summarized graphically using Kaplan-Meier 
plots for each of the treatment groups in mITT analysis set. 
Similar analyses for time to 2 consecutive negative rapid antigen test results obtained at least 
24(-2)h apart will also be performed in the mITT1 analysis set.
9.3.3.2. Time (days) to sustained alleviation of all targeted signs and symptoms through 
Day 28
Sustained alleviation of all targeted COVID-19 signs/symptoms is defined as the event 
occurring on the first of 2 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 2 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 (missing severity at baseline will be treated as 
mild).
Day 27 is the last possible day that symptom alleviation can be achieved (definition includes 
data from the subsequent day) and Day 28 is the last day participants report their daily signs 
and symptoms.
The time to sustained symptom alleviation for the purpose of this study is defined as:

For a participant with sustained symptom alleviation, 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(censored), censoring date 
will be at the last date on which symptom alleviation is assessed, and time will be 
calculated as (Censoring Date) – (First Dose Date) +1 or Day 27 whichever occurs 
first.
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 
and will be censored at day 27.
Cox proportional hazard model analyses will be used for time to sustained symptom 
alleviation in mITT analysis set. Cox proportional hazard model will include treatment, 
geographic region and potential covariates as appropriate.  The treatment group comparison 


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will be presented as the estimate of the hazard ratio, 95% CI and p-value. In addition, time to 
sustained symptom alleviation will be summarized graphically using Kaplan-Meier plots for 
each of the treatment groups in mITT analysis set.
Similar analyses for time to sustained symptom alleviation will also be performed in the 
mITT1 analysis set.
9.3.4. Tertiary/Exploratory Endpoint(s) Analysis
Details on the definitions and analyses for the tertiary/exploratory endpoints specified in 
Section 3 will be described in the SAP.
9.3.5. Safety Analyses
All safety analyses will be performed on the safety population. Safety data including AEs, 
SAEs, AEs leading to discontinuation, vital signs, and clinical laboratory data will be 
summarized descriptively through appropriate data tabulation, descriptive statistics, 
categorical summaries, and graphical presentations in accordance with Pfizer Data Standards.
9.3.6. Other Analyses 
Pharmacogenomic or biomarker data from Retained Research Samples may be collected 
during or after the trial and retained for future analyses; the results of such analyses are not 
planned to be included in the CSR. 
PRO data (ie, SF-36, WPAI, EQ-5D-5L) will be collected during the trial and are not planned 
to be included in the CSR. 
The following analyses will be described in a separate report and will not be included in the 
CSR:

New viral lineages and/or treatment-emergent mutations with demonstrated reduced 
susceptibility to study intervention in vitro will be analyzed to determine the 
emergence of virus with reduced susceptibility in participants with mild-to-moderate 
COVID-19.
9.4. Interim Analyses
No formal interim analysis is planned for this study. However, the sponsor may conduct 
unblinded reviews of the data during the course of the study if requested by regulatory 
authorities including in the support of regulatory submissions. Should an unblinded review 
be requested, details of the unblinding plan will be described in the SAP and a separate data 
unblinding document.
9.5. Sample Size Determination
The study will enroll approximately 411 participants.
The sample size calculation is based on the primary efficacy endpoint as the change in viral 
RNA level from baseline to Day 5 as measured in NP swabs in the mITT analysis set. 
Assuming a SD of 1.8 (based on EPIC-HR, NCT04960202), a sample size of approximately 


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315 evaluable participants (210 participants in nirmatrelvir/ritonavir group and 105 
participants in placebo/ritonavir group) is expected to provide 90% power to detect a 
difference of 0.7 log10 copies/mL in viral RNA between groups using a 2-sided 0.05 alpha 
level test. Assuming approximately 10% of participants will have a negative viral RNA result 
at baseline, and assuming a non-evaluable rate of 15%, approximately 411 participants will 
be randomized in the study to achieve approximately 315 participants evaluable for the 
primary efficacy endpoint. 


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10. SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS
10.1. Appendix 1: Regulatory, Ethical, and Study Oversight Considerations
10.1.1. Regulatory and Ethical Considerations
This study will be conducted in accordance with the protocol and with the following:

Consensus ethical principles derived from international guidelines, including the 
Declaration of Helsinki and CIOMS International Ethical Guidelines;

Applicable ICH GCP guidelines;

Applicable laws and regulations, including applicable privacy laws.
The protocol, protocol amendments, ICD, SRSD(s), and other relevant documents (eg, 
advertisements) must be reviewed and approved by the sponsor, submitted to an IRB/EC by 
the investigator, and reviewed and approved by the IRB/EC before the study is initiated.
Any amendments to the protocol will require IRB/EC approval before implementation of 
changes made to the study design, except for changes necessary to eliminate an immediate 
hazard to study participants.
Protocols and any substantial amendments to the protocol will require health authority 
approval prior to initiation except for changes necessary to eliminate an immediate hazard to 
study participants.
The investigator will be responsible for the following:

Providing written summaries of the status of the study to the IRB/EC annually or 
more frequently in accordance with the requirements, policies, and procedures 
established by the IRB/EC;

Notifying the IRB/EC of SAEs or other significant safety findings as required by 
IRB/EC procedures;

Providing oversight of the conduct of the study at the site and adherence to 
requirements of 21 CFR, ICH GCP guidelines, the IRB/EC, European regulation 
536/2014 for clinical studies, European Medical Device Regulation 2017/745 for 
clinical device research, and all other applicable local regulations.
10.1.1.1. Reporting of Safety Issues and Serious Breaches of the Protocol or ICH GCP
In the event of any prohibition or restriction imposed (ie, clinical hold) by an applicable 
regulatory authority in any area of the world, or if the investigator is aware of any new 
information that might influence the evaluation of the benefits and risks of the study 
intervention, Pfizer should be informed immediately. 
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 


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of any serious breaches of this protocol or of the ICH GCP guidelines that the investigator 
becomes aware of.
10.1.2. Financial Disclosure
Investigators and subinvestigators will provide the sponsor with sufficient, accurate financial 
information as requested to allow the sponsor to submit complete and accurate financial 
certification or disclosure statements to the appropriate regulatory authorities. Investigators 
are responsible for providing information on financial interests during the course of the study 
and for 1 year after completion of the study.
10.1.3. Informed Consent/Assent Process 
10.1.3.1. Informed Consent Process
The investigator or the investigator’s representative will explain the nature of the study, 
including the risks and benefits, to the participant or their legally authorized representative
and answer all questions regarding the study. The participant or their 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 (if allowed by local regulations) will be required to sign a statement 
of informed consent that meets the requirements of 21 CFR 50, local regulations, ICH 
guidelines, privacy and data protection requirements, where applicable, and the IRB/EC or 
study center.
The investigator must ensure that each participant or their 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 their legally authorized representative must be informed that their personal 
study-related data will be used by the sponsor in accordance with local data protection law. 
The level of disclosure must also be explained to the participant or their legally authorized 
representative.
The participant or their legally authorized representative must be informed that their medical 
records may be examined by Clinical Quality Assurance auditors or other authorized 
personnel appointed by the sponsor, by appropriate IRB/EC members, and by inspectors 
from regulatory authorities.
The investigator further must ensure that each study participant or their legally authorized 
representative is fully informed about their right to access and correct their personal data and 
to withdraw consent for the processing of their personal data.
The medical record must include a statement that written informed consent was obtained 
before the participant was enrolled in the study and the date on which the written consent was 
obtained. The authorized person obtaining the informed consent must also sign the ICD.


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Participants or their legally authorized representative must be reconsented to the most current 
version of the IRB/EC-approved ICD(s) during their participation in the study as required per 
local regulations.
A copy of the ICD(s) must be provided to the participant or their legally authorized 
representative (if allowed by local regulations).
10.1.3.2. Informed Assent Process
The investigator or their representative will explain the nature of the study to the participant 
and their parent(s)/legal guardian and answer all questions regarding the study. The 
participant and their parent(s)/legal guardian should be given sufficient time and opportunity 
to ask questions and to decide whether or not to participate in the trial. 
When consent is obtained from a participant’s parent(s)/legal guardian, the participant’s 
assent (affirmative agreement) must be subsequently obtained when the participant has the 
capacity to provide assent, as determined by the IRB/EC. If the investigator determines that a 
participant’s decisional capacity is so limited they cannot reasonably be consulted, then, as 
permitted by the IRB/EC and consistent with local regulatory and legal requirements, the 
participant’s assent may be waived with source documentation of the reason assent was not 
obtained. If the study participant does not provide their own assent, the source documents 
must record why the participant did not provide assent (for example, the child is not of 
assenting age per local regulations or policies), how the investigator determined that the 
person signing the consent was the participant’s parent(s)/legal guardian, the consent signer’s 
relationship to the study participant, and that the participant’s assent was obtained or waived. 
If assent is obtained verbally, it must be documented in the source documents. 
If study participants are minors who reach the age of majority or if a child reaches the age of 
assent (per local IRB/EC requirements) during the study, as recognized under local law, the 
child or adolescent must then provide the appropriate assent or consent to document their 
willingness to continue in the study. For an adolescent who reaches the age of consent, 
parental consent would no longer be valid. If the enrollment of emancipated minors is 
permitted by the IRB/EC and local law, the participant must provide documentation of legal 
status to give consent without the permission of a legally authorized representative. 
Participants and their parent(s)/legal guardian must be informed that their participation is 
voluntary. The participant’s parent(s)/legal guardian will be required to sign a statement of 
informed consent that meets the requirements of 21 CFR 50, local regulations, ICH 
guidelines, HIPAA requirements, where applicable, and the IRB/EC or study center. 
The investigator must ensure that each study participant’s parent(s)/legal guardian and the 
study participant as applicable are 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.  


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The participant’s parent(s)/legal guardian must be informed that the participant’s 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’s parent(s)/legal guardian. 
The participant’s parent(s)/legal guardian must be informed that the participant’s 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’s parent(s)/legal guardian is 
fully informed about their right to access and correct their child’s personal data and to 
withdraw consent for the processing of their child’s personal data, keeping in mind the 
privacy rights that may restrict access of older adolescents’ medical records by their 
parent(s)/legal guardian in certain regions. 
The source documentation must include a statement that written informed consent, and as 
applicable, assent was obtained before the participant was enrolled in the study and the date 
the written consent/assent was obtained. The authorized person obtaining the informed 
consent must also sign the ICD. 
Parent(s)/legal guardian and the participant must be reconsented to the most current version 
of the ICD(s)/assent during their participation in the study as required per local regulations. 
A copy of the ICD(s) and assent, if written, must be provided to the parent(s)/legal guardian 
and the participant.
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 their actual identity and medical record ID. In case of data 
transfer, the sponsor will protect the confidentiality of participants’ personal data consistent 
with the clinical study agreement and applicable privacy laws.


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Information technology systems used to collect, process, and store study-related data are 
secured by technical and organizational security measures designed to protect such data 
against accidental or unlawful loss, alteration, or unauthorized disclosure or access.
The sponsor maintains SOPs on how to respond in the event of unauthorized access, use, or 
disclosure of sponsor information or systems.
10.1.5. Committees Structure
10.1.5.1. Data Monitoring Committee 
This study will 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 safety of participants in the 
study according to the charter. In addition, the E-DMC may monitor the baseline SARS-
CoV-2 RNA levels to ensure the population is consistent with the study design assumptions. 
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 safety data, to regulatory authorities and 
investigators, as appropriate. 
10.1.6. Dissemination of Clinical Study Data
Pfizer fulfills its commitment to publicly disclose clinical study results through posting the 
results of studies on www.clinicaltrials.gov (ClinicalTrials.gov), the EudraCT/CTIS, and/or 
www.pfizer.com, and other public registries and websites in accordance with applicable local 
laws/regulations. In addition, Pfizer reports study results outside of the requirements of local 
laws/regulations pursuant to its SOPs.
In all cases, study results are reported by Pfizer in an objective, accurate, balanced, and 
complete manner and are reported regardless of the outcome of the study or the country in 
which the study was conducted.
www.clinicaltrials.gov
Pfizer posts clinical trial results on www.clinicaltrials.gov for Pfizer-sponsored interventional 
studies (conducted in patients) that evaluate the safety and/or efficacy of a product, 
regardless of the geographical location in which the study is conducted. These results are 
submitted for posting in accordance with the format and timelines set forth by US law.
EudraCT/CTIS
Pfizer posts clinical trial results on EudraCT/CTIS for Pfizer-sponsored interventional studies 
in accordance with the format and timelines set forth by EU requirements.
www.pfizer.com
Pfizer posts CSR synopses and plain-language study results summaries on www.pfizer.com 
for Pfizer-sponsored interventional studies at the same time the corresponding study results 


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are posted to www.clinicaltrials.gov. CSR synopses will have personally identifiable 
information anonymized.
Documents within marketing applications
Pfizer complies with applicable local laws/regulations to publish clinical documents included 
in marketing applications. Clinical documents include summary documents and CSRs 
including the protocol and protocol amendments, sample CRFs, and SAPs. Clinical 
documents will have personally identifiable information anonymized.
Data sharing
Pfizer provides researchers secure access to participant-level data or full CSRs for the 
purposes of “bona-fide scientific research” that contributes to the scientific understanding of 
the disease, target, or compound class. Pfizer will make data from these trials available 
18 months after study completion. Participant-level data will be anonymized in accordance 
with applicable privacy laws and regulations. CSRs will have personally identifiable 
information anonymized.
Data requests are considered from qualified researchers with the appropriate competencies to 
perform the proposed analyses. Research teams must include a biostatistician. Data will not 
be provided to applicants with significant conflicts of interest, including individuals 
requesting access for commercial/competitive or legal purposes.
10.1.7. Data Quality Assurance
All participant data relating to the study will be recorded on printed or electronic CRF unless 
transmitted to the sponsor or designee electronically (eg, laboratory data). The investigator is 
responsible for verifying that data entries are accurate and correct by physically or 
electronically signing the CRF.
Guidance on completion of CRFs will be provided in the CRF Completion Requirements 
document.
The investigator must ensure that the CRFs are securely stored at the study site in encrypted 
electronic form and are password protected to prevent access by unauthorized third parties.
QTLs are predefined parameters that are monitored during the study. Important deviations 
from the QTLs and any remedial actions taken will be summarized in the CSR.
The investigator must permit study-related monitoring, audits, IRB/EC review, and 
regulatory agency inspections and provide direct access to source records and documents. 
This verification may also occur after study completion. It is important that the 
investigator(s) and their relevant personnel are available during the monitoring visits and 
possible audits or inspections and that sufficient time is devoted to the process.
Monitoring details describing strategy, including definition of study-critical data items and 
processes (eg, risk-based initiatives in operations and quality such as risk management and 


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mitigation strategies and analytical risk-based monitoring), methods, responsibilities, and 
requirements, including handling of noncompliance issues and monitoring techniques 
(central, virtual, or on-site monitoring), are provided in the data management plan and 
monitoring plan maintained and utilized by the sponsor or designee. 
The sponsor or designee is responsible for the data management of this study, including 
quality checking of the data.
Records and documents, including signed ICDs, pertaining to the conduct of this study must 
be retained by the investigator for 15 years after study completion unless local regulations or 
institutional policies require a longer retention period. No records may be destroyed during 
the retention period without the written approval of the sponsor. No records may be 
transferred to another location or party without written notification to the sponsor. The 
investigator must ensure that the records continue to be stored securely for as long as they are 
maintained.
When participant data are to be deleted, the investigator will ensure that all copies of such 
data are promptly and irrevocably deleted from all systems.
The investigator(s) will notify the sponsor or its agents immediately of any regulatory 
inspection notification in relation to the study. Furthermore, the investigator will cooperate 
with the sponsor or its agents to prepare the investigator site for the inspection and will allow 
the sponsor or its agent, whenever feasible, to be present during the inspection. The 
investigator site and investigator will promptly resolve any discrepancies that are identified 
between the study data and the participant’s medical records. The investigator will promptly 
provide copies of the inspection findings to the sponsor or its agent. Before response 
submission to the regulatory authorities, the investigator will provide the sponsor or its 
agents with an opportunity to review and comment on responses to any such findings.
10.1.8. Source Documents
Source documents provide evidence for the existence of the participant and substantiate the 
integrity of the data collected. Source documents are filed at the investigator site.
Data reported on the CRF or entered in the eCRF that are from source documents must be 
consistent with the source documents or the discrepancies must be explained. The 
investigator may need to request previous medical records or transfer records, depending on 
the study. Also, current medical records must be available.
Definition of what constitutes source data and its origin can be found in the Source 
Document Locator, 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.


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The sponsor or designee will perform monitoring to confirm that data entered into the CRF 
by authorized site personnel are accurate, complete, and verifiable from source documents; 
that the safety and rights of participants are being protected; and that the study is being 
conducted in accordance with the currently approved protocol and any other study 
agreements, ICH GCP guidelines, and all applicable regulatory requirements.
10.1.9. Study and Site Start and Closure
The study start date is the date of the first participant’s first visit.
The sponsor designee reserves the right to close the study site or terminate the study at any 
time for any reason at the sole discretion of the sponsor, including (but not limited to) 
regulatory authority decision, change in opinion of the IRB/EC, or change in benefit-risk 
assessment. Study sites will be closed upon study completion. A study site is considered 
closed when all required documents and study supplies have been collected and a study-site 
closure visit has been performed.
The investigator may initiate study-site closure at any time upon notification to the sponsor 
or designee/CRO if requested to do so by the responsible IRB/EC or if such termination is 
required to protect the health of study participants.
Reasons for the early closure of a study site by the sponsor may include but are not limited 
to:

Failure of the investigator to comply with the protocol, the requirements of the 
IRB/EC or local health authorities, the sponsor’s procedures, or the ICH GCP 
guidelines;

Inadequate recruitment of participants by the investigator; 

Discontinuation of further study intervention development.
If the study is prematurely terminated or suspended, the sponsor shall promptly inform the 
investigators, the ECs/IRBs, the regulatory authorities, and any CRO(s) used in the study of 
the reason for termination or suspension, as specified by the applicable regulatory 
requirements. The investigator shall promptly inform the participant and should assure 
appropriate participant therapy and/or follow-up.
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
For multicenter trials, the primary publication will be a joint publication developed by the 
investigator and Pfizer reporting the primary endpoint(s) of the study covering all study sites. 
The investigator agrees to refer to the primary publication in any subsequent publications. 
Pfizer will not provide any financial compensation for the investigator’s participation in the 
preparation of the primary congress abstract, poster, presentation, or primary manuscript for 
the study.


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Investigators are free to publish individual center results that they deem to be clinically 
meaningful after publication of the overall results of the study or 12 months after primary 
completion date or study completion at all sites, whichever occurs first, subject to the other 
requirements described in this section.
The investigator will provide Pfizer an opportunity to review any proposed publication or 
any other type of disclosure of the study results (collectively, “publication”) before it is 
submitted or otherwise disclosed and will submit all publications to Pfizer 30 days before 
submission. If any patent action is required to protect intellectual property rights, the 
investigator agrees to delay the disclosure for a period not to exceed an additional 60 days 
upon request from Pfizer. This allows Pfizer to protect proprietary information and to provide 
comments, and the investigator will, on request, remove any previously undisclosed 
confidential information before disclosure, except for any study-intervention or 
Pfizer-related information necessary for the appropriate scientific presentation or 
understanding of the study results. For joint publications, should there be disagreement 
regarding interpretation and/or presentation of specific analysis results, resolution of, and 
responsibility for, such disagreements will be the collective responsibility of all authors of 
the publication.
For all publications relating to the study, the investigator and Pfizer will comply with 
recognized ethical standards concerning publications and authorship, including those 
established by the International Committee of Medical Journal Editors. The investigator will 
disclose any relationship with Pfizer and any relevant potential conflicts of interest, including 
any financial or personal relationship with Pfizer, in any publications. All authors will have 
access to the relevant statistical tables, figures, and reports (in their original format) required 
to develop the publication.
10.1.11. Sponsor’s Medically Qualified Individual 
The contact information for the sponsor’s MQI for the study is documented in the study 
contact list located in the supporting study documentation/study portal or other electronic 
system.
To facilitate access to their investigator and the sponsor’s MQI for study-related medical 
questions or problems from non-study healthcare professionals, participants are provided 
with an ECC at the time of informed consent. The ECC contains, at a minimum, (a) protocol 
and study intervention identifiers, (b) participant’s study identification number, (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 participant and their investigator and site staff, and between the investigator and 
sponsor study team. The ECC is only to be used by healthcare professionals not involved in 
the research study, as a means of reaching the investigator or site staff related to the care of a 
participant. The Pfizer Call Center number is to be used when the investigator and site staff 
are unavailable. The Pfizer Call Center number is not for use by the participant directly; if a 
participant calls that number directly, they 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 2.
Protocol-Required Safety Laboratory Assessments
Hematology
Chemistry
Other
Reflex Testing
Hemoglobin
Hematocrit
RBC count
Platelet count
WBC count
Total neutrophils (Abs)
Eosinophils (Abs)
Monocytes (Abs)
Basophils (Abs)
Lymphocytes (Abs)
Urea 
Serum creatinine and 
eGFR (calculated)a
Glucose 
Sodium
Potassium
Chloride
Total CO2 (bicarbonate)
AST, ALT
Total bilirubin
Alkaline phosphatase
Viral Serology
SARS-CoV-2
At screening:

FSHb

Pregnancy test 
(β-hCG)c

HIV testingd
For suspected DILI:
AST/ALT 
Total bilirubin, direct and 
indirect bilirubin 
Total bile acids, GGT 
Total protein, albumin CK 
PT, INR 
Acetaminophen/paracetamol or 
protein adduct levels 
Hepatitis serology
a.
eGFR will be calculated using the method developed by the 2021 CKD-EPI (Scr only) for participants 
18 years or older or eCrCl using the Cockcroft-Gault formula for participants 12 years to <18 years.
b.
FSH testing is performed locally when needed to confirm postmenopausal status at screening.
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.
d.
Local HIV testing at screening will be performed for participants in Germany as required by the German 
HA.
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 an 
increase in either frequency and/or intensity of the condition.

New condition detected or diagnosed after study intervention administration, even 
though it may have been present before the start of the study.

Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction.

Signs, symptoms, or the clinical sequelae of a suspected overdose of either study 
intervention or a concomitant medication. Overdose per se will not be reported as 
an AE or SAE unless it is an intentional overdose taken with possible 
suicidal/self-harming intent. Such overdoses should be reported regardless of 
sequelae.


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


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An SAE is defined as any untoward medical occurrence that, at any dose, meets one 
or more of the criteria listed below:
d. Results in persistent or significant disability/incapacity

The term disability means a substantial disruption of a person’s ability to conduct 
normal life functions.

This definition is not intended to include experiences of relatively minor medical 
significance, such as uncomplicated headache, nausea, vomiting, diarrhea, 
influenza, and accidental trauma (eg, sprained ankle), that may interfere with or 
prevent everyday life functions but do not constitute a substantial disruption.
e.
Is a congenital anomaly/birth defect
f.
Is a suspected transmission via a Pfizer product of an infectious agent, pathogenic 
or nonpathogenic  
The event may be suspected from clinical symptoms or laboratory findings indicating 
an infection in a participant exposed to a Pfizer product. The terms “suspected 
transmission” and “transmission” are considered synonymous. These cases are 
considered unexpected and handled as serious expedited cases by pharmacovigilance 
personnel. Such cases are also considered for reporting as product defects, if 
appropriate.
g. Other situations:

Medical or scientific judgment should be exercised by the investigator in deciding 
whether SAE reporting is appropriate in other situations, such as significant 
medical events that may jeopardize the participant or may require medical or 
surgical intervention to prevent one of the other outcomes listed in the above 
definition. These events should usually be considered serious.

Examples of such events include invasive or malignant cancers, intensive treatment 
in an emergency room or at home for allergic bronchospasm, blood dyscrasias or 
convulsions that do not result in hospitalization, or development of drug 
dependency or drug abuse.
10.3.3. Recording/Reporting and Follow-Up of AEs and/or SAEs During the Active 
Collection Period 
AE and SAE Recording/Reporting
The table below summarizes the requirements for recording AEs on the CRF and for 
reporting SAEs using the PSSA to Pfizer Safety throughout the active collection period. 
These requirements are delineated for 3 types of events: (1) SAEs; (2) nonserious AEs; and 


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(3) exposure to the study intervention under study during pregnancy or breastfeeding, and 
occupational exposure. 
It should be noted that the PSSA for reporting of SAE information is not the same as the 
AE page of the CRF. When the same data are collected, the forms must be completed in a 
consistent manner. AEs should be recorded using concise medical terminology and the 
same AE term should be used on both the CRF and the PSSA for reporting of SAE 
information.
Safety Event
Recorded on the CRF
Reported using the PSSA 
to Pfizer Safety Within 24 
Hours of Awareness
SAE
All
All
Nonserious AE
All
None
Exposure to the study 
intervention under study 
during pregnancy or 
breastfeeding 
All AEs or SAEs associated 
with EDP or EDB
Note: Instances of EDP or 
EDB not associated with an 
AE or SAE are not captured 
in the CRF
All instances of EDP are 
reported (whether or not 
there is an associated 
SAE)*
All instances of EDB are 
reported (whether or not 
there is an associated 
SAE)**
Environmental or 
occupational exposure to 
the product under study to 
a nonparticipant (not 
involving EDP or EDB)
None. Exposure to a study 
nonparticipant is not 
collected on the CRF
The exposure (whether or 
not there is an associated 
AE or SAE) must be 
reported***
*
EDP (with or without an associated AE or SAE): any pregnancy information is reported to Pfizer 
Safety using the PSSA; if the EDP is associated with an SAE, then the SAE is reported to Pfizer Safety 
using the PSSA. 
** EDB is reported to Pfizer Safety using the PSSA, which would also include details of any SAE that 
might be associated with the EDB. 
*** Environmental or occupational exposure: AEs or SAEs associated with occupational exposure 
are reported to Pfizer Safety using the PSSA. 

When an AE or SAE occurs, it is the responsibility of the investigator to review all 
documentation (eg, hospital progress notes, laboratory reports, and diagnostic 
reports) related to the event.

The investigator will then record all relevant AE or SAE information in the CRF.


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
It is not acceptable for the investigator to send photocopies of the participant’s 
medical records to Pfizer Safety in lieu of completion of the PSSA/AE or SAE 
CRF page.

There may be instances when copies of medical records for certain cases are 
requested by Pfizer Safety. In this case, all participant identifiers, with the 
exception of the participant number, will be redacted on the copies of the medical 
records before submission to Pfizer Safety.

The investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information. Whenever possible, the diagnosis (not 
the individual signs/symptoms) will be documented as the AE or SAE.
Assessment of Intensity
The investigator will make an assessment of intensity for each AE and SAE reported 
during the study and assign it to 1 of the following categories, which are based on the 
DAIDS Table for Grading the Severity of Adult and Pediatric Adverse Events[30], version 
2.1 (July 2017): 
GRADE
Clinical Description of Severity
1
MILD adverse event
2
MODERATE adverse event
3
SEVERE adverse event
4
POTENTIALLY LIFE-THREATENING event 
5
DEATH RELATED TO adverse event
An event is defined as “serious” when it meets at least 1 of the predefined outcomes as 
described in the definition of an SAE, NOT when it is rated as severe.
Assessment of Causality

The investigator is obligated to assess the relationship between study intervention 
and each occurrence of each AE or SAE. The investigator will use clinical 
judgment to determine the relationship.

A “reasonable possibility” of a relationship conveys that there are facts, evidence, 
and/or arguments to suggest a causal relationship, rather than a relationship cannot 
be ruled out.

Alternative causes, such as underlying disease(s), concomitant therapy, and other 
risk factors, as well as the temporal relationship of the event to study intervention 
administration, will be considered and investigated.


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Assessment of Causality

The investigator will also consult the IB and/or product information, for marketed 
products, in their assessment.

For each AE or SAE, the investigator must document in the medical notes that they 
have reviewed the AE or SAE and have provided an assessment of causality.

There may be situations in which an SAE has occurred and the investigator has 
minimal information to include in the initial report to the sponsor. However, it is 
very important that the investigator always make an assessment of causality 
for every event before the initial transmission of the SAE data to the sponsor.

The investigator may change their opinion of causality in light of follow-up 
information and send an SAE follow-up report with the updated causality 
assessment.

The causality assessment is one of the criteria used when determining regulatory 
reporting requirements.

If the investigator does not know whether or not the study intervention caused the 
event, then the event will be handled as “related to study intervention” for reporting 
purposes, as defined by the sponsor. In addition, if the investigator determines that 
an SAE is associated with study procedures, the investigator must record this 
causal relationship in the source documents and CRF, and report such an 
assessment in the dedicated section of the PSSA and in accordance with the SAE 
reporting requirements.
Follow-Up of AEs and SAEs

The investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations, as medically indicated or as requested by the 
sponsor, to elucidate the nature and/or causality of the AE or SAE as fully as 
possible. This may include additional laboratory tests or investigations, 
histopathological examinations, or consultation with other healthcare providers.

If a participant dies during participation in the study or during a recognized 
follow-up period, the investigator will provide Pfizer Safety with a copy of any 
postmortem findings, including histopathology. 

New or updated information will be recorded in the originally submitted 
documents.

The investigator will submit any updated SAE data to the sponsor within 24 hours 
of receipt of the information.


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10.3.4. Reporting of SAEs
SAE Reporting to Pfizer Safety via an Electronic DCT

The primary mechanism for reporting an SAE to Pfizer Safety will be the 
electronic DCT (PSSA).

If the electronic system is unavailable, then the site will use the paper form (see 
next section) to report the event within 24 hours.

The site will enter the SAE data into the electronic DCT (PSSA) or paper form (as 
applicable) as soon as the data become available.

After the study is completed at a given site, the electronic DCT will be taken 
off-line to prevent the entry of new data or changes to existing data.

If a site receives a report of a new SAE from a study participant or receives updated 
data on a previously reported SAE after the electronic DCT has been taken off-line, 
then the site can report this information on a paper SAE form (see next section) or 
to Pfizer Safety by telephone.
SAE Reporting to Pfizer Safety via the CT SAE Report Form

Facsimile transmission of the CT SAE Report Form is the preferred method to 
transmit this information to Pfizer Safety.

In circumstances when the facsimile is not working, an alternative method should 
be used, eg, secured (Transport Layer Security) or password-protected email. If 
none of these methods can be used, notification by telephone is acceptable with a 
copy of the CT SAE Report 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 
No contraception methods are required for male participants in this study, as the calculated 
safety margin is ≥100-fold between the estimated maternal exposure due to seminal transfer 
and the NOAEL for serious manifestations of developmental toxicity in nonclinical studies. 
10.4.1. Female Participant Reproductive Inclusion Criteria
The criteria below are part of Inclusion Criterion 1 (Age and Sex; Section 5.1) and specify 
the reproductive requirements for including female participants. Refer to Section 10.4.3 for a 
complete list of contraceptive methods permitted in the study. 
A female participant is eligible to participate if at least 1 of the following conditions applies:

Is not a WOCBP (see definition in Section 10.4.2).
OR

Is a WOCBP who is pregnant (at least 14 weeks gestation).
OR

Is a WOCBP who is not pregnant at screening and agrees to use a highly effective 
contraceptive method (failure rate of <1% per year) during the intervention period 
and for at least 28 days after the last dose of study intervention, which corresponds to 
the time needed to eliminate any reproductive safety risk of the study intervention(s). 
If a highly effective, user-dependent method is chosen, she agrees to concurrently use 
an effective barrier method of contraception. The investigator should evaluate the 
effectiveness of the contraceptive method in relationship to the first dose of study 
intervention.
The investigator is responsible for review of medical history, menstrual history, and recent 
sexual activity to decrease the risk for inclusion of a woman with an early undetected 
pregnancy. 
10.4.2. 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. Premenarchal.


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2. Premenopausal female with 1 of the following: 

Documented hysterectomy;

Documented bilateral salpingectomy;

Documented bilateral oophorectomy.
For individuals with permanent infertility due to a medical cause other than the above (eg, 
mullerian agenesis, androgen insensitivity), investigator discretion should be applied to 
determining study entry.
Note: Documentation for any of the above categories can come from the site personnel’s 
review of the participant’s medical records, medical examination, or medical history 
interview. The method of documentation should be recorded in the participant’s medical 
record for the study.
3. 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 highly effective nonestrogen hormonal contraception methods 
if she wishes to continue her HRT during the study. Otherwise, she must 
discontinue HRT to allow confirmation of postmenopausal status before study 
enrollment.
10.4.3. Contraception Methods 
Contraceptive use by men or women should be consistent with local availability/regulations 
regarding the use of contraceptive methods for those participating in clinical trials.
The following contraceptive methods are appropriate for this study:
Highly Effective Methods That Have Low User Dependency 
1. Implantable progestogen-only hormone contraception associated with inhibition of 
ovulation.
2. Intrauterine device.
3. Intrauterine hormone-releasing system.
4. Bilateral tubal occlusion.


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5. Vasectomized partner:

Vasectomized partner is a highly effective contraceptive method provided that the 
partner is the sole sexual partner of the WOCBP and the absence of sperm has been 
confirmed. If not, an additional highly effective method of contraception should be 
used. The spermatogenesis cycle is approximately 90 days.
Highly Effective Methods That Are User Dependent 
6.
Combined (estrogen- and progestogen-containing) hormonal contraception associated 
with inhibition of ovulation:

Oral + barrier*

Intravaginal + barrier*

Transdermal + barrier*
7.
Progestogen-only hormone contraception associated with inhibition of ovulation:

Oral + barrier*

Injectable + barrier*
Sexual Abstinence
8.
Sexual abstinence is considered a highly effective method only if defined as 
refraining from heterosexual intercourse during the entire period of risk associated 
with the study intervention. The reliability of sexual abstinence needs to be evaluated 
in relation to the duration of the study and the preferred and usual lifestyle of the 
participant.
* Acceptable barrier methods to be used concomitantly with options 6 or 7 for the study 
include any of the following:

Male or female condom, with or without spermicide;

Cervical cap, diaphragm, or sponge with spermicide;

A combination of male condom with either cervical cap, diaphragm, or sponge 
with spermicide (double-barrier methods).
Because ritonavir may reduce the effect of estradiol-containing contraceptives when agents 
are co-administered, a barrier method or other nonhormonal method of contraception should 
be considered if the participant is using estradiol-containing contraceptives during the 5 days 
of nirmatrelvir/ritonavir treatment and until 1 menstrual cycle after stopping 
nirmatrelvir/ritonavir.


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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 nirmatrelvir/ritonavir or study interventions of this class to 
understand treatments for the disease(s) under study or the disease(s) themselves.

The results of genetic analyses may be reported in the CSR or in a separate study 
summary, or may be used for internal decision making without being included in a 
study report.

The sponsor will store the DNA samples in a secure storage space with adequate 
measures to protect confidentiality. 

The samples will be retained as indicated:

Retained samples will be stored indefinitely or for another period as per local 
requirements. 

Participants may withdraw their consent for the storage and/or use of their Retained 
Research Samples at any time by making a request to the investigator; in this case, 
any remaining material will be destroyed. Data already generated from the samples 
will be retained to protect the integrity of existing analyses. 

Samples for genetic research will be labeled with a code. The key between the code 
and the participant’s personally identifying information (eg, name, address) will be 
held securely at the study site. 


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10.6. Appendix 6: Liver Safety: Suggested Actions and Follow-Up Assessments 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.”
LFTs are not required as a routine safety monitoring procedure in this study. However, should 
an investigator deem it necessary to assess LFTs because a participant presents with clinical 
signs/symptoms, such LFT results should be managed and followed as described below.
In the majority of DILI cases, elevations in AST and/or ALT precede T bili elevations (>2 × 
ULN) by several days or weeks. The increase in T bili typically occurs while AST/ALT is/are 
still elevated above 3 × ULN (ie, AST/ALT and T bili values will be elevated within the same 
laboratory sample). In rare instances, by the time T bili elevations are detected, AST/ALT 
values might have decreased. This occurrence is still regarded as a potential DILI. Therefore, 
abnormal elevations in either AST OR ALT in addition to T bili that meet the criteria outlined 
below are considered potential DILI (assessed per Hy’s law criteria) cases and should always 
be considered important medical events, even before all other possible causes of liver injury 
have been excluded.
The threshold of laboratory abnormalities for a potential DILI case depends on the 
participant’s individual baseline values and underlying conditions. Participants who present 
with the following laboratory abnormalities should be evaluated further as potential DILI 
(Hy’s law) cases to definitively determine the etiology of the abnormal laboratory values:

Participants with AST/ALT and T bili baseline values within the normal range who 
subsequently present with AST OR ALT values ≥3 × ULN AND a T bili value 
≥2 × ULN with no evidence of hemolysis and an alkaline phosphatase value 
<2 × ULN or not available.

For participants with baseline AST OR ALT OR T bili values above the ULN, the 
following threshold values are used in the definition mentioned above, as needed, 
depending on which values are above the ULN at baseline:

Preexisting AST or ALT baseline values above the normal range: AST or ALT 
values ≥2 times the baseline values AND ≥3 × ULN; or ≥8 × ULN (whichever is 
smaller).

Preexisting values of T bili above the normal range: T bili level increased from 
baseline value by an amount of ≥1 × ULN or if the value reaches ≥3 × ULN 
(whichever is smaller).


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Rises in AST/ALT and T bili separated by more than a few weeks should be assessed 
individually based on clinical judgment; any case where uncertainty remains as to whether it 
represents a potential Hy’s law case should be reviewed with the sponsor. 
The participant should return to the investigator site and be evaluated as soon as possible, 
preferably within 48 hours from awareness of the abnormal results. This evaluation should 
include laboratory tests, detailed history, and physical assessment.
In addition to repeating measurements of AST and ALT and T bili for suspected Hy’s law 
cases, additional laboratory tests should include albumin, CK, direct and indirect bilirubin, 
GGT, PT/INR, total bile acids, and alkaline phosphatase. Consideration should also be given 
to drawing a separate tube of clotted blood and an anticoagulated tube of blood for further 
testing, as needed, for further contemporaneous analyses at the time of the recognized initial 
abnormalities to determine etiology. A detailed history, including relevant information, such 
as review of ethanol, acetaminophen/paracetamol (either by itself or as a coformulated 
product in prescription or over-the-counter medications), recreational drug, or supplement 
(herbal) use and consumption, family history, sexual history, travel history, history of contact 
with a jaundiced person, surgery, blood transfusion, history of liver or allergic disease, and 
potential occupational exposure to chemicals, should be collected. Further testing for acute 
hepatitis A, B, C, D, and E infection, liver imaging (eg, biliary tract), and collection of serum 
samples for acetaminophen/paracetamol drug and/or protein adduct levels may be warranted. 
All cases demonstrated on repeat testing as meeting the laboratory criteria of AST/ALT and 
T bili elevation defined above should be considered potential DILI (Hy’s law) cases if no 
other reason for the LFT abnormalities has yet been found. Such potential DILI (Hy’s law) 
cases are to be reported as SAEs, irrespective of availability of all the results of the 
investigations performed to determine etiology of the LFT abnormalities.
A potential DILI (Hy’s law) case becomes a confirmed case only after all results of 
reasonable investigations have been received and have excluded an alternative etiology.


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10.7. Appendix 7: Age-Specific Kidney Function Calculation Recommendations
10.7.1. Adults (18 Years and Above)—2021 CKD-EPI Equations
eGFR (mL/min/1.73 m2)
2021 CKD-
EPI          
Scr Only
Scr
(mg/dL)
Scys
(mg/L)
Recommended eGFR Equation
Female
if ≤ 0.7
N/A
eGFR = 143 × (Scr/0.7)-0.241  ×  (0.9938)Age
Female
if > 0.7
N/A
eGFR = 143 × (Scr/0.7)-1.200  ×  (0.9938)Age
Male
if ≤ 0.9
N/A
eGFR = 142 × (Scr/0.9)-0.302  ×  (0.9938)Age
Male
if > 0.9
N/A
eGFR = 142 × (Scr/0.9)-1.200  ×  (0.9938)Age
Inker LA et al. N Engl J Med. 2021;385:1737-49 [32]. 
10.7.1.1. Adolescents (12 Years to <18 Years)—Cockcroft-Gault Formula
CrCl (mL/min) 
Males:  Cr/Cl = [(140 – age) × body weight (in kg)] / [Scr (in mg/dL) × 72]
Females: Cr/Cl = 0.85 × [(140 – age) × body weight (in kg)] / [Scr (in mg/dL) × 72]
10.7.2. Adverse Event Grading for Kidney Safety Laboratory Abnormalities
AE grading for decline in kidney function (ie, eGFR or eCrCl) will be according to KDIGO 
criteria.


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10.8. Appendix 8: Prohibited and Precautionary Concomitant Medications That May 
Result in DDI 
Nirmatrelvir and ritonavir are both primarily metabolized by CYP3A4. Therefore, 
concomitant use of any medications or substances that are strong inducers of CYP3A4 and 
that are contraindicated in combination with nirmatrelvir/ritonavir are prohibited without the 
appropriate washout prior to the first dose of study intervention.
Nonexhaustive lists of prohibited and precautionary medications are provided below in Table 
3, and Table 4 respectively. If a medication is not listed as contraindicated, it should not 
automatically be assumed it is safe to coadminister. Appropriately qualified site staff will 
review all concomitant medications to determine if they are 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 judgment on the ongoing participation of any 
participant with prohibited medication use during the study.
This list of drugs prohibited for potential DDI concerns with the study intervention 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.
Table 3 lists the drugs prohibited for use with nirmatrelvir/ritonavir, and Table 4 lists 
clinically significant (precautionary) drugs. The drugs listed in Table 3 and Table 4 are a 
guide and not considered a comprehensive list of all possible drugs that may interact with 
nirmatrelvir/ritonavir. The healthcare provider should consult appropriate references, such as 
the prescribing information for the interacting drug for comprehensive information on dosing 
or monitoring with concomitant use of a strong CYP3A inhibitor such as ritonavir.
Table 3.
Drugs That are Contraindicated With Nirmatrelvir/Ritonavir 
Drug Class 
Drugs Within 
Class
Effect on Concentration
Clinical Comments
Alpha 1-adrenoreceptor 
antagonist
alfuzosin
↑ alfuzosin
Co-administration 
contraindicated due to 
potential hypotension. 
Antianginal
ranolazine
↑ ranolazine
Co-administration 
contraindicated due to 
potential for serious and/or 
life-threatening reactions.
Antiarrhythmics
amiodarone, 
dronedarone, 
flecainide, 
propafenone, 
quinidine
↑ antiarrhythmic 
Co-administration 
contraindicated due to 
potential for cardiac 
arrhythmias.
Anticancer drugs
apalutamide
↓ nirmatrelvir/ritonavir
Co-administration 
contraindicated due to 
potential loss of virologic 


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Table 3.
Drugs That are Contraindicated With Nirmatrelvir/Ritonavir 
Drug Class 
Drugs Within 
Class
Effect on Concentration
Clinical Comments
response and possible 
resistance.
Anticonvulsants
carbamazepine,
phenobarbital,
primidone,
phenytoin
↓ nirmatrelvir/ritonavir
Co-administration 
contraindicated due to 
potential loss of virologic 
response and possible 
resistance.
Anti-gout
colchicine
↑ colchicine
Co-administration 
contraindicated due to 
potential for serious and/or 
life-threatening reactions in 
patients with renal and/or 
hepatic impairment.
Antimycobacterial
rifampin,
rifapentine
↓ nirmatrelvir/ritonavir
Co-administration 
contraindicated due to 
potential loss of virologic 
response and possible 
resistance. Alternate 
antimycobacterial drugs 
such as rifabutin should be 
considered.
Antipsychotics
lurasidone, 
pimozide
↑ lurasidone
↑ pimozide
Co-administration 
contraindicated due to 
serious and/or 
life-threatening reactions 
such as cardiac 
arrhythmias.
Benign prostatic 
hyperplasia agents
silodosin
↑ silodosin
Co-administration 
contraindicated due to 
potential for postural 
hypotension.
Cardiovascular agents
eplerenone
ivabradine
↑ eplerenone
↑ ivabradine
Co-administration with 
eplerenone is 
contraindicated due to 
potential for hyperkalemia.
Co-administration with 
ivabradine is 
contraindicated due to 
potential for
bradycardia or conduction
disturbances.
Cystic fibrosis 
transmembrane 
conductance regulator 
potentiators
lumacaftor/ivacaftor
↓ nirmatrelvir/ritonavir
Co-administration 
contraindicated due to 
potential loss of virologic 
response and possible 
resistance. 
Ergot derivatives
dihydroergotamine,
ergotamine,
methylergonovine
↑ dihydroergotamine
↑ ergotamine
↑ methylergonovine
Co-administration 
contraindicated due to 
potential for acute ergot 
toxicity characterized by 


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Table 3.
Drugs That are Contraindicated With Nirmatrelvir/Ritonavir 
Drug Class 
Drugs Within 
Class
Effect on Concentration
Clinical Comments
vasospasm and ischemia of 
the extremities and other 
tissues including the central 
nervous system.
Herbal products
St. John’s Wort 
(hypericum 
perforatum)
↓ nirmatrelvir/ritonavir
Co-administration 
contraindicated due to 
potential loss of virologic 
response and possible 
resistance.
HMG-CoA reductase 
inhibitors
lovastatin,
simvastatin
↑ lovastatin
↑ simvastatin
Co-administration 
contraindicated due to 
potential for myopathy 
including rhabdomyolysis.
Discontinue use of 
lovastatin and 
simvastatin at least 12 
hours prior to initiation of 
nirmatrelvir/ritonavir, 
during the 5 days of 
nirmatrelvir/ritonavir 
treatment, and for 5 days 
after completing 
nirmatrelvir/ritonavir.
Immunosuppressants
voclosporin
↑ voclosporin
Co-administration 
contraindicated
due to potential for acute 
and/or
chronic nephrotoxicity.
Microsomal triglyceride 
transfer protein inhibitor
lomitapide
↑ lomitapide
Co-administration 
contraindicated due to 
potential for hepatotoxicity 
and gastrointestinal adverse 
reactions.
Migraine medications
eletriptan
ubrogepant
↑ eletriptan
↑ ubrogepant
Co-administration of 
eletriptan within at least 72 
hours of 
nirmatrelvir/ritonavir is
contraindicated due to 
potential for serious 
adverse reactions including 
cardiovascular and 
cerebrovascular events.
Co-administration of 
ubrogepant with
nirmatrelvir/ritonavir is 
contraindicated due to
potential for serious 
adverse
reactions.


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Table 3.
Drugs That are Contraindicated With Nirmatrelvir/Ritonavir 
Drug Class 
Drugs Within 
Class
Effect on Concentration
Clinical Comments
Mineralocorticoid 
receptor antagonists
finerenone
↑ finerenone
Co-administration 
contraindicated due to 
potential for serious 
adverse reactions including 
hyperkalemia, hypotension, 
and hyponatremia.
Opioid antagonists
naloxegol
↑ naloxegol
Co-administration 
contraindicated due to the 
potential for opioid 
withdrawal symptoms 
Pulmonary hypertension 
agent (PDE5 inhibitor)
sildenafil 
(Revatio®) 
↑ sildenafil
Co-administration of 
sildenafil with 
nirmatrelvir/ritonavir is 
contraindicated due to the 
potential for sildenafil 
associated adverse events, 
including visual 
abnormalities, hypotension, 
prolonged erection, and 
syncope. 
Sedative/hypnotics 
triazolam, 
oral midazolam
↑ triazolam
↑ midazolam 
Co-administration 
contraindicated due to 
potential for extreme 
sedation and respiratory 
depression. 
Serotonin receptor 1A 
agonist/serotonin 
receptor 2A antagonist 
flibanserin
↑ flibanserin
Co-administration 
contraindicated due to 
potential for hypotension, 
syncope, and CNS 
depression.
Vasopressin receptor 
antagonists
tolvaptan
↑ tolvaptan
Co-administration 
contraindicated due to 
potential for dehydration, 
hypovolemia and 
hyperkalemia.
Table 4.
Established and Other Potentially Significant Drug Interactions 
Drug Class 
Drugs within Class
Effect on 
Concentration
Clinical Comments
Alpha 1-
adrenoreceptor 
antagonist
tamsulosin
↑ tamsulosin
Avoid concomitant use with 
nirmatrelvir/ritonavir.
Antiarrhythmics
lidocaine (systemic),
disopyramide
↑ antiarrhythmic
Caution is warranted and 
therapeutic concentration 
monitoring is recommended for 
antiarrhythmics if available.


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Table 4.
Established and Other Potentially Significant Drug Interactions 
Drug Class 
Drugs within Class
Effect on 
Concentration
Clinical Comments
Anticancer drugs
abemaciclib, 
ceritinib,
dasatinib, 
encorafenib,
ibrutinib, 
ivosidenib, 
neratinib, 
nilotinib, 
venetoclax,
vinblastine, 
vincristine
↑ anticancer drug
Avoid co-administration of 
encorafenib or ivosidenib due 
to potential risk of serious 
adverse events such as QT 
interval prolongation. Avoid 
use of neratinib, venetoclax or 
ibrutinib.
Co-administration of 
vincristine and vinblastine may 
lead to significant hematologic 
or gastrointestinal side effects.
For further information, refer 
to individual product label for 
anticancer drug.
Anticoagulants 
warfarin
rivaroxaban
dabigatran
apixaban
↑↓ warfarin
↑ rivaroxaban
↑ dabigatran
↑ apixaban
Closely monitor INR if 
co-administration with 
warfarin is necessary.
Increased bleeding risk with 
rivaroxaban. Avoid 
concomitant use.
Increased bleeding risk with 
dabigatran. Depending on 
dabigatran indication and renal 
function, reduce dose of 
dabigatran or avoid 
concomitant use. Refer to the 
dabigatran product label for 
further information.
Combined P-gp and strong 
CYP3A4 inhibitors increase 
blood levels of apixaban and 
increase the risk of bleeding. 
Dosing recommendations for 
co-administration of apixaban 
with nirmatrelvir/ritonavir 
depend on the apixaban dose. 
Refer to the apixaban product 
label for more information.
Anticonvulsants
clonazepam
↑ anticonvulsant
A dose decrease may be 
needed for clonazepam when 
co-administered with 
nirmatrelvir/ritonavir and 
clinical monitoring is 
recommended.


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Table 4.
Established and Other Potentially Significant Drug Interactions 
Drug Class 
Drugs within Class
Effect on 
Concentration
Clinical Comments
Antidepressants
bupropion
trazodone
↓ bupropion and 
active metabolite 
hydroxy-bupropion 
↑ trazodone
Monitor for an adequate 
clinical response to bupropion. 
Adverse reactions of nausea, 
dizziness, hypotension, and 
syncope have been observed 
following co-administration of 
trazodone and ritonavir. A 
lower dose of trazodone should 
be considered. Refer to 
trazadone product label for 
further information. 
Antifungals
voriconazole,
ketoconazole, 
isavuconazonium sulfate,
itraconazole
↓ voriconazole 
↑ ketoconazole
↑ isavuconazonium 
sulfate
↑ itraconazole
↑ 
nirmatrelvir/ritonavir 
Avoid concomitant use of 
voriconazole.
Refer to ketoconazole, 
isavuconazonium sulfate, and 
itraconazole product labels for 
further information.
A nirmatrelvir/ritonavir dose 
reduction is not needed.
Anti-HIV protease 
inhibitors
atazanavir,
darunavir,
tipranavir 
↑ protease inhibitor
For further information, refer 
to the respective protease 
inhibitors’ prescribing 
information.
Patients on ritonavir- or 
cobicistat-containing HIV 
regimens should continue their 
treatment as indicated. Monitor 
for increased 
nirmatrelvir/ritonavir or 
protease inhibitor adverse 
events.
Anti-HIV
efavirenz,
maraviroc,
nevirapine,
zidovudine,
bictegravir/
emtricitabine/ 
tenofovir
↑ efavirenz
↑ maraviroc
↑ nevirapine
↓ zidovudine
↑bictegravir
↔ emtricitabine
↑ tenofovir
For further information, refer 
to the respective anti-HIV 
drugs prescribing information.
Anti-infective
clarithromycin,
erythromycin
↑ clarithromycin
↑ erythromycin
Refer to the respective 
prescribing information for 
anti-infective dose adjustment.


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Table 4.
Established and Other Potentially Significant Drug Interactions 
Drug Class 
Drugs within Class
Effect on 
Concentration
Clinical Comments
Antimycobacterial
bedaquiline
rifabutin
↑ bedaquiline
↑ rifabutin
Refer to the bedaquiline 
product label for further 
information.
Refer to rifabutin product label 
for further information on 
rifabutin dose reduction.
Antipsychotics
quetiapine
clozapine
↑ quetiapine
↑ clozapine
If co-administration is 
necessary, reduce quetiapine 
dose and monitor for 
quetiapine-associated adverse 
reactions. Refer to the 
quetiapine prescribing 
information for
recommendations.
If co-administration is 
necessary, consider reducing 
the clozapine dose and monitor 
for adverse reactions.
Calcium channel 
blockers
amlodipine, 
diltiazem,
felodipine,
nicardipine,
nifedipine,
verapamil
↑ calcium channel 
blocker
Caution is warranted and 
clinical monitoring of patients 
is recommended. A dose 
decrease may be needed for 
these drugs when 
co-administered with 
nirmatrelvir/ritonavir.
If co-administered, refer to 
individual product label for 
calcium channel blocker for 
further information.
Cardiac glycosides
digoxin
↑ digoxin
Caution should be exercised 
when co-administering 
nirmatrelvir/ritonavir with 
digoxin, with appropriate 
monitoring of serum digoxin 
levels. 
Refer to the digoxin product 
label for further information.


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Table 4.
Established and Other Potentially Significant Drug Interactions 
Drug Class 
Drugs within Class
Effect on 
Concentration
Clinical Comments
Cardiovascular 
agents
aliskiren,
ticagrelor,
vorapaxar
clopidogrel
cilostazol
↑ aliskiren
↑ ticagrelor
↑ vorapaxar
↓ clopidogrel active 
metabolite
↑ cilostazol
Avoid concomitant use with  
nirmatrelvir/ritonavir.
Dosage adjustment of
cilostazol is recommended. 
Refer to the cilostazol product 
label for more information.
Corticosteroids 
primarily 
metabolized by 
CYP3A
betamethasone,
budesonide,
ciclesonide,
dexamethasone,
fluticasone,
methylprednisolone,
mometasone,
triamcinolone
↑ corticosteroid
Co-administration with 
corticosteroids ( all routes of 
administration) of which 
exposures are significantly 
increased by strong CYP3A 
inhibitors can increase the risk 
for Cushing’s syndrome and 
adrenal suppression.  However, 
the risk of Cushing’s syndrome 
and adrenal suppression 
associated with short-term use 
of a strong CYP3A inhibitor is 
low.
Alternative corticosteroids 
including beclomethasone, 
prednisone, and prednisolone 
should be considered.
Cystic fibrosis 
transmembrane 
conductance 
regulator 
potentiators
ivacaftor
elexacaftor/tezacaftor/
ivacaftor
tezacaftor/ivacaftor
↑ ivacaftor
↑ 
elexacaftor/tezacafto
r/ivacaftor
↑ tezacaftor/ivacaftor
Reduce dosage when co-
administered with 
nirmatrelvir/ritonavir.
Refer to individual product 
labels for further information.
Dipeptidyl 
peptidase 4 
inhibitors
saxagliptin
↑saxagliptin
Dosage adjustment of 
saxagliptin is recommended. 
Refer to the saxagliptin product 
label for more information.
Endothelin 
receptor
antagonists
bosentan
↑ bosentan
↓ 
nirmatrelvir/ritonavir
Discontinue use of bosentan at 
least 36 hours prior to initiation 
of nirmatrelvir/ritonavir. 
Refer to the bosentan product 
label for further information.
Hepatitis C direct 
acting antivirals
elbasvir/grazoprevir,
glecaprevir/pibrentasvir
↑ antiviral 
Increased grazoprevir 
concentrations can result in 
ALT elevations.


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Table 4.
Established and Other Potentially Significant Drug Interactions 
Drug Class 
Drugs within Class
Effect on 
Concentration
Clinical Comments
ombitasvir/paritaprevir/ritona
vir and dasabuvir
sofosbuvir/velpatasvir/voxila
previr
Avoid concomitant use of  
glecaprevir/pibrentasvir with 
nirmatrelvir/ritonavir. 
Refer to the 
ombitasvir/paritaprevir/ritonavi
r and dasabuvir label for 
further information.
Refer to the 
sofosbuvir/velpatasvir/voxilapr
evir product label for further 
information.
Patients on ritonavir-containing 
HCV regimens should continue 
their treatment as indicated. 
Monitor for increased 
nirmatrelvir/ritonavir or HCV 
drug adverse events with 
concomitant use.
HMG-CoA 
reductase 
inhibitors
atorvastatin,
rosuvastatin
↑ atorvastatin
↑ rosuvastatin
Consider temporary 
discontinuation of atorvastatin 
and rosuvastatin during 
treatment with 
nirmatrelvir/ritonavir. 
Atorvastatin and rosuvastatin 
do not need to be held prior to 
or after completing 
nirmatrelvir/ritonavir.
Hormonal 
contraceptive
ethinyl estradiol
↓ ethinyl estradiol
An additional, non-hormonal 
method of contraception should 
be considered during the 5 days 
of nirmatrelvir/ritonavir 
treatment and until one 
menstrual cycle after stopping 
nirmatrelvir/ritonavir.
Immunosuppressa
nts
calcineurin inhibitors:
cyclosporine,
tacrolimus
↑ cyclosporine
↑ tacrolimus
Avoid concomitant use of 
calcineurin inhibitors with 
nirmatrelvir/ritonavir when 
close monitoring of 
immunosuppressant 
concentrations is not feasible. 
If co-administered, dose 
adjustment of the 
immunosuppressant and close 
and regular monitoring for 


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Table 4.
Established and Other Potentially Significant Drug Interactions 
Drug Class 
Drugs within Class
Effect on 
Concentration
Clinical Comments
mTOR inhibitors:
everolimus,
sirolimus
↑ everolimus 
↑ sirolimus
immunosuppressant 
concentrations and adverse 
reactions are recommended 
during and after treatment with 
nirmatrelvir/ritonavir. Obtain 
expert consultation to 
appropriately manage the 
complexity of this 
coadministration..
Avoid concomitant use of 
everolinus and sirolimus and 
nirmatrelvir/ritonavir.
Refer to individual 
immunosuppressant product 
prescribing information and 
latest guidelines for further 
information.
Janus kinase 
(JAK) inhibitors
tofacitinib 
upadacitinib
↑ tofacitinib
↑ upadacitinib
Dosage adjustment of 
tofacitinib is recommended. 
Refer to the tofacitinib product 
label for more information.
Dosage recommendations for 
co-administration of 
upadacitinib with 
nirmatrelvir/ritonavir depends 
on the upadacitinib indication. 
Refer to the upadacitinib 
product label for more 
information.
Long-acting 
beta-adrenoceptor 
agonist
salmeterol
↑ salmeterol
Avoid concomitant use with 
nirmatrelvir/ritonavir. The 
combination may result in 
increased risk of cardiovascular 
adverse events associated with 
salmeterol, including QT 
prolongation, palpitations, and 
sinus tachycardia. 
Migraine 
medications
rimegepant
↑ rimegepant
Avoid concomitant use with  
nirmatrelvir/ritonavir.
Muscarinic 
receptor 
antagonists
darifenacin
↑ darifenacin
The darifenacin daily dose 
should not exceed 7.5 mg when 
co-administered with 
nirmatrelvir/ritonavir. Refer to 
the darifenacin product label 
for more information.


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Table 4.
Established and Other Potentially Significant Drug Interactions 
Drug Class 
Drugs within Class
Effect on 
Concentration
Clinical Comments
Narcotic 
analgesics
fentanyl,
hydrocodone, 
oxycodone,
meperidine
methadone
↑ fentanyl
↑ hydrocodone
↑ oxycodone
↑ meperidine
↓ methadone
Careful monitoring of 
therapeutic and adverse effects 
(including potentially fatal 
respiratory depression) is 
recommended when fentanyl, 
hydrocodone, oxycodone, or 
meperidine is concomitantly 
administered with 
nirmatrelvir/ritonavir. If 
concomitant use with 
nirmatrelvir/ritonavir is 
necessary, consider a dosage 
reduction of the narcotic 
analgesic and monitor patients 
closely at frequent intervals. 
Refer to the individual product 
label for more information. 
Monitor methadone-maintained 
patients closely for evidence of 
withdrawal effects and adjust 
the methadone dose 
accordingly.
Neuropsychiatric 
agents
suvorexant
aripiprazole,
brexpiprazole,
cariprazine,
iloperidone,
lumateperone,
pimavanserin
↑ suvorexant
↑ aripiprazole,
↑ brexpiprazole,
↑ cariprazine,
↑ iloperidone,
↑ lumateperone,
↑ pimavanserin
Avoid concomitant use of 
suvorexant with  
nirmatrelvir/ritonavir.
Dosage adjustment of 
aripiprazole, brexpiprazole, 
cariprazine, iloperidone, 
lumateperone, and 
pimavanserin is recommended. 
Refer to individual product 
label for more information.
Pulmonary 
hypertension 
agents (PDE5 
inhibitors)
Pulmonary 
hypertension 
agents (sGC 
stimulators)
tadalafil (Adcirca®)
riociguat
↑ tadalafil
↑ riociguat
Avoid concomitant use with  
nirmatrelvir/ritonavir.
Dosage adjustment is 
recommended for riociguat. 
Refer to the riociguat product 
label for more information.


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Table 4.
Established and Other Potentially Significant Drug Interactions 
Drug Class 
Drugs within Class
Effect on 
Concentration
Clinical Comments
Erectile 
dysfunction agents 
(PDE5 inhibitors)
avanafil
sildenafil,
tadalafil,
vardenafil
↑ avanafil,
↑ sildenafil,
↑ tadalafil,
↑ vardenafil
Do not use 
nirmatrelvir/ritonavir with 
avanafil because a safe and 
effective avanafil dosage 
regimen has not been 
established.  
Dosage adjustment is 
recommended for use of 
sildenafil, tadalafil, or 
vardenafil with 
nirmatrelvir/ritonavir.  Refer to 
individual product labels for 
more information.
Sedative/hypnotics
buspirone,
clorazepate,
diazepam,
estazolam,
flurazepam,
zolpidem
midazolam (administered 
parenterally)
↑sedative/hypnotic
↑ midazolam
A dose decrease may be 
needed for these drugs when 
co-administered with 
nirmatrelvir/ritonavir and 
monitoring adverse events
Co-administration of 
midazolam (parenteral) should 
be done in a setting which 
ensures close clinical 
monitoring and appropriate 
medical management in case of 
respiratory depression and/or 
prolonged sedation. Dosage 
reduction for midazolam 
should be considered, 
especially if more than a single 
dose of midazolam is 
administered. 
Refer to the midazolam 
product label for further 
information.


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10.9. Appendix 9: Country-Specific Requirements
10.9.1. 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 nirmatrelvir/ritonavir at any 
time.
10.9.2. Germany
Local HIV testing at screening will be performed for participants in Germany as required by 
the German HA (See Appendix 2).
Protocol Inclusion Criterion 1 and associated Section 10.10.1 (Age and Sex) indicate: 
Inclusion Criterion 1: Participants aged 12 years or older and weighing ≥40 kg at screening: 

Participants aged 12 years or older at the time of signing the informed consent. 
Adolescent participants below the age of 18 years (or country-specific age of 
majority) will only be enrolled if approved by the country regulatory/health authority. 
If these approvals have not been granted, only participants 18 years of age (or 
country-specific age of majority) or older at the time of signing of informed consent 
may be enrolled. 
Consistent with the EU conditional marketing authorization of nirmatrelvir/ritonavir, in 
Germany, only adult participants (≥18 years) will be enrolled in the study.


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10.10. Appendix 10: Eligibility Criteria
10.10.1. Age and Sex
Inclusion Criterion 1: Participants aged 12 years or older and weighing ≥40 kg at screening:

Participants aged 12 years or older at the time of signing the informed consent. 
Adolescent participants below the age of 18 years (or country-specific age of 
majority) will only be enrolled if approved by the country regulatory/health authority. 
If these approvals have not been granted, only participants 18 years of age (or 
country-specific age of majority) or older at the time of signing of informed consent 
may be enrolled.

Refer to Appendix 4 for reproductive criteria for female (Section 10.4.1) participants.
10.10.2. Rebound of COVID-19 Signs/Symptoms
Inclusion Criterion 2: Participants must have written documentation, such as electronic health 
record, medical record, or prescription receipt of treatment with nirmatrelvir/ritonavir (verbal 
assertion of treatment is not acceptable) with patient-reported 100% compliance (ie, 
completed a 5 day course of nirmatrelvir/ritonavir). They must have symptom alleviation or 
resolution in COVID-19 signs/symptoms followed by a worsening (rebound) of 
signs/symptoms after completing an initial 5-day course of nirmatrelvir/ritonavir based on 
the judgement of both the participant and investigator.
10.10.3. SARS-CoV-2 Infection
Inclusion Criterion 5: SARS-CoV-2 infection as determined by rapid antigen testing in any 
specimen collected within 24 hours prior to randomization and collected within 2 weeks 
(14 days) after the completion of the initial 5-day treatment course of nirmatrelvir/ritonavir.
Note: If rapid antigen testing is performed at screening and baseline, the baseline result will 
determine eligibility.
10.10.4. Risk of Developing Severe Illness from COVID-19
Inclusion Criterion 6: Has at least 1 characteristic or underlying medical condition associated 
with an increased risk of developing severe illness from COVID-19 including:

Age ≥60 years;

BMI ≥25 kg/m2 (or ≥85th percentile for pediatric participants);

Current smoker (cigarette smoking within the past 30 days) and history of at least 
100 lifetime cigarettes;

Chronic lung disease (if asthma requires daily prescribed therapy);

Diagnosis of hypertension;


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
CVD, defined as history of any of the following: myocardial infarction, TIA, stroke, 
HF, angina with prescribed nitrate, CABG, PCI, carotid endarterectomy, aortic 
bypass, peripheral arterial disease;

Congenital heart disease;

Type 1 or Type 2 diabetes mellitus;

CKD provided the participant does not meet exclusion criterion #5;

Chronic liver disease (provided the participant does not meet exclusion criterion #2); 

Sickle cell disease or thalassemia;

Dementia, neurodevelopmental disorders (eg, cerebral palsy, Down syndrome) or 
other conditions that confer medical complexity (eg, genetic or metabolic syndromes 
and severe congenital anomalies);

Active cancer, other than localized skin cancer, provided that the subject does not 
meet the exclusion criterion for being immunocompromised (Section 5.2, Exclusion 
Criterion 7);

Medical-related technological dependence (eg, CPAP [not related to COVID-19]).
Exclusion Criterion 6: 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.
10.10.5. Prior/Concomitant Therapy
Exclusion Criterion 9: Current use of any prohibited concomitant medication(s).

Current any medications that are highly dependent on CYP3A4 for clearance and 
which are contraindicated in combination with nirmatrelvir/ritonavir (see 
Appendix 8). Coadministration of nirmatrelvir/ritonavir with other medications that 
are not contraindicated but are highly dependent on CYP3A4 for clearance may 
require dose adjustment or additional monitoring (See Appendix 8 in protocol).

Use of any medications or substances that are strong inducers of CYP3A4 and that 
are contraindicated in combination with nirmatrelvir/ritonavir without the appropriate 
washout prior to the first dose of nirmatrelvir/ritonavir (see Appendix 8 in protocol). 
The appropriate washout period for CYP3A4 inducers should be determined based on 
the prescribing information for the concomitant medication and in consultation with 
the medical monitor.


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10.10.6. Other Treatments for COVID-19
Exclusion Criterion 11: Receiving other COVID-19 specific treatments within 30 days of 
randomization and through Day 34, including but not limited to COVID-19 antivirals 
(excluding a single 5-day treatment course of nirmatrelvir/ritonavir that qualifies a 
participant for eligibility), monoclonal antibodies for COVID-19.
10.10.7. Immunocompromised Criteria Details
Exclusion Criterion 7: Immunocompromised with ≥1 of the following:
1. Solid organ (eg, liver, heart, lung or kidney) transplant recipient who is receiving 
immunosuppressive therapy;
2. Receipt of CAR-T cell therapy or HCT either within 2 years of transplantation or who 
are receiving immunosuppressive therapy;
3. Moderate or severe primary immunodeficiency (eg, DiGeorge syndrome, Wiskott 
Aldrich syndrome);
4. Use of at least 1 of the following immune-weakening medications:
a.
Has received corticosteroids equivalent to prednisone ≥20 mg daily for at least 
14 consecutive days within 30 days prior to study entry.
b. Active treatment causing significant immunosuppression, including alkylating 
agents, antimetabolites, transplant-related immunosuppressive drugs, cancer 
chemotherapeutic agents, TNF blockers, or other highly immunosuppressive 
drugs (eg, ustekinumab, anti CD20).
5. Active immunosuppressive treatment for solid tumor;
6. Hematological malignancy (including leukemia, lymphoma, and myeloma);
7. Advanced or untreated HIV infection defined as CD4 cell counts <200/mm3, history 
of an AIDS-defining illness without immune reconstitution, or clinical manifestations 
of symptomatic HIV.


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10.11. Appendix 11: Participant-Reported COVID-19-Related Signs and Symptoms
Sign and Symptom Collection[33]
Eligibility Criterion #5 
Targeted (used for study 
entry)
Signs and Symptom 
Collection
Cough
X
X
Shortness of breath or difficulty breathing
X
X
Fever (documented temperature >38˚C 
[100.4˚F]) or subjective fever (eg, feeling 
feverish)
X
Feeling feverish
X
Chills or shivering
X
X
Fatigue (low energy or tiredness)
X
X
Muscle or body aches
X
X
Diarrhea (loose or watery stools)
X
X
Nausea (feeling like you wanted to throw up)
X
X
Vomiting (throw up)
X
X
Headache
X
X
Sore throat
X
X
Stuffy or runny nose
X
X
Loss of smell 
X
X
Loss of taste
X
X
  


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10.12. Appendix 12: Protocol Amendment History
Amendment 1 (16 September 2022)
Overall Rationale for the Amendment: Modifications to the estimands, primary analysis 
population, as well as a change in one of the secondary endpoints which resulted in 
additional procedures necessitated this amendment. Also included in this amendment are 
updated DDI tables, removal of RT-PCR testing as an option to determine eligibility, 
addition of a tertiary endpoint, corrections, and general editorial changes to correct 
grammatical errors, to maintain consistency, and/or to increase clarity
Section # and Name
Description of Change
Brief Rationale
Substantial or 
Nonsubstantial.
1.1 Synopsis, 3. 
OBJECTIVES, 
ENDPOINTS AND 
ESTIMANDS, 9.1.1.1 
Primary Estimand, 
9.1.1.2 Secondary 
Estimand, 9.2 Analysis 
Set and 9.3.2. Primary 
Endpoint(s)/Estimand(s) 
Analysis 2 
The population in the estimands and 
the primary analysis population was 
updated with the requirement of a 
positive rapid antigen test at baseline to 
align with the inclusion/exclusion 
criteria.
More inclusive and 
generalizable.
Substantial
1.1 Synopsis, 3. 
OBJECTIVES, 
ENDPOINTS AND 
ESTIMANDS, 9.1.1.2 
Secondary Estimands 
and 9.1.2 Multiplicity 
Adjustment
Endpoint of: ‘Proportion of 
participants with SARS-CoV-2 RNA 
in NP swabs below the LLOQ (defined 
as <2.0 log10 copies/mL) on both Days 
5 and 10’. Removed as a secondary 
endpoint and added as a 
tertiary/exploratory endpoint.
Replaced with a new 
secondary endpoint
Substantial
1.1 Synopsis, 3. 
OBJECTIVES, 
ENDPOINTS AND 
ESTIMANDS, 9.1.1.2 
Secondary Estimands, 
9.1.2 Multiplicity 
Adjustment and 9.3.3 
Secondary Endpoints
New secondary endpoint/estimand of: 
‘Time to 2 consecutive negative rapid 
antigen test results.’ Added. The 
corresponding analysis for secondary 
endpoints were updated /added with 
more details.
Based on regulatory 
feedback
Substantial
1.1 Synopsis and 9.5 
Sample Size 
Determination
Updated sample size assumptions and 
the corresponding calculation to reflect 
the change in the primary analysis 
population.
To align with the changes in 
primary analysis population 
and eligibility criteria.
Substantial
1.3. Schedule of 
Activities, 8.7.3. Rapid 
Antigen Assessments, 
and 10.10.3 SAR-CoV-
2 Infection
Amended to add self-administered 
daily rapid antigen tests for all study 
days between scheduled visits until 2 
consecutive negative rapid antigen test 
results are obtained at which point, 
rapid antigen testing will be performed 
only at remaining scheduled visits.
Necessary to support new 
secondary endpoint
Substantial
10.8 Appendix 8: 
Prohibited Concomitant 
Medications That May 
Result in DDI
Text describing Tables 4 and 5 was 
revised to clarify DDI table content. 
Tables were updated with information 
from the Fact Sheet for Healthcare 
Providers: Emergency Use 
Authorization for Paxlovid (August 
2022).
Updates to the list of 
precautionary and prohibited 
medications.
Substantial


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Section # and Name
Description of Change
Brief Rationale
Substantial or 
Nonsubstantial.
3. OBJECTIVES, 
ENDPOINTS AND 
ESTIMANDS
New tertiary endpoint of: ‘Time (days) 
to sustained resolution of all targeted 
signs and symptoms through Day 28 
where sustained resolution is defined 
as the first of two consecutive days 
when all targeted COVID-19 
symptoms are scored as absent. ‘ added
Based on regulatory 
feedback,
Nonsubstantial
1.3 Schedule of 
Activities, Section 8.7.1 
Viral RNA Assessment 
(NP Swab) and 8.7.3 
Rapid Antigen 
Assessments
Clarified in Section 8.7.1 that NP swab 
collection must occur prior to rapid 
antigen assessment, and clarified in 
SoA notes and Section 8.7.3 that rapid 
antigen testing must occur after NP 
swab collection.
To ensure that assessments 
for the primary endpoint are 
prioritized.
Nonsubstantial
4.2 Scientific Rational 
for Study Design and 
6.9 Prior and 
Concomitant Therapy
Described ritonavir as an inhibitor of 
CYP3A4 and provided guidance 
accordingly.
To provide clinical guidance 
for participants who take 
concomitant medications 
metabolized by CYP3A4.
Nonsubstantial
5.1 Inclusion Criteria 
and 10.10.3 and 
throughout the protocol
Removal of ‘confirmed’ in relation to 
SARS-CoV-2 infection
‘Confirmed’ is generally 
used in association with RT-
PCR testing which has been 
removed from the protocol 
Nonsubstantial
6.1.1 Administration
Updated timing of dose administration.
To align with dosing 
administration in other C467 
protocols.
Nonsubstantial
8.1. Administrative and 
Baseline Procedures
The total blood sampling volume 
reduced to approximately 160 mL.
More refined estimate of 
total blood volume received 
from central laboratory for 
the study.
Nonsubstantial
8.1.1.2 Secondary 
Contacts
Added that secondary contacts may be 
used to determine if a participant is lost 
to follow-up or vital status check.
To clarify utility of 
collecting secondary contact 
information.
Nonsubstantial
8.7.6.1. Plasma for 
Protein Analysis
Blood sample volume reduced to 6 mL.
More refined estimate of 
blood volume received from 
central laboratory for the 
study.
Nonsubstantial
10.1.5 Data Monitoring 
Committee
Including E-DMC monitoring of 
baseline SARS-CoV-2 RNA levels.
To ensure population is 
consistent with study design 
assumptions.
Nonsubstantial
10.2 Appendix 2: 
Clinical Laboratory 
Tests
Clarified that FSH testing if needed is 
to be performed locally.
Correction
Nonsubstantial
10.10.4. Risk of 
Developing Severe 
Illness from COVID-19
Added Age ≥60 years.
Correction
Nonsubstantial
10.4.1 Female 
Participant 
Reproductive Inclusion 
Criteria
Text updated for consistency with 
other C467 studies.
Updated to align with other 
C467 protocols
Nonsubstantial
Throughout the protocol
Remove RT-PCR
To simplify eligibility 
assessment, SARS-CoV-2 
infection will be confirmed 
by rapid antigen test only
Nonsubstantial


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Section # and Name
Description of Change
Brief Rationale
Substantial or 
Nonsubstantial.
Throughout the protocol
General editorial changes.
To correct grammatical 
errors, to maintain 
consistency, and/or to 
increase clarity.
Nonsubstantial
Amendment 2 (01 February 2023)
Overall Rationale for the Amendment: The German HA has requested for all participants 
to be enrolled in Germany to undergo HIV testing at screening. Participants who do not 
consent to the screening HIV test will not be able to participate in the study. In addition, 
consistent with the EU conditional marketing authorization of nirmatrelvir/ritonavir, this 
amendment clarifies that in Germany, only adult participants (≥18 years) will be enrolled in 
the study.
Section # and Name
Description of Change
Brief Rationale
Substantial or 
Nonsubstantial.
SoA, Table 2, Section 
10.9.2 Country 
Specific 
Requirements
HIV diagnostics at screening added to 
the laboratory assessments for 
participants in Germany.
As above. 
Nonsubstantial
Title page
Added Clinicaltrials.gov ID
The ID became available at 
the time of the protocol 
amendment.
Nonsubstantial
Multiple sections 
throughout
Minor text updates to clarify protocol 
text and correct minor errors and typos 
from previous versions.
To clarify protocol text and 
correct inadvertent errors.
Nonsubstantial


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Amendment 3 (12 May 2023)
Overall Rationale for the Amendment: The protocol was primarily amended to update the primary analysis population. Additional 
revisions are noted in the table below. 
Description of Change
Brief Rationale
Section # and Name
Substantial Modification(s)
Primary and secondary estimands and the 
mITT analysis set description have been 
updated to include that participants must 
have a positive viral RNA NP swab test 
result at baseline.
The study primary endpoint is based on change in viral SARS-CoV-2 
RNA level measured in NP swabs from Baseline to Day 5, therefore a 
quantifiable viral RNA NP swab test result at baseline is necessary to 
enable assessment of the primary endpoint.
Section 1.1 Synopsis
Section 3 Objectives, Endpoints, and Estimands
Section 9.1.1.1 Primary Estimand
Section 9.1.1.2 Secondary Estimands
Section 9.2 Analysis Sets
Sample size calculation updated.
To align with the update for primary analysis population.
Section 9.5 Sample Size Determination
Non-substantial Modification(s)
Update to text regarding viral RNA 
assessments (NP swab) and rapid antigen 
assessments. 
To align with changes introduced with Protocol Amendment 01 
(16 Sep 2022) because as noted in the Summary of Changes table 
within Protocol Amendment 01, SARS-CoV-2 infection is required to 
be confirmed by rapid antigen test only (PACL dated 03 Oct 2022).
To clarify that the Screening and Baseline (Day 1) visits are exempt 
from the protocol-directed sequencing of NP and RAT (PACL dated 
01 Nov 2022).
Section 1.3 Schedule of Activities
Section 8.7.1 Viral RNA Assessment (NP Swab)
Section 8.7.3 Rapid Antigen Assessments
Update to inform that the EMA has 
granted marketing authorization approval 
for nirmatrelvir/ritonavir.
To update the regulatory status of nirmatrelvir/ritonavir in the EU.
Section 2.3.2 Benefit Assessment
Minor editorial updates including link to 
Table 3 in Appendix 8. 
For clarification and to guide the reviewer to the correct Table in 
Appendix 8. 
Section 6.9 Prior and Concomitant Therapy
Minor editorial updates.
To correct grammatical errors, to maintain consistency, and/or to 
increase clarity, and align with the most current protocol template 
(14 Apr 2023).
Throughout the protocol, including:
Section 10.1.3.2 Informed Assent Process
Section 10.1.4 Data Protection
Section 10.1.6 Dissemination of Clinical Study Data
Section 10.1.7 Data Quality Assurance
Section 10.1.9 Study and Site Start and Closure


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Description of Change
Brief Rationale
Section # and Name
Section 10.1.10 Publication Policy
Updated text on the contraception 
requirements during the 5 days of 
nirmatrelvir/ritonavir treatment.
Updated to align with the latest version of the USPI (dated 
18 Apr 2023)
Section 10.4.3 Contraception Methods
Updated section header. Updates to 
Table 3 (Drugs That are Contraindicated 
With Nirmatrelvir/Ritonavir) and Table 4 
(Established and Other Potentially 
Significant Drug Interactions)
Updated to align with the latest version of the USPI (dated 
18 Apr 2023)
Section 10.8 Appendix 8


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10.13. Appendix 13: Abbreviations
The following is a list of abbreviations that may be used in the protocol. 
Abbreviation
Term
Abs
absolute
AE
adverse event
AKI
acute kidney injury
ALT
alanine aminotransferase
AST
aspartate aminotransferase
AxMP
auxiliary medicinal product
b-hCG
b-human chorionic gonadotropin
BP
blood pressure
CFR
Code of Federal Regulations
CIOMS
Council for International Organizations of Medical Sciences
CK
creatine kinase
CKD-EPI
chronic kidney disease epidemiology 
CO2
carbon dioxide (bicarbonate)
CONSORT
Consolidated Standards of Reporting Trials
COVID-19
coronavirus disease 2019
CRF
case report form
CRO
contract research organization
CSR
Clinical Study Report
CT
computed tomography/clinical trial
CTIS
Clinical Trial Information System
CYP
cytochrome P450
DCT
data collection tool
DDI
drug-drug interaction 
DILI
drug-induced liver injury
DU
dispensable unit
EC
ethics committee
ECC
emergency contact card
ECG
electrocardiogram or electrocardiography
eCrCl
estimated creatinine clearance
eCRF
electronic case report form
EDB
exposure during breastfeeding
E-DMC
External Data Monitoring Committee
EDP
exposure during pregnancy
eGFR
estimated glomerular filtration rate
EGFR
epidermal growth factor receptor
EMA
European Medicines Agency
EOT
end of treatment
EPIC-HR
Evaluation of Protease Inhibition for COVID-19 in High-Risk 
Patients
eSAE
electronic serious adverse event


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Abbreviation
Term
ESR
erythrocyte sedimentation rate
EU
European Union
EudraCT
European Union Drug Regulating Authorities Clinical Trials 
(European Clinical Trials Database)
FSH
follicle-stimulating hormone
GCP
Good Clinical Practice
GGT
gamma-glutamyl transferase
HA
health authority
HCP
health care professional
HIPAA
Health Insurance Portability and Accountability Act
HIV
human immunodeficiency virus
HRT
hormone replacement therapy
IB
Investigator’s Brochure
ICD
Informed Consent Document
ICH
International Council for Harmonisation of Technical Requirements 
for Pharmaceuticals for Human Use
ID
identification
IMP
investigational medicinal product
IND
Investigational New Drug
INR
international normalized ratio
IPAL
Investigational Product Accountability Log
IPM
investigational product manual
IRB
Institutional Review Board
IRT
Interactive Response Technology
JAK
Janus Kinase
KDIGO
Kidney Disease: Improving Global Outcomes
LFT
liver function test
LLOQ
lower limit of quantitation
LTFU
long-term follow up
mITT
modified intent-to-treat
MMRM
mixed model repeated measures approach
MQI
medically qualified individual
NA
not applicable
NCT
National Clinical Trial
NIMP
noninvestigational medicinal product
NOAEL
no observed adverse effect level
NP
nasopharyngeal
OP
oropharyngeal
PACL
protocol administrative change letter
PDE5
phosphodiesterase-5
P-gp
p-glycoprotein
PK
pharmacokinetic(s)
PR
pulse rate
PSSA
Pfizer’s Serious Adverse Event Submission Assistant


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Abbreviation
Term
PT
prothrombin time
QTL
quality tolerance limit
RAT
rapid antigen test
RBC
red blood cell
RNA
ribonucleic acid
RT-PCR
reverse transcription polymerase chain reaction
SAE
serious adverse event
SAP
Statistical Analysis Plan
SARS-CoV-2
severe acute respiratory syndrome coronavirus 2
SC
subcutaneous(ly)
Scr
serum creatinine
Scys
serum cystatin C
sGC
soluble guanylate cyclase
SoA
schedule of activities
SOP
standard operating procedure
SRSD
Single Reference Safety Document
SUSAR
Suspected Unexpected Serious Adverse Reaction
T
telemedicine
T bili
total bilirubin
TCID50
Median Tissue Culture Infectious Dose
ULN
upper limit of normal
US
United States
USPI
United States Prescribing Information
WBC
white blood cell
WOCBP
woman/women of childbearing potential


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11. REFERENCES
1.
Carlin AF, Clark AE, Chaillon A, et al. Virologic and Immunologic Characterization 
of COVID-19 Recrudescence after Nirmatrelvir/Ritonavir Treatment. Preprint: 18 
May 2022. Clin Infect Dis. 2022;10.1093/cid/ciac496.
2.
Gupta K. SJ, Stack G., et al. Rapid Relapse of Symptomatic SARS-CoV-2 Infection 
Following Early Suppression with Nirmatrelvir/Ritonavir. Preprint 26 Apr 2022. 
Report Number: v1. 2022. Available from: https://doi.org/10.21203/rs.3.rs-
1588371/v1.
3.
Charness M. GK, Stack G., Strymish J., Adams E., Lindy D., Mohri H., and Ho D. 
Rapid Relapse of Symptomatic Omicron SARS-CoV-2 Infection Following Early 
Suppression with Nirmatrelvir/Ritonavir. 2022. Available from: 
https://www.researchsquare.com/article/rs-1588371/v3.
4.
Julie Boucau RU, Caitlin Marino, James Regan, James P. Flynn, Manish C. 
Choudhary, Geoffrey Chen, Ashley M. Stuckwisch, Josh Mathews, May Y. Liew, 
Arshdeep Singh, Zahra Reynolds, Surabhi L. Iyer, Grace C. Chamberlin, Tammy D. 
Vyas, Jatin M. Vyas, Sarah E. Turbett, Jonathan Z. Li, Jacob E. Lemieux, Amy K. 
Barczak, Mark J. Siedner. Virologic characterization of symptom rebound following 
nirmatrelvir-ritonavir treatment for COVID-19. medRxiv. 2022.
5.
Ranganath N, O'Horo JC, Challener DW, et al. Rebound Phenomenon after 
Nirmatrelvir/Ritonavir Treatment of Coronavirus Disease-2019 in High-Risk Persons. 
Clin Infect Dis. 2022;10.1093/cid/ciac481.
6.
US Food and Drug Administration. Guidance for assessing COVID-19-related 
symptoms in outpatient adult and adolescent subjects in clinical trials of drugs and 
biological products for COVID. 2020. Available from: 
https://www.fda.gov/regulatory-information/search-fda-guidance-
documents/assessing-covid-19-related-symptoms-outpatient-adult-and-adolescent-
subjects-clinical-trials-drugs. Accessed: 29 June 2021.
7.
John Hopkins University. COVID-19 Dashboard by the Center for Systems Science 
and Engineering (CSSE) at Johns Hopkins University (JHU). Available from: 
https://coronavirus.jhu.edu/map.html. Accessed on: Jun 2020.
8.
US Food and Drug Administration. COVID-19 Vaccines. Available from: 
https://www.fda.gov/emergency-preparedness-and-response/coronavirus-disease-
2019-covid-19/covid-19-vaccines. Accessed on: 29 Jun 2021.
9.
US Food and Drug Administration. Fact sheet for healthcare providers emergency use 
authorization of PaxlovidTM. Available from: 
https://www.fda.gov/media/155050/download. Accessed: 27 July 2022.
10.
US Food and Drug Administration. Fact Sheet for Healthcare Providers: Emergency 
Use Authorization for Molnupiravir. February 2022. Available from: 
https://www.fda.gov/media/155054/download. Accessed: 22 February 2022.
11.
Veklury® (Remdesivir) Significantly Reduced Risk of Hospitalization in High-Risk 
Patients with COVID-19 Available at: https://www.gilead.com/news-and-press/press-
room/press-releases/2021/9/veklury-remdesivir-significantly-reduced-risk-of-
hospitalization-in-highrisk-patients-with-covid19 [press release]. 22 Sep 2021.
12.
Pfizer. Investigator's Brochure PF-07321332. Data on file.


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Protocol C4671042 
Final Protocol Amendment 4, 29 June 2023
PFIZER CONFIDENTIAL
CT02-GSOP Clinical Protocol Template Phase 1 2 3 4 (14 April 2023)
Page 129
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European Medicines Agency. Paxlovid (PF-07321332/ritonavir). Available from: 
https://www.ema.europa.eu/en/documents/overview/paxlovid-epar-medicine-
overview_en.pdf. Accessed: 27 Apr 2023.
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Nakajima Y, Ogai A, Furukawa K, et al. Prolonged viral shedding of SARS-CoV-2 in 
an immunocompromised patient. J Infect Chemother. 2021;27(2):387-89.
15.
Baang JH, Smith C, Mirabelli C, et al. Prolonged Severe Acute Respiratory 
Syndrome Coronavirus 2 Replication in an Immunocompromised Patient. J Infect 
Dis. 2021;223(1):23-27.
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Administration UFD. (2022). Fact Sheet For Patients, Parents, and Caregivers. 
Emergency Use Authorization (EUA) of PAXLOVID For Coronavirus Disease 2019 
(COVID-19). Available from: https://www.fda.gov/media/155051/download. 
Accessed on: March 3.
17.
Food and Drug Administration Guidance for Industry: FDA Guidance for Assessing 
COVID-19-Related Symptoms in Outpatient Adult and Adolescent Subjects in 
Clinical Trials of Drugs and Biological Products for COVID-19 Prevention or 
Treatment. [Internet]. 2020. Available from: https://www.fda.gov/regulatory-
information/search-fda-guidance-documents/assessing-covid-19-related-symptoms-
outpatient-adult-and-adolescent-subjects-clinical-trials-drugs.
18.
Ware J KM, Bjorner J, et al. Development User's Manual for the SF-36v2® Health 
Survey. QualityMetric Incorporated; 2007.
19.
US Bureau of Labor Statistics. Effects of COVID-19 Pandemic on Productivity and 
Costs Statistics. Available from: https://www.bls.gov/covid19/effects-of-covid-19-
pandemic-on-productivity-and-costs-statistics.htm. Accessed on: 08 Jun 2021.
20.
Reilly MC, Zbrozek AS, Dukes EM. The validity and reproducibility of a work 
productivity and activity impairment instrument. Pharmacoeconomics. 
1993;4(5):353-65.
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Rabin R, Gudex C, Selai C, et al. From translation to version management: a history 
and review of methods for the cultural adaptation of the EuroQol five-dimensional 
questionnaire. Value Health. 2014;17(1):70-6.
22.
van Hout B, Janssen MF, Feng YS, et al. Interim scoring for the EQ-5D-5L: mapping 
the EQ-5D-5L to EQ-5D-3L value sets. Value Health. 2012;15(5):708-15.
23.
Ramos-Goni JM, Pinto-Prades JL, Oppe M, et al. Valuation and Modeling of EQ-5D-
5L Health States Using a Hybrid Approach. Med Care. 2017;55(7):e51-e58.
24.
Yang Y, Brazier J, Longworth L. EQ-5D in skin conditions: an assessment of validity 
and responsiveness. Eur J Health Econ. 2015;16(9):927-39.
25.
Janssen MF, Pickard AS, Golicki D, et al. Measurement properties of the EQ-5D-5L 
compared to the EQ-5D-3L across eight patient groups: a multi-country study. Qual 
Life Res. 2013;22(7):1717-27.
26.
Herdman M, Gudex C, Lloyd A, et al. Development and preliminary testing of the 
new five-level version of EQ-5D (EQ-5D-5L). Qual Life Res. 2011;20(10):1727-36.
27.
Agborsangaya CB, Lahtinen M, Cooke T, et al. Comparing the EQ-5D 3L and 5L: 
measurement properties and association with chronic conditions and multimorbidity
in the general population. Health Qual Life Outcomes. 2014;12:74.
28.
EuroQol G. EuroQol--a new facility for the measurement of health-related quality of 
life. Health Policy. 1990;16(3):199-208.


Nirmatrelvir/ritonavir
Protocol C4671042 
Final Protocol Amendment 4, 29 June 2023
PFIZER CONFIDENTIAL
CT02-GSOP Clinical Protocol Template Phase 1 2 3 4 (14 April 2023)
Page 130
29.
U.S. Department of Health and Human Services NIoH, National Heart, Lung, and 
Blood Institute. A Pocket Guide to Blood Pressure Measurement in Children. May 
2007. Available from: https://www.nhlbi.nih.gov/files/docs/bp_child_pocket.pdf. 
Accessed: 16 February 2022.
30.
U.S. Department of Health and Human Services NIoH, National Institute of Allergy 
and Infectious Diseases, Division of AIDS,. Division of AIDS (DAIDS) Table for 
Grading the Severity of Adult and Pediatric Adverse Events, Corrected Version 2.1. 
July 2017. Available from: 
https://rsc.niaid.nih.gov/sites/default/files/daidsgradingcorrectedv21.pdf. Accessed: 
10 Jun 2021.
31.
Benjamini Y, & Hochberg, Y. Controlling the false discovery rate: a practical and 
powerful approach to multiple testing. . Journal of the Royal Statistical Society. 
1995;57:289–300.
32.
Inker LA, Eneanya ND, Coresh J, et al. New Creatinine- and Cystatin C-Based 
Equations to Estimate GFR without Race. N Engl J Med. 2021;385(19):1737-49.
33.
US Food and Drug Administration. Assessing COVID-19-Related Symptoms in 
Outpatient Adult and Adolescent Subjects in Clinical Trials of Drugs and Biological 
Products for COVID-19 Prevention or Treatment. 2020. Available from: 
https://www.fda.gov/regulatory-information/search-fda-guidance-
documents/assessing-covid-19-related-symptoms-outpatient-adult-and-adolescent-
subjects-clinical-trials-drugs. Accessed: 25 Mar 2021.


D o c u m e nt A p pr o v al R e c or d
D o c u m e nt N a m e:
D o c u m e nt Titl e:
Si g n e d B y:
D at e( G M T)
Si g ni n g C a p a cit y
P P D
P P D

SAP_001.pdf: 
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Protocol C4671042
AN INTERVENTIONAL, EFFICACY AND SAFETY, PHASE 2, RANDOMIZED, 
DOUBLE-BLIND, 2-ARM STUDY TO INVESTIGATE A REPEAT 5-DAY COURSE 
OF NIRMATRELVIR/RITONAVIR COMPARED TO PLACEBO/ritonavir IN 
PARTICIPANTS AT LEAST 12 YEARS OF AGE WITH REBOUND OF COVID-19 
SYMPTOMS AND RAPID ANTIGEN TEST POSITIVITY
Statistical Analysis Plan 
(SAP)
Version:
2
Date:
12 Oct  2023 


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TABLE OF CONTENTS
LIST OF TABLES.....................................................................................................................5
LIST OF FIGURES ...................................................................................................................5
APPENDICES ...........................................................................................................................5
1. VERSION HISTORY............................................................................................................6
2. INTRODUCTION .................................................................................................................7
2.1. Modifications to the Analysis Plan Described in the Protocol..................................7
2.2. Study Objectives, Endpoints, and Estimands............................................................7
2.2.1. Primary Estimand(s)...................................................................................10
2.2.2. Secondary Estimand(s)...............................................................................10
2.3. Study Design ...........................................................................................................11
2.4. Sample Size Determination.....................................................................................12
3. ENDPOINTS AND BASELINE VARIABLES:  DEFINITIONS AND 
CONVENTIONS ................................................................................................................12
3.1. Primary Endpoint(s) ................................................................................................12
3.2. Secondary Endpoint(s) ............................................................................................12
3.3. Tertiary/Exploratory Endpoint(s)............................................................................13
3.4. Baseline Variables...................................................................................................14
3.5. Safety Endpoints .....................................................................................................14
3.5.1. Adverse Events...........................................................................................14
3.5.2. Laboratory Data..........................................................................................14
3.5.3. Vital Signs ..................................................................................................15
4. ANALYSIS SETS (POPULATIONS FOR ANALYSIS)...................................................15
5. GENERAL METHODOLOGY AND CONVENTIONS....................................................16
5.1. Hypotheses and Decision Rules ..............................................................................16
5.2. General Methods .....................................................................................................16
5.2.1. Analyses for Binary Endpoints...................................................................16
5.2.2. Analyses for Continuous Endpoints ...........................................................17
5.2.3. Analyses for Categorical Endpoints ...........................................................17
5.2.4. Analyses for Time-to-Event Endpoints ......................................................17
5.3. Methods to Manage Missing Data ..........................................................................17
6. ANALYSES AND SUMMARIES ......................................................................................17


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6.1. Primary Endpoint(s) ................................................................................................17
6.1.1. Main Analysis.............................................................................................17
6.1.2. Sensitivity/Supplementary Analyses ..........................................................18
6.2. Secondary Endpoint(s) ............................................................................................18
6.2.1. Time to 2 Consecutive Negative Rapid Antigen Test Results 
Obtained at least 24(-2)h Apart through Day 28 .............................................18
6.2.2. Time (days) to Sustained Alleviation of All Targeted Signs and 
Symptoms through Day 28 ..............................................................................19
6.2.3. Incidence of Treatment Emergent Adverse Events (TEAEs); 
Incidence of SAEs and AEs Leading to Discontinuation................................20
6.3. Tertiary/Exploratory Endpoints...............................................................................20
6.3.1. Proportion of Participants with SARS-CoV-2 RNA in NP Swab 
below the LLOQ on Days 3, 5, 10, 15, 21, 28, and 34 ....................................20
6.3.2. Proportion of Participants with Sustained NP Swab SARS-CoV-2 
RNA below the LLOQ (defined as <2.0 log10 copies/mL) from Day 5 
through Day 34 ................................................................................................20
6.3.3. Proportion of Participants with SARS-CoV-2 RNA in NP Swabs 
below the LLOQ (defined as <2.0 log10 copies/mL) on both Days 5 and 
10......................................................................................................................20
6.3.4. Change in SARS-CoV-2 RNA Level in NP Swabs from Baseline to 
Days 3, 10, 15, 21, 28, and 34..........................................................................20
6.3.5. Time to Sustained NP Swab SARS-CoV-2 RNA below the LLOQ 
(defined as <2.0 log10 copies/mL) and Remains below the LLOQ 
through Day 34 for Participants with NP Swab SARS-CoV-2 RNA 
Greater than or Equal to the LLOQ at Baseline...............................................21
6.3.6. Rebound in SARS-CoV-2 RNA Level in NP Swabs at Follow-up ie, 
Any Study Visit from Day 10 to through Day 34, Defined as a Half 
(0.5) Log10 Copies/mL Increase or Greater in SARS-CoV-2 RNA Level 
Relative to SARS-CoV-2 RNA Level on Day 5 and with a Follow-up 
Viral RNA Level ≥2.5 Log10 Copies/mL.......................................................22
6.3.7. Endpoints Related to Infectious Titer.........................................................22
6.3.8. Change from Baseline in SARS-CoV-2 Viral RNA Level in Plasma, 
Over Time........................................................................................................23
6.3.9. Proportion of Participants with COVID-19-related Hospitalization 
>24h or Death from Any Cause through Day 28.............................................23
6.3.10. Number of COVID-19-related Medical Visits through Day 34 ...............23


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6.3.11. Time (days) to Sustained Resolution of All Targeted Signs and 
Symptoms through Day 28 ..............................................................................23
6.3.12. Other analyses...........................................................................................24
6.4. Subset Analyses.......................................................................................................24
6.5. Baseline and Other Summaries and Analyses.........................................................24
6.5.1. Baseline and Other Characteristics Summaries..........................................24
6.5.2. Study Conduct and Participant Disposition................................................25
6.5.3. Study Treatment Exposure .........................................................................25
6.5.4. Prior and Concomitant Medications...........................................................25
6.6. Safety Summaries and Analyses .............................................................................25
6.6.1. Adverse Events...........................................................................................25
6.6.2. Laboratory Data..........................................................................................25
6.6.3. Vital Signs ..................................................................................................26
7. INTERIM ANALYSES.......................................................................................................26
7.1. Interim Analyses and Summaries............................................................................26
7.2. Data Monitoring Committee ...................................................................................26
8. REFERENCES ....................................................................................................................27
APPENDICES .........................................................................................................................28


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LIST OF TABLES
Table 1.
Summary of Changes..................................................................................6
LIST OF FIGURES
Figure 1.
Study Schema ...........................................................................................12
APPENDICES
Appendix 1. Summary of Efficacy Analyses...........................................................................28
Appendix 2. Data Derivation Details.......................................................................................33
Appendix 2.1. Definition and Use of Visit Windows in Reporting.........................................33
Appendix 3. List of Abbreviations...........................................................................................35
Appendix 4. Participant-Reported COVID-19-Related Signs and Symptoms........................36


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1. VERSION HISTORY
Table 1.
Summary of Changes
Version/
Date
Associated 
Protocol 
Amendment
Rationale
Specific Changes
Version 1/
30 Sep 2022
Protocol 
amendment 1
16 Sep 2022
Original SAP
N/A
Version 2/
12 Oct 2023
Protocol 
amendment 4
29 Jun 2023
Protocol 
amendment 4
changes, 
regulatory 
feedback and 
other  
clarification

Updated the analysis populations in 
Section 2.2, 4, 5.1, 6.1, 6.2 and 6.3 for
primary, secondary and relevant 
tertiary/exploratory
obejective/estimand/endpoints to align 
with protocol change.

Updated Section 2.4 sample size to align 
with protocol change.

Added site exclusion for efficacy related 
analysis sets in Section 4. 

Added secondary analyses for primary and 
sencondary endpoints in Section 6.1 and 
6.2 to align with protocol change. Updated 
the multiplicity adjustment acordingly in 
Section 5.1.

Removed the analysis details for infectious 
titer by TCID50 and by virus recovery in 
Section 3.4, 4 and 6.3.  These analyses will 
be specified in virology analysis plan. 

Add analysis details for potential 
covariates in Section 6.2.1 and 6.2.2 

Added analysis details for time to 
sustained NP Swab SARS-CoV-2 RNA 
below the LLOQ in Section 6.3.5.

Added two alternative definitions/analyses
of rebound in Section 6.3.6.

Added other analysis for the concordance 
of rapid antigen and RT-PCR test results in 
Section 6.3.12.

Added additional subgroups analyses in 
Sectoin 6.4.

Updated Appendix 1 to align with the 
analysis updates/changes in SAP main 
body.

Updated the handling of multiple 
measurements on the same day for lab data 
in Appendix 2.1.


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Table 1.
Summary of Changes
Version/
Date
Associated 
Protocol 
Amendment
Rationale
Specific Changes

Added Appendix 4 for Participant-
Reported COVID-19-Related Signs and 
Symptoms

Editorial change throughout the document.
2. INTRODUCTION
Nirmatrelvir, a potent and selective SARS-CoV-2 3CL orally administered protease inhibitor, 
is being investigated in participants with rebound of COVID-19 symptoms and rapid antigen 
test positivity.
The purpose of this study is to evaluate the efficacy, safety and tolerability of a second 5-day 
treatment course of nirmatrelvir/ritonavir in participants with a rebound in COVID-19 
symptoms and a positive rapid antigen test within 2 weeks (14 days) following completion of 
an initial 5-day treatment course.
This statistical analysis plan (SAP) provides the detailed methodology for summary and 
statistical analyses of the data collected in Study C4671042.  
2.1. Modifications to the Analysis Plan Described in the Protocol
Not Applicable.
2.2. Study Objectives, Endpoints, and Estimands
Objectives
Endpoints
Estimands
Primary: 
Primary:
Primary: 

To compare the effect of 
nirmatrelvir/ritonavir to 
placebo/ritonavir on viral 
RNA level in NP swabs in 
participants with mild-to-
moderate COVID-19.
The change in viral SARS-CoV-2 
RNA level as measured in NP 
swabs from baseline to Day 5.

The difference in mean change of 
SARS-CoV-2 RNA level in NP swabs 
from baseline to Day 5 between 
nirmatrelvir/ritonavir and 
placebo/ritonavir group in participants 
with a rebound in COVID-19 
symptoms and a positive rapid antigen 
test within 2 weeks following 
completion of an initial 5-day 
treatment course ,who have a positive 
viral RNA NP swab test result at 
baseline. This will be estimated 
without regard to study treatment 
discontinuation and without regard to 
prohibited therapies.


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Objectives
Endpoints
Estimands
Secondary: 
Secondary:
Secondary: 

To compare the effect of 
nirmatrelvir/ritonavir to 
placebo/ritonavir on the 
duration of viral shedding.
Time to 2 consecutive negative 
rapid antigen test results obtained 
at least 24 (-2) h apart through 
Day 28.

The hazard ratio for time to 
2 consecutive negative rapid antigen 
test results obtained at least 24 (-2) h 
apart through Day 28 between 
nirmatrelvir/ritonavir and 
placebo/ritonavir group in participants 
with rebound in COVID-19 symptoms 
and a positive rapid antigen test within 
2 weeks following completion of an 
initial 5-day treatment course, who 
have a positive viral RNA NP swab
test result at baseline. This will be 
estimated without regard to study 
treatment discontinuation and without 
regard to prohibited therapies.

To compare the effect of 
nirmatrelvir/ritonavir to 
placebo/ritonavir on the 
duration and severity of signs 
and symptoms in participants 
with mild-to-moderate 
COVID-19. 
Time (days) to sustained 
alleviation of all targeted signs and 
symptoms through Day 28 where 
sustained alleviation is defined as 
the first of 2 consecutive days 
when any symptoms scored as 
moderate or severe at baseline are 
scored as mild or absent and any 
symptoms scored as mild or absent 
at baseline are scored as absent.

The hazard ratio for time to sustained 
alleviation of all targeted signs and 
symptoms through Day 28 between 
nirmatrelvir/ritonavir and 
placebo/ritonavir group in participants 
with rebound in COVID-19 symptoms 
and a positive rapid antigen test within 
2 weeks following completion of an 
initial 5-day treatment course, who 
have a positive viral RNA NP swab
test result at baseline. This will be 
estimated without regard to study 
treatment discontinuation and without 
regard to prohibited therapies.

To describe the safety and 
tolerability of 
nirmatrelvir/ritonavir in 
participants with mild-to-
moderate COVID-19.
Incidence of TEAEs. Incidence of 
SAEs and AEs leading to 
discontinuation.

Not applicable.
Tertiary/Exploratory:
Tertiary/Exploratory:
Tertiary/Exploratory:

To compare the effect of 
nirmatrelvir/ritonavir to 
placebo/ritonavir on viral 
RNA level in NP swabs in 
participants with mild-to-
moderate COVID-19.
Proportion of participants with 
SARS-CoV-2 RNA in NP swab 
below the LLOQ on Days 3, 5, 10, 
15, 21, 28, and 34.
Proportion of participants with 
sustained NP swab SARS-CoV-2 
RNA below the LLOQ (defined as 
<2.0 log10 copies/mL) from Day 5 
through Day 34.
Proportion of participants with 
SARS-CoV-2 RNA in NP swabs 
below the LLOQ (defined as 

Not applicable.


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Objectives
Endpoints
Estimands
<2.0 log10 copies/mL) on both 
Days 5 and 10.
The change in SARS-CoV-2 RNA 
level in NP swabs from baseline to 
Days 3, 10, 15, 21, 28, and 34.
Time to sustained NP swab 
SARS-CoV-2 RNA below the 
LLOQ (defined as <2.0 log10
copies/mL) and remains below the 
LLOQ through Day 34 for 
participants with NP swab 
SARS-CoV-2 RNA greater than or 
equal to the LLOQ at baseline.
Rebound in SARS-CoV-2 RNA 
level in NP swabs at follow-up 
(ie, any study visit from Day 10 to 
through Day 34, defined as a half 
(0.5) log10 copies/mL increase or 
greater in SARS-CoV-2 RNA 
level relative to SARS-CoV-2 
RNA level on Day 5 and with a 
follow-up viral RNA level 
≥2.5 log10 copies/mL.

To compare the effect of 
nirmatrelvir/ritonavir on the 
rate of cell culture infectious 
virus over time in participants 
with mild-to-moderate 
COVID-19
In participants with detectable viral 
titers at baseline by TCID50:
Time to negative infectious titer 
by TCID50.
Change in TCID50 from baseline 
to Days 3, 5, 10, 15, 21, 28, and 
34.
Proportion of participants with 
negative infectious titer by 
TCID50 on Days 3, 5, 10, 15, 21, 
28, and 34.
In participants with positive viral titers 
at baseline by virus recovery:

Time to negative infectious titer 
by virus recovery.

Proportion of participants with 
negative infectious titer by virus 
recovery on Days 3, 5, 10, 15, 21, 
28, and 34.

Not applicable

To compare the effect of 
nirmatrelvir/ritonavir to 
placebo/ritonavir on viral 
concentration in plasma in 
participants with mild-to-
moderate COVID-19.
Change from baseline in SARS-
CoV-2 viral RNA level in plasma, 
over time.

Not applicable.


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Objectives
Endpoints
Estimands

To compare the effect of 
nirmatrelvir/ritonavir to 
placebo/ritonavir on COVID-
19-related hospitalization and 
all-cause mortality in 
participants with mild-to-
moderate COVID-19.
Proportion of participants with 
COVID-19-related hospitalization 
>24h or death from any cause 
through Day 28.

Not applicable.

To compare the effect of 
nirmatrelvir/ritonavir to 
placebo/ritonavir on COVID-
19-related healthcare resource 
utilization in participants with 
mild-to-moderate COVID-19.
Number of COVID-19-related 
medical visits through Day 34.

Not applicable.

To compare the effect of 
nirmatrelvir/ritonavir to 
placebo/ritonavir on the 
duration and severity of signs 
and symptoms in participants 
with mild-to-moderate 
COVID-19.
Time (days) to sustained 
resolution of all targeted signs and 
symptoms through Day 28 where 
sustained resolution is defined as 
the first of two consecutive days 
when all targeted COVID-19 
symptoms are scored as absent.  

Not applicable
2.2.1. Primary Estimand(s)
The primary estimand is the difference in mean change of SARS-CoV-2 RNA level in NP 
swabs from baseline to Day 5 between nirmatrelvir/ritonavir and placebo/ritonavir group in 
patients with a rebound in COVID-19 symptoms and a positive rapid antigen test within 
2 weeks following completion of an initial 5-day treatment course, who have a positive viral 
RNA NP swab test result at baseline. This will be estimated without regard to study treatment 
discontinuation and without regard to prohibited therapies.
2.2.2. Secondary Estimand(s)
Estimands for the secondary endpoints are:

The hazard ratio for time to 2 consecutive negative rapid antigen test results obtained 
at least 24 (-2) h apart through Day 28 between nirmatrelvir/ritonavir and 
placebo/ritonavir group in participants with rebound in COVID-19 symptoms and a 
positive rapid antigen test within 2 weeks following completion of an initial 5-day 
treatment course, who have a positive viral RNA NP swabtest result at baseline. This 
will be estimated without regard to study treatment discontinuation and without 
regard to prohibited therapies.

The hazard ratio for time to sustained alleviation of all targeted signs and symptoms 
through Day 28 between nirmatrelvir/ritonavir and placebo/ritonavir group in 
participants with rebound in COVID-19 symptoms and a positive rapid antigen test 
within 2 weeks following completion of an initial 5-day treatment course, who have a 
positive viral RNA NP swabtest result at baseline. This will be estimated without 
regard to study treatment discontinuation and without regard to prohibited therapies.


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2.3. Study Design
This Phase 2, randomized, double-blind, placebo-controlled study will evaluate the efficacy 
and safety of a repeat 5-day treatment course of nirmatrelvir/ritonavir or placebo/ritonavir for 
the treatment of mild-to-moderate COVID-19. Participants must have written documentation, 
such as an electronic health record, medical record, or prescription receipt of treatment with 
nirmatrelvir/ritonavir (verbal assertion of treatment is not acceptable) with patient-reported 
100% compliance (ie, completed a 5 day course of nirmatrelvir/ritonavir). They must have 
experienced alleviation or resolution in COVID-19 signs/symptoms followed by a worsening 
(rebound) of signs/symptoms along with a positive rapid antigen test after completing an 
initial 5-day course of nirmatrelvir/ritonavir. 
The onset of rebound in COVID-19 symptoms along with evidence of SARS-CoV-2 
infection must occur within 2 weeks (14 days) after completion of an initial 5-day course of 
nirmatrelvir/ritonavir. A 2-week time-period for rebound symptoms and SARS-CoV-2 
infection was selected to enroll a population that has a presumptive recurrence of the same 
viral illness and not a new SARS-CoV-2 infection. Symptom burden including alleviation, 
resolution and worsening (rebound) to qualify for the study is based on the judgment of both
the participant along with investigator judgment.
Eligible participants for this study will be randomly assigned (2:1 allocation of active to 
placebo) to receive:

nirmatrelvir plus ritonavir orally q12h for 5 days; or

placebo plus ritonavir orally q12h for 5 days.
Randomization will be stratified by geographic region. 
Participants will be screened within 24 hours before randomization.  
Participants must be randomized within 48 hours from the onset of the rebound COVID-19 
symptoms and must be randomized within 24 hours of a positive baseline rapid antigen test. 
The total study duration is up to 24 weeks, including study intervention administration 
through Day 5 or Day 6, efficacy and safety assessments through Day 34, and long-term 
follow up at Weeks 12 and 24. 
Participants are eligible if they are at least 12 years of age (and weigh ≥40 kg at screening) 
and they must have at least 1 characteristic or underlying medical condition associated with 
an increased risk of developing severe illness from COVID-19. However, participants who 
are immunocompromised are excluded from this study as they may have prolonged viral 
shedding due to their immunocompromised state. Participants will be eligible for enrollment 
irrespective of COVID-19 vaccination/boosted status (except for time course restrictions 
listed in the exclusion criteria).
An independent E-DMC will review unblinded data to ensure the safety of participants on an 
ongoing basis throughout the duration of the study.


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The study schematic is provided in Figure 1.
Figure 1.
Study Schema
2.4. Sample Size Determination
The study will enroll approximately 411 participants.
The sample size calculation is based on the primary efficacy endpoint as the change in viral 
RNA level from baseline to Day 5 as measured in NP swabs in the mITT analysis set. 
Assuming a SD of 1.8 (based on EPIC-HR, NCT04960202), a sample size of approximately 
315 evaluable participants (210 participants in nirmatrelvir/ritonavir group and 105 
participants in placebo/ritonavir group) is expected to provide 90% power to detect a 
difference of 0.7 log10 copies/mL in viral RNA between groups using a 2-sided 0.05 alpha 
level test. Assuming approximately 10% of participants will have a negative viral RNA result 
at baseline, and assuming a non-evaluable rate of 15%, approximately 411 participants will 
be randomized in the study to achieve approximately 315 participants evaluable for the 
primary efficacy endpoint. 
3. ENDPOINTS AND BASELINE VARIABLES: DEFINITIONS AND 
CONVENTIONS
3.1. Primary Endpoint(s)

The primary endpoint is the change in viral SARS-CoV-2 RNA level as measured in 
NP swabs from baseline to Day 5.
3.2. Secondary Endpoint(s)

Time to 2 consecutive negative rapid antigen test results obtained at least 24 (-2) h 
apart through Day 28.


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
Time (days) to sustained alleviation of all targeted signs and symptoms through 
Day 28 where sustained alleviation is defined as the first of 2 consecutive days when 
any symptoms scored as moderate or severe at baseline are scored as mild or absent 
and any symptoms scored as mild or absent at baseline are scored as absent.

Incidence of TEAEs. Incidence of SAEs and AEs leading to discontinuation.
3.3. Tertiary/Exploratory Endpoint(s)

Proportion of participants with SARS-CoV-2 RNA in NP swab below the LLOQ on 
Days 3, 5, 10, 15, 21, 28, and 34.

Proportion of participants with sustained NP swab SARS-CoV-2 RNA below the 
LLOQ (defined as <2.0 log10 copies/mL) from Day 5 through Day 34.

Proportion of participants with SARS-CoV-2 RNA in NP swabs below the LLOQ 
(defined as <2.0 log10 copies/mL) on both Days 5 and 10.

The change in SARS-CoV-2 RNA level in NP swabs from baseline to Days 3, 10, 15, 
21, 28, and 34.

Time to sustained NP swab SARS-CoV-2 RNA below the LLOQ (defined as 
<2.0 log10 copies/mL) and remains below the LLOQ through Day 34 for participants 
with NP swab SARS-CoV-2 RNA greater than or equal to the LLOQ at baseline.

Rebound in SARS-CoV-2 RNA level in NP swabs at follow-up (ie, any study visit 
from Day 10 to through Day 34, defined as a half (0.5) log10 copies/mL increase or 
greater in SARS-CoV-2 RNA level relative to SARS-CoV-2 RNA level on Day 5 and 
with a follow-up viral RNA level ≥2.5 log10 copies/mL.

Time to negative infectious titer by TCID50 in participants with detectable viral titers 
at baseline by TCID50.

Change in TCID50 from baseline to Days 3, 5, 10, 15, 21, 28, and 34 in participants 
with detectable viral titers at baseline by TCID50.

Proportion of participants with negative infectious titer by TCID50 on Days 3, 5, 10, 
15, 21, 28, and 34 in participants with detectable viral titers at baseline by TCID50.

Time to negative infectious titer by virus recovery in participants with positive viral 
titers at baseline by virus recovery.

Proportion of participants with negative infectious titer by virus recovery on Days 3, 
5, 10, 15, 21, 28, and 34 in participants with positive viral titers at baseline by virus 
recovery.


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
Change from baseline in SARS-CoV-2 viral RNA level in plasma, over time.

Proportion of participants with COVID-19-related hospitalization >24h or death from 
any cause through Day 28.

Number of COVID-19-related medical visits through Day 34.

Time (days) to sustained resolution of all targeted signs and symptoms through 
Day 28 where sustained resolution is defined as the first of two consecutive days 
when all targeted COVID-19 symptoms are scored as absent.  
3.4. Baseline Variables
Baseline visit (Day 1) will be defined as the latest measurement between Day -1 and Day 1.
For viral load data from NP swabs, viral load data from plasma samples, the baseline window 
will be Day -1 to Day 1, but post-dose samples that are collected within 1 hour post start of 
dosing will be treated as baseline.
For vital signs, signs and symptoms, and laboratory assessments, the baseline window will be 
Day -1 to Day 1, without any consideration to the time factor.  
3.5. 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.
3.5.1. 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 AE is considered a treatment-emergent adverse
event (TEAE) if the event started on or after the study medication start date and time.
3.5.2. Laboratory Data
Laboratory data includes hematology, chemistry, and other safety tests. To determine if there 
are any clinically significant laboratory abnormalities, the hematological and chemistry and 
other safety tests will be assessed against the criteria specified in the Pfizer reporting 
standards. This assessment will take into account whether each participant’s baseline test 
results are within or outside the laboratory reference range for particular laboratory
parameter.


Pr ot oc ol C 4 6 7 1 0 4 2 (P F -0 7 3 2 1 3 3 2 ) Statistical A nal ysis Pl a n
D M B 0 2 -G S O P -R F 0 2 7. 0 St atistic al A n alysis Pl a n Te m pl ate 3 1 -Ja n-2 0 2 2
P FI Z E R C O N FI D E N TI A L
T M F D oc I D: 9 8. 0 3
Pa ge 1 5 of 3 6
3. 5. 3. Vit al Si g ns
Vital si g n meas ure me nts , i ncl u di n g te m perat ure, p ulse rate, res pirat or y rate, o x yge n 
sat urati o n le vel, a n d bl o o d press ure .
4. A N A L Y SI S S E T S ( P O P U L A TI O N S F O R A N A L Y SI S )
D ata f or all partici pa nts will be assesse d t o deter mi ne if partici pa nts meet t he criteria f or 
i ncl usi o n i n eac h a nalys is p o p ulati o n pri or t o u n bli n di n g a n d releasi n g t he data base a n d 
classificati o ns will be d oc u me nte d per sta n dar d o perati n g pr oce d ures.
P o p ul ati o n
Descri pti o n
F ull a nal ys is set ( F A S)
All partici pa nts ra n d o ml y  assi g ne d t o st u d y i nter ve nti o n. 
Safet y  a nalys is set 
( S A S)
All partici pa nts ra n d o ml y  assi g ne d t o st u d y i nter ve nti o n a n d w h o 
ta ke at least 1 d ose of st u d y i nter ve nti o n. 
Partici pa nts will be a nal yze d acc or di n g t o t he st u d y i nter ve nti o n 
t he y recei ve d.
mI T T
All partici pa nts ra n d o ml y  assi g ne d t o st u d y i nter ve nti o n w h o ta ke 
at least 1 d ose of st u d y i nter ve nti o n a n d w h o ha ve a p ositi ve viral 
R N A N P s wa b test res ult (≥ 2. 0 l o g1 0 c o pies/ m L) at baseli ne.
Partici pa nts will be a nal yze d acc or di n g t o t he st u d y i nter ve n ti o n 
t he y were ra n d o mize d.
Per pr ot oc ol ( P P)
All partici pa nts i n t he mI T T a nal ys is set wit h o ut i m p orta nt 
pr ot oc ol de viati o ns c o nsi dere d t o i m pact t he i nter pretati o n of t he 
pri mar y  efficac y e n d p oi nt. Pr ot oc ol de viati o ns will be re vie we d t o 
ge nerate t he lis t of partici pa nts wit h si g nifica nt de viati o ns t o be 
e xcl u de d fr o m t he P P a nal ysis set. T he P P e xcl usi o n criteria will 
be fi nalize d pri or t o brea ki n g t he bli n d.
mI T T 1
All partici pa nts ra n d o ml y  assi g ne d t o st u d y i nter ve nti o n w h o ta ke 
at least 1 d ose of st u d y i nter ve nti o n a n d w h o ha ve a p ositi ve ra pi d 
a nti ge n test res ult at baseli ne.
Partici pa nts will be a nal yze d acc or di n g t o t he st u d y i nter ve nti o n 
t he y were ra n d o mize d.
T he pri mar y  a nalys is set f or efficac y will be t he mI T T. m T T 1 will be use d f or rele va nt 
efficac y en d p oi nts . Safet y  A nal ysis Set ( S A S) will be use d i n t he a nalys es of t he safet y data.
A ll partici pa nts fr o m 
will be e xcl u de d fr o m t he efficac y a nal yses d ue t o G C P 
iss ues.   
C CI


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5. GENERAL METHODOLOGY AND CONVENTIONS
5.1. Hypotheses and Decision Rules
The primary hypothesis is to test whether or not there is a difference in mean change of viral 
RNA level in NP swabs from baseline to Day 5 between nirmatrelvir/ritonavir and the 
placebo/ritonavir group:
Null hypothesis:  H0    	
/
	 −/ = 0           
Alternative hypothesis: Ha    	
/
	 −/ ≠0          
Where µnirmatrelvir/ritonavir and µplacebo/ritonavir are mean change of viral RNA level
(log10 copies/mL) in NP swabs from baseline to Day 5 for nirmatrelvir/ritonavir and 
placebo/ritonavir groups.
The overall Type I error rate across the primary and key secondary efficacy endpoints will be 
controlled at alpha = 0.05. Following the positive test of the primary efficacy endpoint in the 
primary analysis set (mITT), the secondary analysis for the primary efficacy endpoint using 
the mITT1 analysis set will be tested. 
Following the positive test of the secondary analysis,, the following key secondary efficacy 
endpoints will be tested using Hochberg method:1

Time to 2 consecutive negative rapid antigen test results obtained at least 24 (-2)h 
apart through Day 28 in the mITT analysis set.

Time (days) to sustained alleviation of all targeted signs and symptoms through 
Day 28 where sustained alleviation is defined as the first of two consecutive days 
when any symptoms scored as moderate or severe at baseline are scored as mild or 
absent and any symptoms scored as mild or absent at baseline are scored as absent in 
the mITT analysis set.
5.2. General Methods
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 and qualitative variables will be summarized by frequency tables with 
number and proportion in each category. 
5.2.1. Analyses for Binary Endpoints
For binary endpoints, the proportion of participants with the event will be summarized for 
each group. Where appropriate, logistic regression will be utilized to estimate the odds ratio 
and its corresponding 95% confidence interval. 


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5.2.2. Analyses for Continuous Endpoints
For continuous endpoints, descriptive statistics will be provided by treatment group. Where 
appropriate, analysis of covariance (ANCOVA) or mixed model for repeated measures 
(MMRM) analysis will be utilized.
5.2.3. Analyses for Categorical Endpoints
For categorical endpoints, the number and proportion of participants for each category will 
be summarized for treatment group. 
5.2.4. Analyses for Time-to-Event Endpoints
For time-to-event endpoints, a Cox proportional hazard regression model will be performed 
and the estimate of the hazard ratio, its confidence interval and p-value will be provided. In 
addition, time-to-event endpoints will be summarized graphically using Kaplan-Meier plots 
for each treatment group.
5.3. Methods to Manage Missing Data
Missing viral load will not be imputed in general. MMRM will be used to analyze viral load 
data to handle Missing at Random (MAR), and it allows for inclusion of participants with 
partial longitudinal data in the analysis.
For safety data, missing and partial dates will be programmatically handled according to
Pfizer standards.
6. ANALYSES AND SUMMARIES
6.1. Primary Endpoint(s)
The primary efficacy endpoint is the change in viral SARS-CoV-2 RNA level from baseline 
to Day 5 as measured in NP swabs.
6.1.1. Main Analysis
The primary analysis for mean change in SARS-CoV-2 RNA level from baseline will be 
performed using a MMRM. The analysis will include the fixed effects of treatment, 
geographic region, baseline viral RNA level, visit, and treatment-by-visit interaction. An 
unstructured (co)variance structure will be used to model the within-participant variability. 
The LS means and treatment difference for each visit will be calculated and presented with 
their corresponding 95% CIs. The primary comparison for treatment effect will be the 
difference in LS means and 95% CI at Day 5. The primary analysis will be performed using 
mITT analysis set.
The secondary analysis for primary endpoint will be performed using the mITT1 analysis set.
In the analysis, samples with result “<LLOQ” will be imputed as 1.7 log10 copies/mL, and 
samples with result “undetectable” will be imputed as 0.0 log10 copies/mL.


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6.1.2. Sensitivity/Supplementary Analyses
Supplementary Analysis:

A supplementary analysis of the primary endpoint will be conducted using MMRM in 
PP analysis set.
6.2. Secondary Endpoint(s)
6.2.1. Time to 2 Consecutive Negative Rapid Antigen Test Results Obtained at least 
24(-2)h Apart through Day 28
The event of 2 consecutive negative rapid antigen test results obtained at least 24(-2)h apart 
through Day 28 is defined as achieving two consecutive non-missing rapid antigen test with 
negative results through Day 28, where the two tests are at least 22 hours and at most 7 days 
apart. For the event of 2 consecutive negative rapid antigen test results obtained at least 
24(-2)h apart through Day 28, the date of the first negative rapid antigen test result will be 
considered the First Event Date.
Time to 2 consecutive negative rapid antigen test results obtained at least 24(-2)h apart for 
the purpose of this study is defined as:

For a participant achieving the event, time to event will be calculated as (First Event 
Date) – (First Dose Date) +1.

For a participant not achieving the event (censored), censoring date will be at the last 
date of rapid antigen test measurement, and time will be calculated as (Censoring 
Date) – (First Dose Date) +1 or Day 27 whichever occurs first (Day 27 is the last 
possible day to achieve 2 consecutive negative rapid antigen test results obtained at 
least 24(-2)h apart through Day 28).
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 the event and will be censored at 
Day 27.
Cox proportional hazard model analyses will be used for time to 2 consecutive negative rapid 
antigen test results obtained at least 24(-2)h apart in mITT analysis set. Cox proportional 
hazard model will include treatment, geographic region, baseline viral load (< 4 or ≥ 4) and
time since the last vaccination (≤6 months, > 6 months or unvaccinated) as appropriate. The 
treatment group comparison will be presented as the estimate of the hazard ratio, 95% CI and 
p-value. In addition, time to 2 consecutive negative rapid antigen test results obtained at least 
24(-2)h apart will be summarized graphically using Kaplan-Meier plots for each of the 
treatment groups in mITT analysis set. 
The log-rank test will be performed as additional analysis to compare the treatment group 
using mITT analysis set.


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Similar analyses for time to 2 consecutive negative rapid antigen test results obtained at least 
24(-2)h apart will also be performed in the mITT1 analysis set.
6.2.2. Time (days) to Sustained Alleviation of All Targeted Signs and Symptoms 
through Day 28
Sustained alleviation of all targeted COVID-19 signs/symptoms is defined as the event 
occurring on the first of 2 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 2 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 (missing severity at baseline will be treated as 
mild).
Day 27 is the last possible day that symptom alleviation can be achieved (definition includes 
data from the subsequent day) and Day 28 is the last day participants report their daily signs 
and symptoms.
The time to sustained symptom alleviation for the purpose of this study is defined as:

For a participant with sustained symptom alleviation, 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(censored), censoring date 
will be at the last date on which symptom alleviation is assessed, and time will be 
calculated as (Censoring Date) – (First Dose Date) +1 or Day 27 whichever occurs 
first.
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 
and will be censored at Day 27.
Cox proportional hazard model analyses will be used for time to sustained symptom 
alleviation in mITT analysis set. Cox proportional hazard model will include treatment, 
geographic region baseline viral load (< 4 or ≥ 4) and time since the last vaccination (≤6 
months, > 6 months or unvaccinated) as appropriate. The treatment group comparison will be 
presented as the estimate of the hazard ratio, 95% CI and p-value. In addition, time to 
sustained symptom alleviation will be summarized graphically using Kaplan-Meier plots for 
each of the treatment groups in mITT analysis set.
Similar analyses for time to sustained symptom alleviation will also be performed in the 
mITT1 analysis set.


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6.2.3. Incidence of Treatment Emergent Adverse Events (TEAEs); Incidence of SAEs
and AEs Leading to Discontinuation
The incidence of TEAEs will be summarized by treatment group, by System Organ Class
(SOC) and preferred term (PT) using the SAS.
The incidence of SAEs and AEs leading to discontinuation will be summarized by treatment
group using the SAS.
6.3. Tertiary/Exploratory Endpoints
6.3.1. Proportion of Participants with SARS-CoV-2 RNA in NP Swab below the LLOQ 
on Days 3, 5, 10, 15, 21, 28, and 34
The number and proportion of participants with SARS-CoV-2 RNA level in NP swabs 
<2.0 log10 copies/mL at 3, 5, 10, 15, 21, 28, and 34 will be summarized by treatment group. 
The analysis will be done using mITT analysis set.
6.3.2. Proportion of Participants with Sustained NP Swab SARS-CoV-2 RNA below the 
LLOQ (defined as <2.0 log10 copies/mL) from Day 5 through Day 34
The number and proportion of participants with sustained NP swab SARS-CoV-2 RNA 
< LLOQ (defined as <2.0 log10 copies/mL) from Day 5 through Day 34 will summarized by 
treatment group using mITT analysis set. 
Sustained SARS-CoV-2 RNA below the LLOQ from Day 5 through Day 34 is defined as 
having all non-missing measurements from Day 5 to Day 34 below the LLOQ and no more 
than 3 visits with missing SARS-CoV-2 RNA levels (scheduled collection on Days 5, 10, 15, 
21, 28 and 34).
6.3.3. Proportion of Participants with SARS-CoV-2 RNA in NP Swabs below the LLOQ 
(defined as <2.0 log10 copies/mL) on both Days 5 and 10
The number and proportion of participants with SARS-CoV-2 RNA in NP swabs below the 
LLOQ (defined as <2.0 log10 copies/mL) on both Days 5 and 10 will be summarized by 
treatment group. The analysis will be done using mITT analysis set.
6.3.4. Change in SARS-CoV-2 RNA Level in NP Swabs from Baseline to Days 3, 10, 15, 
21, 28, and 34
Change in SARS-CoV-2 RNA level in NP swabs from baseline to Days 3, 10, 15, 21, 28, and 
34 will be analyzed similarly to the primary endpoint using MMRM model in the mITT
analysis set. The LS means and treatment difference for each visit will be calculated and 
presented with their corresponding 95% CIs.


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6.3.5. Time to Sustained NP Swab SARS-CoV-2 RNA below the LLOQ (defined as 
<2.0 log10 copies/mL) and Remains below the LLOQ through Day 34 for Participants 
with NP Swab SARS-CoV-2 RNA Greater than or Equal to the LLOQ at Baseline
Time to sustained NP swab SARS-CoV-2 RNA below the LLOQ (defined as <2.0 log10
copies/mL) and remains below the LLOQ through Day 34 will be summarized graphically 
using Kaplan-Meier plots for each of the treatment groups. The analyses will be done 
similary as in Section 6.2.2 using the mITT analysis set, which includes participants with 
baseline viral load ≥LLOQ.
Sustained is defined as NP swab SARS-CoV-2 RNA level not ≥2.0 log10 copies/mL at any 
study visit (through Day 34) following the first study visit where the participant's NP swab 
SARS-CoV-2 RNA <LLOQ. 
Let t represent the study day t between Day 5 and 28 visit inclusive for which there is a 
measurement of SARS-CoV-2 RNA level. 
Then a sustained event will correspond to the first possible value of t to satisfy the following 
criteria:
a) The Day t SARS-CoV-2 RNA level is <LLOQ 
b) At least one SARS-CoV-2 RNA measurement is <LLOQ after Day t
c) All available (non-missing) SARS-CoV-2 RNA measurements between Day t and 
Day 34 visit are <LLOQ 
d) No more than 50% missingness between Day t and Day 34 are missing.
There are limitations to the timing of the first event date as NP viral RNA is generally only 
captured at scheduled visits during the study. 
The Day 28 visit is the last possible day the sustained NP swab SARS-CoV-2 RNA<LLOQ 
can be achieved.
The time to the sustained event is defined as:

For a participant with sustained event at Day t, the First Event Date is the date of the 
Day t measurement, and time to event will be calculated as (First Event Date) – (First 
Dose Date) +1.

For a participant for which no possible value of t ≤ the Day 28 visit satisfies the 
criteria for a sustained event (censored), censoring date will be the date of the last 
available protocol-specified SARS-CoV-2 RNA measurement other than Day 34
visit, and time will be calculated as (Censoring Date) – (First Dose Date) +1.


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6.3.6. Rebound in SARS-CoV-2 RNA Level in NP Swabs at Follow-up ie, Any Study 
Visit from Day 10 to through Day 34, Defined as a Half (0.5) Log10 Copies/mL Increase 
or Greater in SARS-CoV-2 RNA Level Relative to SARS-CoV-2 RNA Level on Day 5 
and with a Follow-up Viral RNA Level ≥2.5 Log10 Copies/mL
The number and proportion of participants with rebound in SARS-CoV-2 RNA level in NP 
swabs up at follow-up will be summarized by treatment group. The analyses will be done 
using mITT analysis set.
In addition, two alternative definitions of rebound will also be evaluated: 

Rebound that is defined as: SARS-CoV-2 RNA level in NP swabs at follow up 
(ie, any study visit after Day 5 through Day 34) that is defined as a half (0.5) log10
copies/mL increase or greater in SARS-CoV-2 RNA level relative to SARS-CoV-
2 RNA level on Day 5, with a follow-up viral RNA level ≥3.0 log10 copies/mL. 

Rebound that is defined as: SARS-CoV-2 RNA level in NP swabs at follow up 
(ie, any study visit after Day 5 through Day 28) that is defined as a half (0.5) log10
copies/mL increase or greater in SARS-CoV-2 RNA level relative to SARS-CoV-
2 RNA level based on Day 5, with a follow-up viral RNA level ≥3.0 log10
copies/mL. 
The rebound analyses will be restricted to those participants with non-missing SARS-CoV-2 
RNA measurement on DAY 5 and at least one non-missing measurement among after Day 5 
visit through the Day 34 visit (or through the Day 28 visit for the second alternative 
definition of rebound analysis).
6.3.7. Endpoints Related to Infectious Titer
The analyses for the following endpoionts related to infectious titer will be specified in 
virology analysis plan. 

Time to negative infectious titer by TCID50 in participants with detectable viral titers 
at baseline by TCID50.

Change in TCID50 from baseline to Days 3, 5, 10, 15, 21, 28, and 34 in participants 
with detectable viral titers at baseline by TCID50.

Proportion of participants with negative infectious titer by TCID50 on Days 3, 5, 10, 
15, 21, 28, and 34 in participants with detectable viral titers at baseline by TCID50.

Time to negative infectious titer by virus recovery in participants with positive viral 
titers at baseline by virus recovery.

Proportion of participants with negative infectious titer by virus recovery on Days 3,
5, 10, 15, 21, 28, and 34 in participants with positive viral titers at baseline by virus 
recovery.


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6.3.8. Change from Baseline in SARS-CoV-2 Viral RNA Level in Plasma, Over Time
Change from baseline in SARS-CoV-2 viral RNA level in plasma, over time will be analyzed 
similar to the primary endpoint using MMRM model in mITT analysis set. The LS means 
and treatment difference for each visit will be calculated and presented with their
corresponding 95% CIs.
6.3.9. Proportion of Participants with COVID-19-related Hospitalization >24h or Death 
from Any Cause through Day 28
The number and proportion of participants with COVID-19-related hospitalization >24h or 
death from any cause through Day 28 will be summarized by treatment group. The analyses 
will be done using the mITT analysis set.
6.3.10. Number of COVID-19-related Medical Visits through Day 34
Number of COVID-19-related medical visits through Day 34 will be summarized by 
treatment group descriptively (n, mean, standard deviation, median, min, max). The analysis 
will be done using the mITT analysis set.
6.3.11. Time (days) to Sustained Resolution of All Targeted Signs and Symptoms 
through Day 28
Sustained resolution of all targeted COVID-19 signs/symptoms is defined as the event 
occurring on the first of 2 consecutive days when all targeted COVID-19 symptoms are 
scored as absent. The first day of the 2 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 resolution (missing severity at baseline will be treated as 
mild).
Day 27 is the last possible day that symptom resolution can be achieved (definition includes 
data from the subsequent day) and Day 28 is the last day participants report their daily signs 
and symptoms.
The time to sustained symptom resolution for the purpose of this study is defined as:

For a participant with sustained symptom resolution, 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 resolution (censored), censoring date 
will be at the last date on which symptom resolution is assessed, and time will be 
calculated as (Censoring Date) – (First Dose Date) +1 or Day 27 whichever occurs 
first.


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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 resolution
and will be censored at day 27.
Time to sustained symptom resolution will be analyzed similarly as in Section 6.2.2.
6.3.12. Other analyses
For the rapid antigen test and NP swab SARS-CoV-2 RNA/RT-PCR test that are collected on 
the same study day, the corcordance analysis will be performed at each visit, across post-
baseline visits and across all visits for the each treatment group and overall/combined 
treatment group in mITT1 analysis set.  Kappa statistic will be provided as a measurement of 
agreement between rapid antgen test and RT-PCR for across post-baseline visits and across 
all visits.
6.4. Subset Analyses
Subgroup analyses of the primary endpoint (if data permitted) will include:

Age group (<18, 18 to <60, ≥60) and (<65, ≥65);

Gender;

Race;

Ethincity; 

BMI category (<25, 25 to <30, ≥30);

Baseline viral load  (<7 log10 copies/mL, ≥7 log10 copies/mL; <4 log10 copies/mL, ≥4 
log10 copies/mL);

Geographic region (US, Ex-US) .
A forest plot will display confidence intervals across subgroups. 
6.5. Baseline and Other Summaries and Analyses
6.5.1. Baseline and Other Characteristics Summaries
The baseline and demographic characteristics will be summarized by treatment group within
the FAS and other analysis set as appropriate. This will include age, gender, race, height, and
baseline weight, etc. Other characteristics including household characteristics will also be 
summarized by treatment group within the FAS.


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6.5.2. Study Conduct and Participant Disposition
Study conduct and participant disposition will be summarized within the FAS. The number 
of participants randomized, treated, completing and discontinuing from the study, as well as 
the number of participants in each analysis set will be summarized by treatment group. For 
participants who did not complete the study, the reasons for withdrawal from the study will 
be presented.
6.5.3. Study Treatment Exposure
Duration of treatment will be summarized within the SAS.
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.
Compliance over the whole treatment period will be calculated as follows:
Compliance = Actual Number of Doses Received * 100
Planned Number of Doses
A participant is considered compliant if between 80% and 115% of the planned number of
doses is received. The compliance will be summarized in the following categories: 
<80%, 80% to 115%, and >115% by the number and percentage of participants in each 
treatment group.
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 the SAS 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 CDISC and CaPS 
for safety reporting for the following parameters: AEs, laboratory parameters, and vital signs.
6.6.1. Adverse Events
AEs will be coded according to the Medical Dictionary for Regulatory Activities (MedDRA) 
and will be summarized by treatment group within the SAS.
6.6.2. Laboratory Data
Laboratory values and the corresponding changes from baseline will be summarized with 
descriptive statistics by treatment group in the SAS. Laboratory data will be reported in 
accordance with CDISC and CaPS for safety reporting.


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6.6.3. Vital Signs
Vital sign data and the corresponding changes from baseline will be descriptively 
summarized by treatment within the SAS. Vital sign data will be reported in accordance with 
CDISC and CaPS.
7. INTERIM ANALYSES
7.1. Interim Analyses and Summaries
No formal interim analysis is planned for this study. However, the sponsor may conduct 
unblinded reviews of the data during the course of the study if requested by regulatory 
authorities including in the support of regulatory submissions. Should an unblinded review 
be requested, details of the unblinding plan will be described in a SAP and a separate data 
unblinding document.
7.2. Data Monitoring Committee
This study will use an E-DMC. The E-DMC is independent of the study team and includes 
only external members. The E-DMC charter describes the role of the E-DMC in more detail.
The E-DMC will be responsible for ongoing monitoring of the safety of participants in the 
study according to the charter. In addition, the E-DMC may monitor the baseline 
SARS-CoV-2 RNA levels to ensure the population is consistent with the study design 
assumptions. 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 safety data, to 
regulatory authorities and investigators, as appropriate. 


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8. REFERENCES
1.
Benjamini Y, & Hochberg, Y. Controlling the false discovery rate: a practical and 
powerful approach to multiple testing. . Journal of the Royal Statistical Society. 
1995;57:289–300.


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APPENDICES
Appendix 1. Summary of Efficacy Analyses
Endpoint
Analysis Type
Population
Data Inclusion and Rules for 
Handling Intercurrent Events 
and Missing Data 
Analysis Model
Change in viral SARS-CoV-2 
RNA level as measured in NP 
swabs from baseline to Day 5
Primary
mITT
All data collected will be included 
regardless of study treatment 
discontinuation and prohibited 
therapies.
MMRM method to take account of 
missing at random.
MMRM
Change in viral SARS-CoV-2 
RNA level as measured in NP 
swabs from baseline to Day 5
Secondary
mITT1
All data collected will be included 
regardless of study treatment 
discontinuation and prohibited 
therapies.
MMRM method to take account of 
missing at random.
MMRM
Change in viral SARS-CoV-2 
RNA level as measured in NP 
swabs from baseline to Day 5
Supplementary
PP
MMRM method to take account of 
missing at random.
MMRM
Change in viral SARS-CoV-2 
RNA level as measured in NP 
swabs from baseline to Day 5
Subgroup analyses 
for the primary 
endpoint
mITT
All data collected will be included 
regardless of study treatment 
discontinuation and prohibited 
therapies.
MMRM method to take account of 
missing at random.
Subgroups defined in Section 6.4
MMRM


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Endpoint
Analysis Type
Population
Data Inclusion and Rules for 
Handling Intercurrent Events 
and Missing Data 
Analysis Model
Time to 2 consecutive negative 
rapid antigen test results obtained 
at least 24(-2)h apart through 
Day 28
Secondary
mITT
mITT1
All data collected will be included 
regardless of study treatment 
discontinuation and prohibited 
therapies.
Missing data will not be imputed.
Cox proportional 
hazard model; KM 
curves; Log-rank test
Time (days) to sustained 
alleviation of all targeted signs and 
symptoms through Day 28
Secondary
mITT
mITT1
All data collected will be included 
regardless of study treatment 
discontinuation and prohibited 
therapies.
Missing data will not be imputed.
Cox proportional 
hazard model; KM 
curves
Proportion of participants with 
SARS-CoV-2 RNA in NP swab 
below the LLOQ on Days 3, 5, 10, 
15, 21, 28, and 34
Exploratory
mITT
Missing data will not be imputed.
Descriptive summary
Proportion of participants with 
sustained NP swab SARS-CoV-2 
RNA below the LLOQ (defined as 
<2.0 log10 copies/mL) from Day 5 
through Day 34
Exploratory
mITT
Missing data will not be imputed.
Descriptive summary
Proportion of participants with 
SARS-CoV-2 RNA in NP swabs 
below the LLOQ (defined as <2.0 
log10 copies/mL) on both Days 5 
and 10
Exploratory
mITT
Missing data will not be imputed.
Descriptive summary


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Endpoint
Analysis Type
Population
Data Inclusion and Rules for 
Handling Intercurrent Events 
and Missing Data 
Analysis Model
Change in SARS-CoV-2 RNA 
level in NP swabs from baseline to 
Days 3, 10, 15, 21, 28, and 34
Exploratory
mITT
MMRM method to take account of 
missing at random.
MMRM
Time to sustained NP swab SARS-
CoV-2 RNA below the LLOQ 
(defined as <2.0 log10 copies/mL) 
and remains below the LLOQ 
through Day 34
Exploratory
mITT
Missing data will not be imputed.
Cox proportional 
hazard model; KM 
curves
Rebound in SARS-CoV-2 RNA 
level in NP swabs at follow-up 
(ie, any study visit after Day 5 to 
through Day 34, defined as a half 
(0.5) log10 copies/mL increase or 
greater in SARS CoV-2 RNA 
level relative to SARS-CoV-2 
RNA level on Day 5 and with a 
follow-up viral RNA level
≥2.5 log10 copies/mL
Exploratory
mITT
Missing data will not be imputed.
Descriptive summary


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Endpoint
Analysis Type
Population
Data Inclusion and Rules for 
Handling Intercurrent Events 
and Missing Data 
Analysis Model
Rebound in SARS-CoV-2 RNA 
level in NP swabs at follow-up 
(ie, any study visit after Day 5 to 
through Day 34, defined as a half 
(0.5) log10 copies/mL increase or 
greater in SARS CoV-2 RNA 
level relative to SARS-CoV-2 
RNA level on Day 5 and with a 
follow-up viral RNA level
≥3log10 copies/mL
Exploratory
mITT
Missing data will not be imputed.
Descriptive summary
Rebound in SARS-CoV-2 RNA 
level in NP swabs at follow-up 
(ie, any study visit after Day 5 to 
through Day 28, defined as a half 
(0.5) log10 copies/mL increase or 
greater in SARS CoV-2 RNA 
level relative to SARS-CoV-2 
RNA level on Day 5 and with a 
follow-up viral RNA level
≥3log10 copies/mL
Exploratory
mITT
Missing data will not be imputed.
Descriptive summary
Change from baseline in SARS-
CoV-2 viral RNA level in plasma, 
over time
Exploratory
mITT
MMRM method to take account of 
missing at random.
MMRM
Proportion of participants with 
COVID-19-related hospitalization 
Exploratory
mITT
Missing data will not be imputed.
Descriptive summary


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Endpoint
Analysis Type
Population
Data Inclusion and Rules for 
Handling Intercurrent Events 
and Missing Data 
Analysis Model
>24h or death from any cause 
through Day 28
Number of COVID-19-related 
medical visits through Day 34
Exploratory
mITT
Missing data will not be imputed.
Descriptive summary
Time (days) to sustained 
resolution of all targeted signs and 
symptoms through Day
Exploratory
mITT
mITT1
Missing data will not be imputed.
Cox proportional 
hazard model; KM 
curves
Corcordance analysis of RAT and 
SARS-CoV-2 viral RNA level in 
NP swabs
Other
mITT1
Missing data will not be imputed.
Descriptive summary


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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 for viral RNA data and infectious 
titer data:
Visit Label
Target Day
Visit Window
Baseline (Day 1)
Day 1
Days -1 to 1
Day 3
Day 3
Days 2 to 4
Day 5
Day 5
Days 4 to 7
Day 10
Day 10
Days 8 to 12
Day 15
Day 15
Days 13 to 17
Day 21
Day 21
Days 18 to 24
Day 28
Day 28
Days 25 to 30
Day 34
Day 34
Days 31 to 37
The following table defines the visit windows and labels for vital sign data:
Visit Label
Target Day
Visit Window
Baseline (Day 1)
Day 1
Days -1 to 1
Day 3
Day 3
Days 2 to 4
Day 5
Day 5
Days 4 to 7
Day 10
Day 10
Days 8 to 21
Day 34
Day 34
Days 22 to 37
The following table defines the visit windows and labels for Lab data:
Visit Label
Target Day
Visit Window
Baseline (Day 1)
Day 1
Days -1 to 1
Day 5
Day 5
Days 2 to 19
Day 34
Day 34
Days 20 to 37
These visit windows will be applied to visit-wise summary and may be revised for analysis 
and reporting purpose when deemed appropriate.


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For viral RNA data collected in NP swab or plasma, and vital sign data collected on study 
Day 4, it has falls into Day 3 visit and Day 5 visit due to an overlap between Day 3 and Day 
5 visit windows, the decision made is to assign the window according to the nominal visit. If 
the nominal visit is “ET” visit, it will be assigned to Day 5 visit.
For lab data, if there are multiple measurements on the same day, the average will be used.
For vital sign data, if there are multiple measurements on the same day, the latest
measurement will be used.
For viral RNA data collected in NP swab or plasma and infectious titer data, if there are 
multiple measurements on the same day, the largest value will be used.
For rapid antigen test data, if there are multiple measurements with negative and positive 
results on the same day, the positive result will be used.
If two or more measurements fall into the same visit window, keep the one closest to the
Target Day. If two measurements are equal distance from the Target Day in absolute value,
the later visit should be used.


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Appendix 3. List of Abbreviations
Abbreviation
Term
AE
adverse event
ANCOVA
analysis of covariance
BMI
body mass index
CaPS
Clinical Data Interchange Standards Consortium and Pfizer Standards
CDARS
Clinical Data Analysis and Reporting System (of US Food and Drug 
Administration)
CDISC
Clinical Data Interchange Standards Consortium
CI
confidence interval
COVID-19
coronavirus disease 2019
DMC
data monitoring committee
E-DMC
external data monitoring committee 
EPIC-HR
Evaluation of Protease Inhibition for COVID-19 in High-Risk Patients
FAS
full analysis set
h
hour
LLOQ
lower limit of quantitation
LOD
limit of detection
LS
least-squares
MAR
missing at random
MedDRA
Medical Dictionary for Regulatory Activities
mITT
modified intent-to-treat
MMRM
mixed-effects model with repeated measures
NCT
National Clinical Trial
NP
nasopharyngeal
PP
per-protocol
PT
preferred term
RNA
ribonucleic acid
SAE
serious adverse event
SAP
statistical analysis plan
SD
standard deviation
SOC
System Organ Class
TCID50
Median Tissue Culture Infectious Dose
TEAE
treatment-emergent adverse event
US
United States
WHO 
World Health Organization


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Appendix 4. Participant-Reported COVID-19-Related Signs and Symptoms
Sign and Symptom Collection
Eligibility Criterion #5 
Targeted (used for 
study entry)
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
X
Loss of taste
X
X