Conditions: COVID-19
Keywords: Severe acute respiratory syndrome coronavirus 2 (SARS-Cov-2) kidney disease kidney failure renal disease renal failure dialysis renal dialysis hemodialysis coronavirus disease 2019 (COVID-19) COVID Paxlovid antiviral nirmatrelvir mild to moderate COVID-19 high risk
Allocation: NON_RANDOMIZED | Intervention model: PARALLEL
Enrollment: 15
Healthy volunteers: no

Brief summary:
The purpose of this study is to learn about the side effects (safety) of the study medicine PF-07321332 (nirmatrelvir)/ritonavir for the treatment of mild to moderate COVID-19 infection in adults with severe renal impairment. The study will also look at the amounts of study drug in your blood. There will be 24 participants in this study; 12 of them will have severe renal impairment and not be on hemodialysis and 12 of them will be on hemodialysis.

All participants in this study will take PF-07321332 (nirmatrelvir)/ritonavir by mouth for 5 days. During this time, they will have to collect blood samples to measure the study drug levels in their blood. After taking the study drug for 5 days, the participants will have follow-up visits for about another 28 days for a total of about 34 days in the study. The study team will check how each participant is doing during regular visits at the study clinic.

Detailed description:

Arms:
arm 1: Patients with Covid-19 infection and severe renal impairment. Capsule and tablet once a day by mouth. arm 2: Patients with Covid-19 infection and severe renal impairment. Capsule and tablet once a day by mouth.

Interventions: intervention 1: PF-07321332 (nirmatrelvir)/ritonavir
Intervention descriptions: intervention 1: Patients with Covid-19 infection and severe renal impairment. Capsule and tablet once a day by mouth.

Protocol document:
Prot_000.pdf: 
PF-07321332 (Nirmatrelvir)/ritonavir
Protocol C4671028
Final Protocol Amendment 2, 09 Feb 2023
PFIZER CONFIDENTIAL
Page 1
Title Page
A PHASE 1, OPEN-LABEL, NON-RANDOMIZED STUDY TO INVESTIGATE THE 
SAFETY AND PK FOLLOWING MULTIPLE ORAL DOSES OF PF-07321332 
(NIRMATRELVIR)/RITONAVIR IN ADULT PARTICIPANTS WITH COVID-19 
AND SEVERE RENAL IMPAIRMENT EITHER ON HEMODIALYSIS OR NOT ON 
HEMODIALYSIS
Study Intervention Number:
PF-07321332/Ritonavir
Study Intervention Name:
PF-07321332 (nirmatrelvir)/ritonavir
US IND Number:
153517
EudraCT Number:
2023-503870-19-00
ClinicalTrials.gov ID:  
NCT05487040
Pediatric Investigational Plan Number 
NA
Protocol Number:
C4671028
Phase:
1
Brief Title: A Phase 1, Open-label, Non-randomized Safety and PK Study of Multiple 
Oral Doses of PF-07321332 (Nirmatrelvir)/Ritonavir in Adult Participants with COVID-19 
and Severe Renal Impairment 
This document and accompanying materials contain confidential information belonging to Pfizer. Except as 
otherwise agreed to in writing, by accepting or reviewing these documents, you agree to hold this 
information in confidence and not copy or disclose it to others (except where required by applicable law) or 
use it for unauthorized purposes. In the event of any actual or suspected breach of this obligation, Pfizer must 
be promptly notified.


PF-07321332 (Nirmatrelvir)/ritonavir
Protocol C4671028
Final Protocol Amendment 2, 09 Feb 2023
PFIZER CONFIDENTIAL
Page 2
Document History
Document 
Version Date
Amendment 2
09 Feb 2023
Amendment 1
23 Jun 2022
Original protocol
25 Mar 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).
Protocol Amendment Summary of Changes Table
Amendment 2 (09 Feb 2023) 
Overall Rationale for the Amendment: To add additional blood to plasma ratio sample 
either on Day 3 or Day 4 or Day 5 in Cohort 1 and on Day 1 in Cohort 2; and to provide 
additional clarification on blood to plasma ratio sample processing.
Section # and 
Name
Description of 
Change
Brief Rationale
Substantial or 
Nonsubstantial
Title page
Added EudraCT 
number and
ClinicalTrials.gov ID
EudraCT number and
ClinicalTrials.gov ID
are now available for 
this study.
Nonsubstantial
Section 1.3. Schedule 
of Activities – PK 
Sampling Schemas 
1-12; Section 8.5.3 PK 
Samples for Analysis 
of PF-07321332 
(nirmatrelvir) and 
Ritonavir; Section 
8.5.4. Blood to Plasma 
Ratio Analysis of 
PF-07321332 
(nirmatrelvir) and 
ritonavir
Updates to implement 
collection of 1
additional blood to 
plasma ratio sample at 
steady state. 
Flexibility to collect 
the sample on a 
different day if a 
sample was missed.
This additional blood 
to plasma ratio sample 
will help in providing 
accurate normalization 
for Tasso PK when 
compared with 
nirmatrelvir/ritonavir 
plasma concentrations.
Substantial
Section 9.4 Interim 
Analyssis
Added text for 
unblinded reviews of 
the data 
Added text based on 
text in SAP. 
Nonsubstantial


PF-07321332 (Nirmatrelvir)/ritonavir
Protocol C4671028
Final Protocol Amendment 2, 09 Feb 2023
PFIZER CONFIDENTIAL
Page 3
Section # and 
Name
Description of 
Change
Brief Rationale
Substantial or 
Nonsubstantial
Title page
Added EudraCT 
number and
ClinicalTrials.gov ID
EudraCT number and
ClinicalTrials.gov ID
are now available for 
this study.
Nonsubstantial
Section 1.3 SoA;
Section 10.2. Clinical 
Laboratory Tests, 
Table 3;
Section 10.9.1.
Country Specific 
Requirements
HIV test at screening 
added to the 
laboratory assessments 
for participants in 
Germany.
The German Health 
Authority 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.
Nonsubstantial


PF-07321332 (Nirmatrelvir)/ritonavir
Protocol C4671028
Final Protocol Amendment 2, 09 Feb 2023
PFIZER CONFIDENTIAL
Page 4
TABLE OF CONTENTS
LIST OF TABLES.....................................................................................................................9
1. PROTOCOL SUMMARY...................................................................................................10
1.1. Synopsis ..................................................................................................................10
1.2. Schema ....................................................................................................................17
1.3. Schedule of Activities .............................................................................................18
2. INTRODUCTION ...............................................................................................................40
2.1. Study Rationale .......................................................................................................40
2.2. Background .............................................................................................................40
2.2.1. Clinical Overview.......................................................................................42
2.3. Benefit/Risk Assessment.........................................................................................43
2.3.1. Risk Assessment.........................................................................................44
2.3.2. Benefit Assessment.....................................................................................46
2.3.3. Overall Benefit/Risk Conclusion................................................................46
3. OBJECTIVES, ENDPOINTS, AND ESTIMANDS ...........................................................47
4. STUDY DESIGN.................................................................................................................47
4.1. Overall Design.........................................................................................................47
4.2. Scientific Rationale for Study Design.....................................................................48
4.2.1. Choice of Contraception/Barrier Requirements .........................................49
4.2.2. Collection of Retained Research Samples..................................................49
4.3. Justification for Dose ..............................................................................................49
4.4. End of Study Definition ..........................................................................................50
5. STUDY POPULATION......................................................................................................50
5.1. Inclusion Criteria.....................................................................................................51
5.2. Exclusion Criteria....................................................................................................52
5.3. Lifestyle Considerations..........................................................................................53
5.3.1. Contraception..............................................................................................53
5.3.2. Other Considerations ..................................................................................54
5.3.2.1. Hemodialysis.............................................................................54
5.4. Screen Failures ........................................................................................................54
6. STUDY INTERVENTION(S) AND CONCOMITANT THERAPY.................................54
6.1. Study Intervention(s) Administered........................................................................54


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PFIZER CONFIDENTIAL
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6.1.1. Administration............................................................................................56
6.2. Preparation, Handling, Storage, and Accountability...............................................56
6.2.1. Preparation and Dispensing........................................................................57
6.3. Assignment to Study Intervention...........................................................................57
6.4. Blinding...................................................................................................................58
6.5. Study Intervention Compliance...............................................................................58
6.6. Dose Modification...................................................................................................59
6.7. Continued Access to Study Intervention After the End of the Study......................59
6.8. Treatment of Overdose............................................................................................59
6.9. Prior and Concomitant Therapy..............................................................................59
6.9.1. Permitted During the Study ........................................................................60
6.9.2. Prohibited in the study................................................................................60
7. DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL...........................................................................61
7.1. Discontinuation of Study Intervention ....................................................................61
7.2. Participant Discontinuation/Withdrawal From the Study.......................................61
7.2.1. Withdrawal of Consent...............................................................................62
7.3. Lost to Follow-Up ...................................................................................................62
8. STUDY ASSESSMENTS AND PROCEDURES...............................................................63
8.1. Administrative and Baseline Procedures.................................................................63
8.1.1. Tasso sample training and collection..........................................................64
8.1.2. Medical History ..........................................................................................64
8.1.3. Telehealth Visits.........................................................................................64
8.1.4. Home Health Visits.....................................................................................65
8.2. Efficacy Assessments..............................................................................................66
8.2.1. COVID-19-Related Medical Visit Details..................................................66
8.3. Safety Assessments .................................................................................................66
8.3.1. Targeted Physical Examinations.................................................................66
8.3.2. Height and Weight......................................................................................67
8.3.3. Vital Signs ..................................................................................................67
8.3.4. Clinical Safety Laboratory Assessments ....................................................67
8.3.5. Pregnancy Testing ......................................................................................68


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Protocol C4671028
Final Protocol Amendment 2, 09 Feb 2023
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8.3.5.1. At-Home Pregnancy Testing.....................................................68
8.4. Adverse Events, Serious Adverse Events, and Other Safety Reporting .................68
8.4.1. Time Period and Frequency for Collecting AE and SAE Information.......69
8.4.1.1. Reporting SAEs to Pfizer Safety...............................................70
8.4.1.2. Recording Nonserious AEs and SAEs on the CRF...................70
8.4.2. Method of Detecting AEs and SAEs ..........................................................70
8.4.3. Follow-Up of AEs and SAEs......................................................................70
8.4.4. Regulatory Reporting Requirements for SAEs...........................................71
8.4.5. Environmental Exposure, Exposure During Pregnancy or 
Breastfeeding, and Occupational Exposure.....................................................71
8.4.5.1. Exposure During Pregnancy......................................................71
8.4.5.2. Exposure During Breastfeeding ................................................73
8.4.5.3. Occupational Exposure .............................................................73
8.4.6. Cardiovascular and Death Events (Not Applicable)...................................74
8.4.7. Disease-Related Events and/or Disease-Related Outcomes Not 
Qualifying as AEs or SAEs (Not Applicable) .................................................74
8.4.8. Adverse Events of Special Interest (Not Applicable).................................74
8.4.8.1. Lack of Efficacy........................................................................74
8.4.9. Medical Device Deficiencies (Not Applicable)..........................................74
8.4.10. Medication Errors.....................................................................................74
8.5. Pharmacokinetics ....................................................................................................75
8.5.1. Non-Hemodialysis ......................................................................................75
8.5.2. Hemodialysis ..............................................................................................75
8.5.3. PK Samples for Analysis of PF-07321332 (nirmatrelvir) and 
Ritonavir ..........................................................................................................76
8.5.4. Blood to Plasma Ratio Analysis of PF-07321332 (nirmatrelvir) and 
Ritonavir ..........................................................................................................77
8.5.5. Electronic diary (eDiary) ............................................................................77
8.6. Genetics...................................................................................................................77
8.6.1. Specified Genetics (Not Applicable)..........................................................77
8.6.2. Retained Research Samples for Genetics ...................................................77
8.7. Biomarkers ..............................................................................................................78
8.7.1. Viral Load Assessments .............................................................................78


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Protocol C4671028
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8.7.2. Specified Protein Research.........................................................................78
8.7.2.1. Specified Biomarker Research (Plasma)...................................78
8.7.3. Retained Research Samples for Biomarkers...............................................78
8.8. Immunogenicity Assessments.................................................................................79
8.9. Health Economics ...................................................................................................79
9. STATISTICAL CONSIDERATIONS ................................................................................79
9.1. Statistical Hypothesis ..............................................................................................79
9.2. Analysis Sets ...........................................................................................................79
9.3. Statistical Analyses .................................................................................................80
9.3.1. General Considerations...............................................................................80
9.3.2. Primary Endpoints Analyses.......................................................................80
9.3.3. Secondary Endpoints Analyses...................................................................81
9.3.5. Other Safety Analyses ................................................................................82
9.4. Interim Analyses .....................................................................................................82
9.5. Sample Size Determination.....................................................................................82
10. SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS..........................................................................................................84
10.1. Appendix 1: Regulatory, Ethical, and Study Oversight Considerations...............84
10.1.1. Regulatory and Ethical Considerations ....................................................84
10.1.1.1. Reporting of Safety Issues and Serious Breaches of the 
Protocol or ICH GCP.........................................................................84
10.1.2. Financial Disclosure .................................................................................85
10.1.3. Informed Consent/Assent Process ............................................................85
10.1.4. Data Protection .........................................................................................86
10.1.5. Committees Structure ...............................................................................86
10.1.5.1. Data Monitoring Committee ...................................................86
10.1.6. Dissemination of Clinical Study Data ......................................................87
10.1.7. Data Quality Assurance ............................................................................88
10.1.8. Source Documents....................................................................................89
10.1.9. Study and Site Start and Closure ..............................................................89
10.1.10. Publication Policy...................................................................................90
10.1.11. Sponsor’s Medically Qualified Individual..............................................91
CCI


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10.2. Appendix 2: Clinical Laboratory Tests .................................................................92
10.3. Appendix 3: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-Up, and Reporting .....................................................................93
10.3.1. Definition of AE .......................................................................................93
10.3.2. Definition of an SAE ................................................................................94
10.3.3. Recording/Reporting and Follow-Up of AEs and/or SAEs During 
the Active Collection Period............................................................................95
10.3.4. Reporting of SAEs....................................................................................99
10.4. Appendix 4: Contraceptive and Barrier Guidance ..............................................100
10.4.1. Male Participant Reproductive Inclusion Criteria..................................100
10.4.2. Female Participant Reproductive Inclusion Criteria...............................100
10.4.3. Woman of Childbearing Potential ..........................................................100
10.4.4. Contraception Methods...........................................................................101
10.5. Appendix 5: Genetics..........................................................................................103
10.6. Appendix 6: Liver Safety: Suggested Actions and Follow-Up Assessments 
and Study Intervention Rechallenge Guidelines .....................................................104
10.7. Appendix 7: Kidney Safety Monitoring Guidelines ...........................................106
10.7.1. Laboratory Assessment of Change in Kidney Function and 
Detection of Kidney Injury............................................................................106
10.7.2. Age-Specific Kidney Function Calculation Recommendations.............106
10.7.2.1. Adults (18 Years and Above)—2021 CKD-EPI 
Equations .........................................................................................106
10.7.3. Adverse Event Grading for Kidney Safety Laboratory 
Abnormalities.................................................................................................107
10.8. Appendix 8: Concomitant Medications That May Result in DDI.......................108
10.9. Appendix 9: Country-Specific Requirements .....................................................116
10.9.1. Germany .................................................................................................116
10.10. Appendix 10: Definition of COVID-19 Severity..............................................117
10.11. Appendix 11: Protocol Amendment History.....................................................118
10.12. Appendix 12: Abbreviations .............................................................................122
11. REFERENCES ................................................................................................................126


PF-07321332 (Nirmatrelvir)/ritonavir
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LIST OF TABLES
Table 1.
PF-07321332 (nirmatrelvir) PK Parameters Following Single Dose 
of PF-07321332 (nirmatrelvir)/Ritonavir 100 mg/100 mg in Severe 
Renal Impairment Patients........................................................................83
Table 2.
Percentile Range and Width of 90% Confidence Intervals for the 
Mean PK Parameter..................................................................................83
Table 3.
Protocol-Required Safety Laboratory Assessments .................................92
Table 4.
Established and Other Potentially Significant Drug Interactions...........109


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1. PROTOCOL SUMMARY 
1.1. Synopsis 
Protocol Title: 
A Phase 1, Open-Label, Non-Randomized Study to Investigate the Safety and PK Following 
Multiple Oral Doses of PF-07321332 (Nirmatrelvir)/Ritonavir in Adult Participants with 
COVID-19 and Severe Renal Impairment Either on Hemodialysis or not on Hemodialysis.
Brief Title: A Phase 1, Open-label, Non-randomized Safety and PK Study of Multiple Oral 
Doses of PF-07321332 (Nirmatrelvir)/Ritonavir in Adult Participants with COVID-19 and 
Severe Renal Impairment. 
Regulatory Agency Identification Number(s):
US IND Number:
153517
EudraCT Number:
NA 
ClinicalTrials.gov ID:  
NCT05487040
Pediatric Investigational Plan Number:
NA
Protocol Number:
C4671028
Phase:
1
Rationale:
The purpose of this study is to evaluate the safety and PK of PF-07321332 
(nirmatrelvir)/ritonavir in adults with severe renal impairment and COVID-19. Eligible 
participants include those with severe renal impairment (defined as eGFR 
<30 mL/min/1.73 m2) and not yet receiving HD (Cohort 1) and individuals receiving HD
(Cohort 2).
Objectives, Endpoints, and Estimands:
Objectives
Endpoints
Estimands
Primary: 
Primary:
Primary:

To describe the safety 
and tolerability of 
PF-07321332 
(nirmatrelvir)/ritonavir 
in adult participants 
with COVID-19 and 
severe renal 
impairment.
Incidence of TEAEs.
Incidence of SAEs and AEs 
leading to discontinuations.
Not Applicable.


PF-07321332 (Nirmatrelvir)/ritonavir
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Objectives
Endpoints
Estimands
Secondary:
Secondary:
Secondary:

To evaluate the effect of 
severe renal impairment 
on the PK of 
PF-07321332 
(nirmatrelvir) in 
participants not on HD.

To evaluate the effect of 
severe renal impairment 
on the PK of 
PF-07321332 
(nirmatrelvir) in 
participants on HD.
Plasma PF-07321332 
(nirmatrelvir) PK parameters 
including Cmax, CL/F, Vz/F, 
AUC0-tau, t½, and Ctrough 
estimated from the 
population PK model.
Not Applicable.

To evaluate the effect of 
HD on the PK of 
PF-07321332 
(nirmatrelvir).
HD clearance (CLd) of 
PF-07321332 (nirmatrelvir). 
Fraction of PF-07321332 
(nirmatrelvir) dose removed 
from the body by dialysis 
(Fd).
Not Applicable.
Overall Design:
This is a Phase 1, open-label study to evaluate the effect of severe renal impairment on the 
PK of PF-07321332 (nirmatrelvir)/ritonavir and the safety and tolerability of PF-07321332 
(nirmatrelvir)/ritonavir in non-hospitalized adult participants with COVID-19 and severe 
renal impairment and not yet receiving intermittent HD (Cohort 1) and severe renal 
impairment receiving intermittent HD (Cohort 2). The study will be conducted in 2 parallel 
cohorts. Cohort 1 will enroll eligible participants with severe renal impairment (defined as 
eGFR <30 mL/min/1.73 m2) and not on HD. Cohort 2 will enroll eligible participants with 
severe renal impairment and on HD. All eligible participants will be assigned to receive a 
single dose of PF-07321332 (nirmatrelvir)/ritonavir 300 mg/100 mg orally on Day 1
followed by PF-07321332 (nirmatrelvir)/ritonavir 150 mg/100 mg QD from Day 2 to Day 5.
Population PK model-based simulations showed that the PF-07321332 (nirmatrelvir) single 
dose of 300 mg on Day 1 followed by 150 mg of PF-07321332 (nirmatrelvir) QD on Day 2 
to Day 5 with ritonavir 100 mg in severe renal impaired participants gives comparable 
exposure (AUC0-24 and Cmax) to COVID-19 patients with normal renal function at the 300 mg 
PF-07321332 (nirmatrelvir)/ 100 mg ritonavir BID dose for 5 days. Published reports and 
internal data (C4671011 data on file) show ritonavir PK is comparable between normal 
healthy participants and severe renal impairment patients and only small fraction of ritonavir 
dose is removed by HD.1, 23, 24Ritonavir 100 mg QD or BID dose has been used for several 
protease inhibitors (eg, darunavir) with small difference in dose normalized Ctrough of protease 
inhibitors. Additionally, the PK of PF-07321332 (nirmatrelvir) with 100 mg QD of ritonavir 
in severe renal impairment participants is expected to be similar to those of healthy 


PF-07321332 (Nirmatrelvir)/ritonavir
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participants taking 100 mg BID of ritonavir. Therefore, the ritonavir dose of 100 mg QD was 
selected for this study.
This study will use the program-level E-DMC which is independent of the study team and 
includes only external members, and is responsible for the ongoing monitoring of the 
efficacy and safety of participants in the program’s studies according to the E-DMC charter
(Section 10.1.5.1).
Number of Participants:
Approximately 24 participants (12 participants in Cohort 1 and 12 participants in Cohort 2) 
will be assigned to study intervention. 
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 
assignment to study intervention. 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.
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:
Age and Sex:
1. Participants ≥18 years of age (or the minimum country specific age of consent if >18) at 
the time of the Screening Visit.

WOCBP may be enrolled.

WOCBP must agree to use an effective method of contraception described in 
Section 5.3. Refer to Appendix 4 for reproductive criteria for male and female 
participants.
Disease Characteristics:
2. Mild-to-moderate COVID-19 disease as defined in Appendix 9 with confirmed 
SARS-CoV-2 infection in any specimen collected within 5 days prior to treatment 
assignment.


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Note: RT-PCR is the preferred method; however, with evolving approaches to 
confirmation of SARS-CoV-2 infection, other molecular or antigen tests that detect viral 
RNA or protein are allowed. The test result must be available to confirm eligibility. 
Participants may be enrolled based on positive results of a rapid SARS-CoV-2 antigen 
test performed at screening.
3. Initial onset of signs/symptoms attributable to COVID-19 within 5 days prior to the day 
of treatment assignment. 
Other Inclusion Criteria:
4. Participants who are willing and able to comply with all scheduled visits, treatment plan, 
laboratory tests, lifestyle considerations, and other study procedures. 
Additional Inclusion Criteria for Cohort 1 (Severe Renally Impaired and not on HD): 
5. Severe renal impairment defined as eGFR <30 mL/min/1.73m2 (using the 2021 CKD-EPI 
serum creatinine only eGFR formula in Section 10.7.2.1) measured by clinical laboratory 
testing on at least 2 occasions, one of which must be within 3 months of Screening and 
not receiving intermittent HD treatments.
Additional Inclusion Criteria for Cohort 2 (Receiving HD): 
6. Receiving stable intermittent HD for at least 6 weeks prior to Screening. 
Exclusion Criteria 
Participants are excluded from the study if any of the following criteria apply:
Medical Conditions:
1. Current need for hospitalization or anticipated need for hospitalization within 48 hours 
after treatment assignment in the clinical opinion of the site investigator. 
2. Renal transplant recipients.
3. History of severe chronic liver disease (eg, jaundice, ascites, hepatic encephalopathy, 
history of bleeding esophageal or gastric varices). No laboratory testing is needed.
4. Known HIV infection with viral load >400 copies/mL or HIV infection with CD4+ cell 
count <200/mm3.

Participants in Germany will be excluded if the screening HIV test is positive or if 
they do not consent to have an HIV test at screening.
5. Any comorbidity requiring hospitalization (excludes hospitalization for renal failure or 
HD) and/or surgery within 7 days prior to study entry, or that is considered life 
threatening within 30 days prior to study entry, as determined by the investigator.


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6. History of hypersensitivity or other contraindication to any of the components of the 
study intervention, as determined by the investigator.
7. 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:
8. Current use of any medications that are highly dependent of CYP3A4 for clearance and 
which are contraindicated in combination with PF-07321332 (nirmatrelvir)/ritonavir 
(Appendix 8). Participants taking lovastatin and simvastatin may enroll, provided that 
they have discontinued use at least 12 hours prior to initiation of PF-07321332 
(nirmatrelvir)/ritonavir and refrain from use during treatment and for 5 days after the last 
dose of PF-07321332 (nirmatrelvir)/ritonavir. Coadministration of PF-07321332 
(nirmatrelvir)/ritonavir with medications that are highly dependent on CYP3A4 for 
clearance may require dose adjustment or additional monitoring (See Appendix 8).
9. Use of any medications or substances that are strong inducers of CYP3A4 and that are 
contraindicated in combination with PF-07321332 (nirmatrelvir)/ritonavir without the 
appropriate washout prior to the first dose of PF-07321332 (nirmatrelvir)/ritonavir (see 
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. 
10. Has received or is expected to receive mAb treatment, convalescent COVID-19 plasma, 
or anti-viral treatment (eg, molnupiravir, remdesivir) for the current SARS-CoV-2 
infection (See Section 6.9).
Prior/Concurrent Clinical Study Experience:
11. Is unwilling to abstain from participating in another interventional clinical study with an 
investigational compound or device, including those for COVID-19 therapeutics, through 
the end of study. Previous administration with any investigational drug or vaccine within 
30 days (or as determined by the local requirement) or 5 half-lives preceding the first 
dose of study intervention used in this study (whichever is longer).
12. Known prior participation in this trial or other trial involving PF-07321332 (nirmatrelvir).
Diagnostic Assessments:
None.
Other Exclusion Criteria:
13. Females who are pregnant or breastfeeding.


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Page 15
14. 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 will receive a single dose of PF-07321332 (nirmatrelvir)/ritonavir 
300 mg/100 mg orally on Day 1 followed by PF-07321332 (nirmatrelvir)/ritonavir 
150 mg/100 mg QD from Day 2 to Day 5. The total study duration is up to 38 days and
includes a 1-to-2-day screening period where participants can be screened on one day and 
randomized the next day or screened and randomized on the same day. Screening procedures 
can be performed over 2 days, but the participant must be randomized by the second day 
(Day 1) and begin study treatment. Therefore, Screening and Randomization can take no 
longer than 2 consecutive days. After Screening, the participant takes study intervention for 
5 days and completes the safety follow-up period through Day 34. This equates to a total 
study duration of up to 38 days. 
Study Intervention(s)
Intervention Name
PF-07321332 (nirmatrelvir)/ritonavir
Arm Name
(group of participants 
receiving a specific 
treatment or no 
treatment)
All participants will receive the same treatment open-label
Unit Dose Strength(s)
PF-07321332 (nirmatrelvir) 150 mg
Ritonavir 100 mg
Route of Administration
Oral
Use
Experimental
IMP or NIMP/AxMP
IMP
Study Arm(s)
Arm Title
PF-07321332 (nirmatrelvir)/ritonavir (5-Days)
Arm Type
Experimental
Arm Description
Participants will receive PF-07321332/ritonavir 300 mg/100 mg on Day 1 
followed by PF-07321332/ritonavir 150 mg/100 mg QD from Day 2 to Day 5.


PF-07321332 (Nirmatrelvir)/ritonavir
Protocol C4671028
Final Protocol Amendment 2, 09 Feb 2023
PFIZER CONFIDENTIAL
Page 16
Statistical Methods:
The sample size of 12 evaluable participants per cohort is considered to provide a suitable 
estimate of the precision of PK parameters of PF-07321332 (nirmatrelvir) in severe renal 
impairment patients on HD and not on HD, as this provided 40% precision (the width of 90% 
CI) for AUCinf and Cmax. To ensure sufficient PK data for analysis, any participant with 
insufficient PK samples for analysis may be replaced.  
TEAEs will be summarized with the number and percent of participants in the SAS through 
Day 34 for two cohorts and overall. 
For summary statistics by sampling time, the nominal PK sampling time will be used. For 
individual participant plots by time, the actual PK sampling time will be used. PF-07321332 
(nirmatrelvir)/ritonavir plasma concentration data will be analyzed using a population PK 
analysis approach (nonlinear mixed effects models). Box and whisker plots for individual 
participant parameters (AUCinf and Cmax) will be constructed by each cohort and overlaid 
with geometric means.
Ethical Considerations:
Data from the Phase 3 study (Study C4671005) support the use of PF-07321332 
(nirmatrelvir)/ritonavir in patients who are at high-risk for progression to severe COVID-19 
including hospitalization or death. Patients with severe renal impairment affected by 
COVID-19 are considered at high-risk of progressing to severe infection. PF-07321332 
(nirmatrelvir) PK and safety was evaluated in severe renal impairment (Study C4671011). A 
single dose of PF-07321332 (nirmatrelvir) 100 mg/ritonavir 100 mg was generally safe and 
well-tolerated in both healthy and renally impaired adult participants (Study C4671011).
Given the limited treatment options to treat COVID-19 infections in the severe renal 
impairment population, participants may experience the benefit of improvement of the 
clinical course of their SARS-CoV-2 infection through participation in this study while 
receiving close monitoring and more frequent assessments compared to the standard of care. 
PK and safety in PF-07321332 (nirmatrelvir) has not yet been evaluated in HD patients. The 
study design will be open-label and will allow for close monitoring for any potential safety 
events related to PF-07321332 (nirmatrelvir)/ritonavir in the severe renal impairment 
population both on and not on HD.


PF-07321332 (Nirmatrelvir)/ritonavir
Protocol C4671028
Final Protocol Amendment 2, 09 Feb 2023
PFIZER CONFIDENTIAL
Page 17
1.2. Schema


PF-07321332 (Nirmatrelvir)/ritonavir
Protocol C4671028
Final Protocol Amendment 2, 09 Feb 2023
PFIZER CONFIDENTIAL
Page 18
1.3. Schedule of Activities
The SoA table provides an overview of the protocol visits and procedures. Refer to the STUDY ASSESSMENTS AND 
PROCEDURES section of the protocol for detailed information on each procedure and assessment required for compliance with the 
protocol. 
The investigator may schedule visits (unplanned visits) in addition to those listed in the SoA table, in order to conduct evaluations or 
assessments required to protect the well-being of the participant. 
Visit Identifier
Screening
Baseline
(Day 1)
Day 5
Day 10
Day 14
Day
21
Day
34
ET 
Notes
Visit Window
Day -1 to Day 1
0 days
0 days 
±1 day
±2 days
±2 days
±3 days
Type of Visit
In-Person Site or 
Home Health Visit
with Telehealth
In-Person 
Site Visit
In-Person 
Site or 
Home 
Health 
Visit
Telehealth 
Visit
In-Person 
Site, Home 
Health or 
Telehealth 
Visit
Telehealth 
Visit
In-Person 
Site, Home 
Health or
Telehealth 
Visit
In-Person 
Site, Home 
Health or 
Telehealth 
Visit
ELIGIBILITY
Informed consent
X

See Section 10.1.3.
Verify inclusion/exclusion 
criteria
X

See Sections 5.1 and 5.2.
Demographics and medical 
history
X

COVID-19 vaccination status will be 
collected as part of the medical history.
PHYSICAL EXAMINATION & VITAL SIGNS
Targeted physical examination
X
X
X
[X]
[X]
[X]

Will be completed at all in-person visits. 
If not done at Screening, the procedures 
listed may be completed on Day 1 to 
assess eligibility prior to randomization 
and dispensing treatment.

Previously identified AEs (either by 
interview, physical exam, or other 
assessment) should be monitored to the 
extent possible if telehealth is used.

Targeted physical examinations see
Section 8.3.1.

Vital signs see Section 8.3.3. (Further 
details for HD treatment days).
Vital signs
X
X
X


PF-07321332 (Nirmatrelvir)/ritonavir
Protocol C4671028
Final Protocol Amendment 2, 09 Feb 2023
PFIZER CONFIDENTIAL
Page 19
Visit Identifier
Screening
Baseline
(Day 1)
Day 5
Day 10
Day 14
Day
21
Day
34
ET 
Notes
Visit Window
Day -1 to Day 1
0 days
0 days 
±1 day
±2 days
±2 days
±3 days
Type of Visit
In-Person Site or 
Home Health Visit
with Telehealth
In-Person 
Site Visit
In-Person 
Site or 
Home 
Health 
Visit
Telehealth 
Visit
In-Person 
Site, Home 
Health or 
Telehealth 
Visit
Telehealth 
Visit
In-Person 
Site, Home 
Health or
Telehealth 
Visit
In-Person 
Site, Home 
Health or 
Telehealth 
Visit
Weight, height
X
X

Height may be self-reported.

HD treatment days will require database 
entry of pre- and post-dialysis weight. 
See Section 8.3.2.
LABORATORY
Hematology
[X]
X
X
[X]
[X]
[X]

Screening visit: Laboratory assessments 
are not required at screening unless 
deemed necessary by the investigator to 
confirm eligibility. The medical 
laboratory test abnormalities within 
3 months prior to screening must be 
closely assessed. 

Screening visit: If Laboratory 
assessments cannot be verified within 
3 months of screening, local laboratory 
testing should be performed at screening 
to confirm eligibility for the study.

Baseline laboratory assessments should 
be collected prior to first dose of study 
intervention. 

SARS-CoV-2 serology sample should be 
collected if an in-person (in clinic or 
home health) visit is conducted at Day 
14 ±2, Day 34 ±3 or ET visits.

Safety laboratory tests (hematology, 
blood chemistry) at Days 14±2 and 34±3 
/ET are required only if clinically 
significant abnormal laboratory values 
were present from a sample drawn at the
previous study visit when laboratory 
assessments were performed. 

Abnormal laboratory values related to 
AEs should be followed until resolution. 
See Section 8.3.4 and Appendix 2.
Blood chemistry
[X]
X
X
[X]
[X]
[X]
SARS-CoV-2 Serology (IgG 
and IgM)
[X]
X
X
[X]
[X]
[X]


PF-07321332 (Nirmatrelvir)/ritonavir
Protocol C4671028
Final Protocol Amendment 2, 09 Feb 2023
PFIZER CONFIDENTIAL
Page 20
Visit Identifier
Screening
Baseline
(Day 1)
Day 5
Day 10
Day 14
Day
21
Day
34
ET 
Notes
Visit Window
Day -1 to Day 1
0 days
0 days 
±1 day
±2 days
±2 days
±3 days
Type of Visit
In-Person Site or 
Home Health Visit
with Telehealth
In-Person 
Site Visit
In-Person 
Site or 
Home 
Health 
Visit
Telehealth 
Visit
In-Person 
Site, Home 
Health or 
Telehealth 
Visit
Telehealth 
Visit
In-Person 
Site, Home 
Health or
Telehealth 
Visit
In-Person 
Site, Home 
Health or 
Telehealth 
Visit
Pregnancy test (β-hCG)
X
X
X

A negative urine pregnancy test must be 
confirmed at screening and prior to 
dispensing treatment for all WOCBP. 
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 ±3 or ET visit. 

Local urine testing (ie, at the site, home, 
etc) will be standard for the protocol 
unless serum testing is required by local 
regulation or IRB/EC or the participant 
is anuric. 

See Section 8.3.5, Appendix 2 and 
Appendix 4.
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 and Appendix 9.
Rapid antigen testing
X

Only required if a participant does not 
have results of a positive SARS-CoV-2 
test that was obtained within 5 days prior 
treatment assignment.

See Section 5.1.
CCI


PF-07321332 (Nirmatrelvir)/ritonavir
Protocol C4671028
Final Protocol Amendment 2, 09 Feb 2023
PFIZER CONFIDENTIAL
Page 21
Visit Identifier
Screening
Baseline
(Day 1)
Day 5
Day 10
Day 14
Day
21
Day
34
ET 
Notes
Visit Window
Day -1 to Day 1
0 days
0 days 
±1 day
±2 days
±2 days
±3 days
Type of Visit
In-Person Site or 
Home Health Visit
with Telehealth
In-Person 
Site Visit
In-Person 
Site or 
Home 
Health 
Visit
Telehealth 
Visit
In-Person 
Site, Home 
Health or 
Telehealth 
Visit
Telehealth 
Visit
In-Person 
Site, Home 
Health or
Telehealth 
Visit
In-Person 
Site, Home 
Health or 
Telehealth 
Visit
Specified biomarker research 
(plasma)
X
X
[X]
[X]
[X]

Samples will be collected at Day 1 and 
Day 5 for all participants. 

If an in-person (site or home health) visit 
is conducted, this sample should be 
collected at Day 14 ±2 days, Day 34 ±3 
days and ET visits.

See Section 8.7.2.1.
Retained Research Samples for 
biomarkers (Prep B2.5)
X
X
[X]
[X]
[X]

Samples will be collected at Day 1 and 
Day 5 for all participants. 

See Section 8.7.3.

If an in-person (site or home health) visit 
is conducted, this sample should be 
collected at Day 14 ±2 days, Day 34 ±3 
days or ET visits.
Retained research samples for 
genetics (Prep D1)
X

Prep D1 Retained Research Samples for 
Genetics: If not collected on the 
designated collection day, collect at the 
next available time point when 
biospecimens are being collected in 
conjunction with a participant visit.

See Section 8.6.2.
PHARMACOKINETICS
Tasso M20 Device Training 
X

For Tasso collection, the site staff should 
confirm and document in the source that 
the participant (and/or caregivers) 
receives training on sample collection 
and can collect a sample for training 
purposes only at Screening.

Eligibility should be assessed against 
available information prior to conducting 
Tasso Training. See Section 8.1.
CCI


PF-07321332 (Nirmatrelvir)/ritonavir
Protocol C4671028
Final Protocol Amendment 2, 09 Feb 2023
PFIZER CONFIDENTIAL
Page 22
Visit Identifier
Screening
Baseline
(Day 1)
Day 5
Day 10
Day 14
Day
21
Day
34
ET 
Notes
Visit Window
Day -1 to Day 1
0 days
0 days 
±1 day
±2 days
±2 days
±3 days
Type of Visit
In-Person Site or 
Home Health Visit
with Telehealth
In-Person 
Site Visit
In-Person 
Site or 
Home 
Health 
Visit
Telehealth 
Visit
In-Person 
Site, Home 
Health or 
Telehealth 
Visit
Telehealth 
Visit
In-Person 
Site, Home 
Health or
Telehealth 
Visit
In-Person 
Site, Home 
Health or 
Telehealth 
Visit

The participant (and/or caregiver) should 
demonstrate proficiency with Tasso 
collection. If the participant has not yet 
shown proficiency at screening during a 
training Tasso collection, the Day 1 
required Tasso PK sample collection 
needs to be observed in-clinic.

Site should consider contacting the 
participant (and/or caregiver) for the first 
time a Tasso sample collection is 
performed at home, via a telehealth visit.

See Section 8.5.
For participants not on HD 
(Cohort 1): PK sample collected 
at in-person visits or collected 
using Tasso device
X (See PK schema)

Cohort 1: See PK sampling schema for 
participants with severe renal 
impairment not on HD (Cohort 1).

The Tasso PK and and venous blood 
(split venous blood sample into 2 
aliquotes; whole blood and plasma) will 
be collected on-site (investigational site
or home health visit)) for PK analyses
as per the PK Sampling Schema. 

See PK schema below and Section 8.5.
For participants on HD (Cohort 
2): PK sample collected at in-
person visits, at dialysis 
(venous) or collected using 
Tasso device
X (See PK schema)

See PK sampling schema for participants 
with severe renal impairment on HD 
(Cohort 2).

The Tasso PK and venous blood (split 
venous blood sample into 2 aliquotes; 
whole blood and plasma) will be
collected on-site (investigational site or 
HD center) for PK analyses as per the 
PK Sampling Schemas.

See PK schemas below and Section 8.5.
TREATMENT 
ASSIGNMENT
X

Participants will be assigned treatment 
using an IRT system. 


PF-07321332 (Nirmatrelvir)/ritonavir
Protocol C4671028
Final Protocol Amendment 2, 09 Feb 2023
PFIZER CONFIDENTIAL
Page 23
Visit Identifier
Screening
Baseline
(Day 1)
Day 5
Day 10
Day 14
Day
21
Day
34
ET 
Notes
Visit Window
Day -1 to Day 1
0 days
0 days 
±1 day
±2 days
±2 days
±3 days
Type of Visit
In-Person Site or 
Home Health Visit
with Telehealth
In-Person 
Site Visit
In-Person 
Site or 
Home 
Health 
Visit
Telehealth 
Visit
In-Person 
Site, Home 
Health or 
Telehealth 
Visit
Telehealth 
Visit
In-Person 
Site, Home 
Health or
Telehealth 
Visit
In-Person 
Site, Home 
Health or 
Telehealth 
Visit

See Section 6.3.
STUDY INTERVENTION
Study intervention 
administration
Day 1 through Day 5 
(5 doses total)

All participants take 2 tablets of 
PF-07321332 (nirmatrelvir) and 
1 capsule of ritonavir (300 mg/100 mg) 
on Day 1. On Days 2-5, take 1 tablet of 
PF-07321332 (nirmatrelvir) and 
1 capsule of ritonavir (150 mg/100 mg)
daily. Take the tablet and capsule
approximately 10 minutes or less apart, 
if feasible, but no more than 15 minutes 
apart.

For non-HD pts (Cohort 1):

Participants should take the first
dose of study intervention on Day 1 
during the in-clinic visit. 

The participant selects a once daily 
dosing time for Days 2-5. Day 2 
dose should be taken no earlier 
than 14 hours and no later than 
28 hours after the Day 1 dose.

The remaining doses (Days 3-5) 
should be taken at approximately 
the same time (±4 hours) as the 
Day 2 dose.

For HD participants (Cohort 2):

If Day 1 dose is taken on a non-
HD day:
o
Participants should take the 
Day 1 dose of study 
intervention during the 
in-clinic visit.
o
For Days 2-5, the participant 
selects a once daily dosing 


PF-07321332 (Nirmatrelvir)/ritonavir
Protocol C4671028
Final Protocol Amendment 2, 09 Feb 2023
PFIZER CONFIDENTIAL
Page 24
Visit Identifier
Screening
Baseline
(Day 1)
Day 5
Day 10
Day 14
Day
21
Day
34
ET 
Notes
Visit Window
Day -1 to Day 1
0 days
0 days 
±1 day
±2 days
±2 days
±3 days
Type of Visit
In-Person Site or 
Home Health Visit
with Telehealth
In-Person 
Site Visit
In-Person 
Site or 
Home 
Health 
Visit
Telehealth 
Visit
In-Person 
Site, Home 
Health or 
Telehealth 
Visit
Telehealth 
Visit
In-Person 
Site, Home 
Health or
Telehealth 
Visit
In-Person 
Site, Home 
Health or 
Telehealth 
Visit
time that would be after HD.
Day 2 dose should be taken no 
earlier than 14 hours and no 
later than 28 hours after the 
Day 1 dose.
o
The remaining doses (Days 3-
5) should be taken at 
approximately the same time 
(±4 hours) as the Day 2 dose.

If Day 1 dose is taken on an HD 
day:
o
Participants should take the 
Day 1 dose of study 
intervention in the clinic after 
HD.
o
On study Day 2, the 
participant selects a once daily 
dosing time that would be 
after the typical time the 
participant would complete
HD on HD days. Day 2 dose
should be taken no earlier than 
14 hours and no later than 
28 hours after the Day 1 dose.
o
The remaining doses (Days 3-
5) should be taken at 
approximately the same time 
(±4 hours) as the Day 2 dose.

See Section 6.1.


PF-07321332 (Nirmatrelvir)/ritonavir
Protocol C4671028
Final Protocol Amendment 2, 09 Feb 2023
PFIZER CONFIDENTIAL
Page 25
Visit Identifier
Screening
Baseline
(Day 1)
Day 5
Day 10
Day 14
Day
21
Day
34
ET 
Notes
Visit Window
Day -1 to Day 1
0 days
0 days 
±1 day
±2 days
±2 days
±3 days
Type of Visit
In-Person Site or 
Home Health Visit
with Telehealth
In-Person 
Site Visit
In-Person 
Site or 
Home 
Health 
Visit
Telehealth 
Visit
In-Person 
Site, Home 
Health or 
Telehealth 
Visit
Telehealth 
Visit
In-Person 
Site, Home 
Health or
Telehealth 
Visit
In-Person 
Site, Home 
Health or 
Telehealth 
Visit
STUDY PROCEDURES
Collect/update secondary 
contacts
X
X

The investigator will capture contact 
information for at least 2 individuals 
who the site can contact if the participant 
is unable to be reached after multiple 
attempts.
Record COVID-19-related 
medical visits (Hospitalization 
and ER visit)
X
X
X
X
X
X

COVID-19 related hospitalizations and 
emergency department visits which have 
occurred since the last assessment will 
be collected. 

See Section 8.2.1.
Vital Status Check
X
X

Record the vital status (whether the 
participant is alive or dead) in the 
appropriate CRF.

See Section 7.2.1.
Study kit dispensed and 
participant instructed on its use
X

The study kit includes documents and 
materials that will facilitate participant 
completion of at-home study procedures.
Participant-completed electronic 
diary (study intervention log)
Day 1 through Day 5

The electronic diary will be provided or 
application downloaded to participant’s 
own device and training completed at the 
Baseline visit.

Daily dosing will be entered in an 
electronic diary Days 1 through Day 5. 
The Day 1 dose at the site should be 
entered in the eDiary by the participant 
(or caregiver) while on site.

For participants who are using an eDiary 
provided through the study, the eDiary 
will be collected on Day 5, the next 
scheduled visit or ET visit after 
completion of dosing log entries on the 
device.


PF-07321332 (Nirmatrelvir)/ritonavir
Protocol C4671028
Final Protocol Amendment 2, 09 Feb 2023
PFIZER CONFIDENTIAL
Page 26
Visit Identifier
Screening
Baseline
(Day 1)
Day 5
Day 10
Day 14
Day
21
Day
34
ET 
Notes
Visit Window
Day -1 to Day 1
0 days
0 days 
±1 day
±2 days
±2 days
±3 days
Type of Visit
In-Person Site or 
Home Health Visit
with Telehealth
In-Person 
Site Visit
In-Person 
Site or 
Home 
Health 
Visit
Telehealth 
Visit
In-Person 
Site, Home 
Health or 
Telehealth 
Visit
Telehealth 
Visit
In-Person 
Site, Home 
Health or
Telehealth 
Visit
In-Person 
Site, Home 
Health or 
Telehealth 
Visit
Investigational Site check of 
participant eDiary dosing 
entries
Day 1 through Day 5

On Days 1-5, site personnel will review 
eDiary participant dosing entries daily 
on the Trial Manager portal and contact 
participant if not completed.

See Section 6.5.
Record HD Details (Cohort 2 
only)
HD Days during
Day 1 through Day 5

During HD treatment, site staff should 
record relevant HD details on the 
designated CRF.
Retrieval of unused study 
intervention and empty study 
intervention containers 
X
[X]
[X]

If the Day 5 visit is conducted prior to 
last dose of study intervention on Day 5, 
empty study intervention containers, and 
unused study intervention should be 
returned at the next in-person visit (Day 
14). The electronic diary should be 
reviewed and device should be returned 
if applicable.

See Section 6.5.
Study intervention 
accountability
X
[X]
[X]

Study intervention accountability should 
be performed at Day 5 visit. If Day 5 
visit is prior to last dose of study 
intervention on Day 5, study intervention 
accountability can be performed at the 
next in-person visit (Day 14).

See Section 6.2.
Contraception check 
X
X
X
X
X
X
X
X

See Section 5.3.1.
Prior/concomitant medications
X
X
X
X
X
X
X
X

All prescription and over-the-counter 
medications including vaccines taken by 
the participant within 30 days before 
study entry (considered prior treatment) 
will be recorded. 

Concomitant therapies will be collected 
through the Day 34 visit.

See Section 6.9.


PF-07321332 (Nirmatrelvir)/ritonavir
Protocol C4671028
Final Protocol Amendment 2, 09 Feb 2023
PFIZER CONFIDENTIAL
Page 27
Visit Identifier
Screening
Baseline
(Day 1)
Day 5
Day 10
Day 14
Day
21
Day
34
ET 
Notes
Visit Window
Day -1 to Day 1
0 days
0 days 
±1 day
±2 days
±2 days
±3 days
Type of Visit
In-Person Site or 
Home Health Visit
with Telehealth
In-Person 
Site Visit
In-Person 
Site or 
Home 
Health 
Visit
Telehealth 
Visit
In-Person 
Site, Home 
Health or 
Telehealth 
Visit
Telehealth 
Visit
In-Person 
Site, Home 
Health or
Telehealth 
Visit
In-Person 
Site, Home 
Health or 
Telehealth 
Visit
Adjunctive therapeutic 
procedures 
X
X
X
X
X
X
X
X

Non-drug treatments and procedures will 
be collected through the Day 34 visit. 
Serious and nonserious AE
monitoring
X
X
X
X
X
X
X
X

AEs should be assessed by means of a 
telehealth visit if not feasible via an in-
person visit. See Section 8.1.3.

See Section 8.4.

Screening: Assessments indicated in brackets [X] will be performed only if needed to confirm eligibility.

Day 1- Day 34: Assessments indicated in brackets [X] will be performed for in-person (in-clinic or home health) visits and if required per the SoA.

Day 10 and Day 21 visits will be conducted by telehealth. Telehealth visits may be an in-person visit at the discretion of the investigator.

Day 34 visit may be conducted by telehealth if no in-person procedures need to be performed.

ET visit may be conducted by telehealth if no in-person procedures need to be performed or if a participant no longer wants to complete an in-person visit.

All efforts should be made to collect the PK sample on the day of study as designated in the PK schema for participants not on HD and for participants on HD. The visit windows listed in 
the SoA do not apply to the PK sample collection timepoints. Visit windows are applicable for study procedures (except PK sample collection).


PF-07321332 (Nirmatrelvir)/ritonavir
Protocol C4671028
Final Protocol Amendment 2, 09 Feb 2023
PFIZER CONFIDENTIAL
Page 28
PK SAMPLING SCHEMA 1 – COHORT 1: Severe Renal Impairment not on HD
Study Day
1
2
3
4
5
PF-07321332 
(nirmatrelvir)/ritonavir 
administration
X
X
X
X
Xa
Hours after doseb
1- 3
4 -8
9 to 15
0
1 – 4
0
0.5-6
9 to 15
PK blood sampling (Tasso)
Xc
Xc
Xc
Xd
Xc
Xd
Xc
Xc
Blood:Plasma Ratio sample
(venous)
Xe
[Xe]
[Xe]
[Xe]
a.
For Day 5 in-person (site or home health) visit:

If the time of the scheduled visit is within the dosing window (± 4 hours), participants should wait to take the dose of PF-07321332 
(nirmatrelvir)/ritonavir during the in-person visit. The dose will be taken after the pre-dose PK sample has been obtained and thereafter PK 
samples will be obtained according to the PK timepoint schedule; 

If the time of the scheduled visit is not within the dosing window (± 4 hours), participants should take the dose of PF-07321332 
(nirmatrelvir)/ritonavir at the participant’s usual time and PK samples will be obtained according to the PK timepoint schedule. 
b.
Hours are in reference to the QD dose of PF-07321332 (nirmatrelvir)/ritonavir on each study day. The Day 1 dose should be taken at the clinic 
visit.
c.
Tasso blood sample: After dosing study drug, Tasso device placed by participant, caregiver, home health provider, or other healthcare provider (as 
appropriate).
d.
Tasso blood sample: Prior to dosing study drug, Tasso device placed by participant, caregiver, home health provider, or other healthcare provider
(as appropriate).
e.
Blood:Plasma Ratio venous sample: Collect immediately before or after the Tasso sample but no longer than 15 minutes between the samples. The 
blood:plasma ratio sample tube is divided into 1 blood sample (in a cryovial) and, after centrifugation, 1 plasma sample (in another cryovial) 
(reference the Central Lab Manual). Collect first sample on Day 1 and second sample either on Day 3 or Day 4 or Day 5. It is advised to have 
second sample collected on Day 5, given the need for in-person visit.


PF-07321332 (Nirmatrelvir)/ritonavir
Protocol C4671028
Final Protocol Amendment 2, 09 Feb 2023
PFIZER CONFIDENTIAL
Page 29
PK SAMPLING SCHEMA 2 – COHORT 2: HD cohort with 1st Dose on HD day that is Monday
Study Day
Day 1 – HD
MONDAY
Day 2 – no HD
TUESDAY
Day 3 – HD
WEDNESDAY
Day 4 – no HD
THURSDAY
Day 5 – HD
FRIDAY
PF-07321332 
(nirmatrelvir)/ritonavir 
administration
Xb
X
Xb
X
Xb
Hours after dosea
1 – 3
Before and During HD
0
0.5 – 3
4 – 8
9 – 15 
Before HD start
PK blood sampling (Tasso)
Xf
Xc
Xc
Xf
Xf
Xf
[Xc]
PK blood sampling during 
HD (arterial and venous
ports)
Xd
Xe
Hematology blood sample 
(hematocrit)
Xi
Blood:Plasma Ratio sample 
(venous)
Xh
Xg, h
[Xh]
[Xg, h]
a.
Hours are in reference to the QD dose of PF-07321332 (nirmatrelvir)/ritonavir on each study day. The Day 1 dose should be taken at the clinic 
visit.
b.
On dialysis days, participants will take study intervention as soon as feasible after HD. 
c.
Tasso blood sample: Tasso device placed by participant, caregiver, home health provider, or other healthcare provider (as appropriate). 
d.
Venous blood samples: HD staff to obtain PK blood samples from the HD filter arterial port and the venous port at 0 hr (prior to start of HD) and at 
0.5, 1, 2, 3, and 4 hours post start of dialysis.
e.
Day 5 PK blood sample: If participant goes to HD treatment prior to going to investigational site on Day 5, then HD staff to obtain this venous 
sample prior to the start of dialysis from the venous HD line. If participant goes to investigational site prior to going to HD on Day 5, then 
investigational site staff can obtain PK sample using the Tasso device.
f.
Tasso blood samples: After dosing study drug, Tasso device placed by participant, caregiver, home health provider, or other healthcare provider (as 
appropriate). Collect the consecutive PK samples within the prescribed windows with each sample taken a minimum of 2 hours apart.
g.
Blood:Plasma Ratio venous sample: Collect at 0 hr prior to start of HD.
h.
Blood:Plasma Ratio venous sample: Collect immediately before or after a Tasso sample but no longer than 15 minutes between the samples. The 
blood:plasma ratio sample tube is divided into 1 blood sample (in a cryovial) and, after centrifugation, 1 plasma sample (in another cryovial) 
(reference the Central Lab Manual). Collect blood:plasma ratio samples on Day 1 and Day 3. If one sample is missed, it may be collected on Day 4 
or Day 5. Always collect a corresponding Tasso sample for each blood:plasma ratio sample.
i.
Hematocrit: Obtain 2 hematology blood samples (hematocrit) - one at time 0 hr (venous port sample) and one time of the last PK draw (venous port
sample) during HD (hematocrit needed for CLd calculations).


PF-07321332 (Nirmatrelvir)/ritonavir
Protocol C4671028
Final Protocol Amendment 2, 09 Feb 2023
PFIZER CONFIDENTIAL
Page 30
PK SAMPLING SCHEMA 3 - COHORT 2: HD cohort with 1st Dose on HD day that is Tuesday
Study Day
Day 1 – HD
TUESDAY
Day 2 - no HD
WEDNESDAY
Day 3 - HD
THURSDAY
Day 4 - no HD
FRIDAY
Day 5 - HD
SATURDAY
PF-07321332 
(nirmatrelvir)/ritonavir 
administration
Xb
X
Xb
X
Xb
Hours after dosea
1 – 3
Before and During HD
0
0.5 - 3
4 - 8
9 - 15 
Before HD start
PK blood sampling (Tasso)
Xf
Xc
Xc
Xf
Xf
Xf
[Xc]
PK blood sampling during 
HD (arterial and venous
ports)
Xd
Xe
Hematology blood sample 
(hematocrit)
Xi
Blood:Plasma Ratio sample 
(venous)
Xh
Xg, h
[Xh]
[Xg, h]
a.
Hours are in reference to the dose of PF-07321332 (nirmatrelvir)/ritonavir on each study day. The Day 1 dose should be taken at the clinic visit.
b.
On dialysis days, participants will take study intervention as soon as feasible after HD. 
c.
Tasso blood sample: Tasso device placed by participant, caregiver, home health provider, or other healthcare provider (as appropriate). 
d.
Venous blood samples: HD staff to obtain PK blood samples from the HD filter arterial port and the venous port at 0 hr (prior to start of HD) and at 
0.5, 1, 2, 3, and 4 hours post start of dialysis. 
e.
Day 5 PK blood sample: If participant goes to HD treatment prior to going to investigational site on Day 5, then HD staff to obtain this venous 
sample prior to the start of dialysis from the venous HD line. If participant goes to investigational site prior to going to HD on Day 5, then 
investigational site staff can obtain PK sample using the Tasso device.
f.
Tasso blood samples: After dosing study drug, Tasso device placed by participant, caregiver, home health provider, or other healthcare provider (as 
appropriate). On Day 4, collect the consecutive PK samples within the prescribed windows with each sample taken a minimum of 2 hours apart.
g.
Blood:Plasma Ratio venous sample: Collect at 0 hr prior to start of HD.
h.
Blood:Plasma Ratio venous sample: Collect immediately before or after a Tasso sample but no longer than 15 minutes between the samples. The 
blood:plasma ratio sample tube is divided into 1 blood sample (in a cryovial) and, after centrifugation, 1 plasma sample (in another cryovial) 
(reference the Central Lab Manual). Collect blood:plasma ratio samples on Day 1 and Day 3. If one sample is missed, it may be collected on Day 4 
or Day 5. Always collect a corresponding Tasso sample for each blood:plasma ratio sample.
i.
Hematocrit: Obtain two hematology blood samples (hematocrit) - one at time 0 hr (venous port sample) and one time of the last PK draw (venous 
port sample) during HD (hematocrit needed for CLd calculations).


PF-07321332 (Nirmatrelvir)/ritonavir
Protocol C4671028
Final Protocol Amendment 2, 09 Feb 2023
PFIZER CONFIDENTIAL
Page 31
PK SAMPLING SCHEMA 4 - COHORT 2: HD cohort with 1st Dose on HD day that is Wednesday
Study Day
Day 1 – HD
WEDNESDAY
Day 2 - no HD
THURSDAY
Day 3 - HD
FRIDAY
Day 4 - no HD
SATURDAY
Day 5 - no HD
SUNDAY
PF-07321332 
(nirmatrelvir)/ritonavir 
administration
Xb
X
Xb
X
Xc
Hours after dosea
1 - 3
Before and During HD
0
0.5 - 3
4 - 8
9 - 15
0
PK blood sample (Tasso)
Xf
Xd
Xd
Xf
Xf
Xf
Xc, d
PK blood sampling during 
HD (arterial and venous
ports)
Xe
Hematology blood sample 
(hematocrit)
Xi
Blood:Plasma Ratio sample 
(venous)
Xh
Xg, h
[Xh]
[Xh]
a.
Hours are in reference to the dose of PF-07321332 (nirmatrelvir)/ritonavir on each study day. The Day 1 dose should be taken at the clinic visit.
b.
On dialysis days, participants will take study intervention as soon as feasible after HD. 
c.
For the Day 5-in-person visit, 1) if the time of the scheduled visit is within the dosing window (± 4 hours), participants should wait to take the dose 
of PF-07321332 (nirmatrelvir)/ritonavir until the in-person visit. The dose will be taken after the pre-dose PK sample has been obtained; 2). If the 
time of the scheduled visit is not within the dosing window (± 4 hours), participants should take the dose of PF-07321332 (nirmatrelvir)/ritonavir at 
the participant’s usual time and PK samples taken per the schedule. 
d.
Tasso blood sample: Tasso device placed by participant, caregiver, home health provider, or other healthcare provider (as appropriate). 
e.
Venous blood samples: HD staff to obtain PK blood samples from the HD filter arterial port and the venous port at 0 hr (prior to start of HD) and at 
0.5, 1, 2, 3, and 4 hours post start of dialysis. 
f.
Tasso blood samples: After dosing study drug, Tasso device placed by participant, caregiver, home health provider, or other healthcare provider (as 
appropriate). On Day 4, collect the consecutive PK samples within the prescribed windows with each sample taken a minimum of 2 hours apart.
g.
Blood:Plasma Ratio venous sample: Collect at 0 hr prior to start of HD.
h.
Blood:Plasma Ratio venous sample: Collect immediately before or after a Tasso sample but no longer than 15 minutes between the samples. The 
blood:plasma ratio sample tube is divided into 1 blood sample (in a cryovial) and, after centrifugation, 1 plasma sample (in another cryovial) 
(reference the Central Lab Manual). Collect blood:plasma ratio samples on Day 1 and Day 3. If one sample is missed, it may be collected on Day 4 
or Day 5. Always collect a corresponding Tasso sample for each blood:plasma ratio sample.
i.
Hematocrit: Obtain 2 hematology blood samples (hematocrit) - one at time 0 hr (venous port sample) and one time of the last PK draw (venous port 
sample) during HD (hematocrit needed for CLd calculations).


PF-07321332 (Nirmatrelvir)/ritonavir
Protocol C4671028
Final Protocol Amendment 2, 09 Feb 2023
PFIZER CONFIDENTIAL
Page 32
PK SAMPLING SCHEMA 5 - COHORT 2: HD cohort with 1st Dose on HD day that is Thursday
Study Day
Day 1 – HD
THURSDAY
Day 2 - no HD
FRIDAY
Day 3 - HD
SATURDAY
Day 4 - no HD
SUNDAY
Day 5 - no HD
MONDAY
PF-07321332 
(nirmatrelvir)/ritonavir 
administration
Xb
X
Xb
X
Xc
Hours after dosea
1 - 3
Before and During HD
0
0.5 - 3
4 - 8
9 - 15 
0
PK blood sample (Tasso)
Xf
Xd
Xd
Xf
Xf
Xf
Xd, h
PK blood sampling during 
HD (arterial and venous
ports)
Xe
Hematology blood sample 
(hematocrit)
Xi
Blood:Plasma Ratio sample 
(venous)
Xh
Xg,h
[Xh]
[Xh]
a.
Hours are in reference to the dose of PF-07321332 (nirmatrelvir)/ritonavir on each study day. The Day 1 dose should be taken at the clinic visit.
b.
On dialysis days, participants will take study intervention as soon as feasible after HD. 
c.
For the Day 5-in-person visit, 1) if the time of the scheduled visit is within the dosing window (± 4 hours), participants should wait to take the dose 
of PF-07321332 (nirmatrelvir)/ritonavir until the in-person visit. The dose will be taken after the pre-dose PK sample has been obtained; 2). If the 
time of the scheduled visit is not within the dosing window (± 4 hours), participants should take the dose of PF-07321332 (nirmatrelvir)/ritonavir at 
the participant’s usual time and PK samples taken per the schedule. 
d.
Tasso blood sample: Tasso device placed by participant, caregiver, home health provider, or other healthcare provider (as appropriate). 
e.
Venous blood samples: HD staff to obtain PK blood samples from the HD filter arterial port and the venous port at 0 hr (prior to start of HD) and at 
0.5, 1, 2, 3, and 4 hours post start of dialysis.
f.
Tasso blood samples: After dosing study drug, Tasso device placed by participant, caregiver, home health provider, or other healthcare provider (as 
appropriate). On Day 4, collect the consecutive PK samples within the prescribed windows with each sample taken a minimum of 2 hours apart.
g.
Blood:Plasma Ratio venous sample: Collected at 0 hr prior to start of HD.
h.
Blood:Plasma Ratio venous sample: Collected immediately before or after a Tasso sample but no longer than 15 minutes between the samples. The 
blood:plasma ratio sample tube is divided into 1 blood sample (in a cryovial) and, after centrifugation, 1 plasma sample (in another cryovial) 
(reference the Central Lab Manual). Collect blood:plasma ratio samples on Day 1 and Day 3. If one sample is missed, it may be collected on Day 4 
or Day 5. Always collect a corresponding Tasso sample for each blood:plasma ratio sample.
i.
Hematocrit: Obtain 2 hematology blood samples (hematocrit) - one at time 0 hr (venous port sample) and one time of the last PK draw (venous port 
sample) during HD (hematocrit needed for CLd calculations).


PF-07321332 (Nirmatrelvir)/ritonavir
Protocol C4671028
Final Protocol Amendment 2, 09 Feb 2023
PFIZER CONFIDENTIAL
Page 33
PK SAMPLING SCHEMA 6 - COHORT 2: HD cohort with 1st Dose on HD day that is Friday
Study Day
Day 1 – HD
FRIDAY
Day 2 - no HD
SATURDAY
Day 3 - no HD
SUNDAY
Day 4 - HD
MONDAY
Day 5 - no HD
TUESDAY 
PF-07321332 
(nirmatrelvir)/ritonavir 
administration
Xb
X
X
Xb
Xc
Hours after dosea
1 - 3
0
0.5 - 3
4 - 8
9-15
Before and During HD
0
PK blood sampling (Tasso)
Xe
Xd
Xe
Xe
Xe
Xd
Xd
PK blood sampling during 
HD (arterial and venous
ports)
Xf
Hematology blood sample 
(hematocrit)
Xi
Blood:Plasma Ratio sample 
(venous)
Xh
[Xh]
Xg, h
[Xh]
a.
Hours are in reference to the dose of PF-07321332 (nirmatrelvir)/ritonavir on each study day. The Day 1 dose should be taken at the clinic visit.
b.
On dialysis days, participants should take the dose of study intervention as soon as feasible after HD.
c.
For the Day 5 in-person visit, 1) if the time of the scheduled visit is within the dosing window (± 4 hours), participants should wait to take the dose 
of PF-07321332 (nirmatrelvir)/ritonavir until the in-person visit. The dose will be taken after the pre-dose PK sample has been obtained; 2). If the 
time of the scheduled visit is not within the dosing window (± 4 hours), participants should take the dose of PF-07321332 (nirmatrelvir)/ritonavir at 
the participant’s usual time and PK samples taken per the schedule. 
d.
Tasso blood sample: Tasso device placed by participant, caregiver, home health provider, or other healthcare provider (as appropriate). 
e.
Tasso blood samples: After dosing study drug, Tasso device placed by participant, caregiver, home health provider, or other healthcare provider (as 
appropriate). Collect the consecutive PK samples within the prescribed windows and with each sample a minimum of 2 hours apart. 
f.
Venous blood samples: HD staff to obtain PK blood samples from the HD filter arterial port and venous port at 0 hr (prior to start of HD) and at 
0.5, 1, 2, 3, and 4 hours post start of dialysis. 
g.
Blood:Plasma Ratio venous sample: Collected at 0 hr prior to start of HD
h.
Blood:Plasma Ratio venous sample: Collected immediately before or after a Tasso sample but no longer than 15 minutes between the samples. The 
blood:plasma ratio sample tube is divided into 1 blood sample (in a cryovial) and, after centrifugation, 1 plasma sample (in another cryovial) 
(reference the Central Lab Manual). Collect blood:plasma ratio samples on Day 1 and Day 4. If one sample is missed, it may be collected on Day 3
or Day 5. Always collect a corresponding Tasso sample for each blood:plasma ratio sample.
i.
Hematocrit: Obtain 2 hematology blood samples (hematocrit) - one at time 0 hr (venous port sample) and one time of the last PK draw (venous port 
sample) during HD (hematocrit needed for CLd calculations).


PF-07321332 (Nirmatrelvir)/ritonavir
Protocol C4671028
Final Protocol Amendment 2, 09 Feb 2023
PFIZER CONFIDENTIAL
Page 34
PK SAMPLING SCHEMA 7 - COHORT 2: HD cohort with 1st Dose on HD day that is Saturday
Study Day
Day 1 – HD
SATURDAY
Day 2 - no HD
SUNDAY
Day 3 - no HD
MONDAY
Day 4 - HD
TUESDAY
Day 5 - no HD 
WEDNESDAY
PF-07321332 
(nirmatrelvir)/ritonavir 
administration
Xb
X
X
Xb
Xc
Hours after dosea
1 - 3
0
0.5 - 3
4 - 8
9-15
Before and During HD
0
PK blood sampling (Tasso)
Xe
Xd
Xe
Xe
Xe
Xd
Xd
PK blood sampling during 
HD (arterial and venous
ports)
Xf
Hematology blood sample 
(hematocrit)
Xi
Blood:Plasma Ratio sample 
(venous)
Xh
[Xh]
Xg, h
[Xh]
a.
Hours are in reference to the dose of PF-07321332 (nirmatrelvir)/ritonavir on each study day. The Day 1 dose should be taken at the clinic visit.
b.
On dialysis days, participants should take the dose of study intervention as soon as feasible after HD.
c.
For the Day 5 in-person visit, 1) if the time of the scheduled visit is within the dosing window (± 4 hours), participants should wait to take the dose 
of PF-07321332 (nirmatrelvir)/ritonavir until the in-person visit. The dose will be taken after the pre-dose PK sample has been obtained; 2). If the 
time of the scheduled visit is not within the dosing window (± 4 hours), participants should take the dose of PF-07321332 (nirmatrelvir)/ritonavir at 
the participant’s usual time and PK samples taken per the schedule. 
d.
Tasso blood sample: Tasso device placed by participant, caregiver, home health provider, or other healthcare provider (as appropriate).  
e.
Tasso blood samples: After dosing study drug, Tasso device placed by participant, caregiver, home health provider, or other healthcare provider (as 
appropriate). Collect the consecutive PK samples within the prescribed windows with each sample taken a minimum of 2 hours apart.
f.
Venous blood samples: HD staff to obtain PK blood samples from the HD filter arterial port and venous port at 0 hr (prior to start of HD) and at 
0.5, 1, 2, 3, and 4 hours post start of dialysis. 
g.
Blood:Plasma Ratio venous sample: Collected at 0 hr prior to start of HD.
h.
Blood:Plasma Ratio venous sample: Collected immediately before or after a Tasso sample but no longer than 15 minutes between the samples. The 
blood:plasma ratio sample tube is divided into 1 blood sample (in a cryovial) and, after centrifugation, 1 plasma sample (in another cryovial) 
(reference the Central Lab Manual). Collect blood:plasma ratio samples on Day 1 and Day 4. If one sample is missed, it may be collected on Day 3 
or Day 5. Always collect a corresponding Tasso sample for each blood:plasma ratio sample.
i.
Hematocrit: Obtain 2 hematology blood samples (hematocrit) - one at time 0 hr (venous port sample) and one time of the last PK draw (venous port 
sample) during HD (hematocrit needed for CLd calculations).


PF-07321332 (Nirmatrelvir)/ritonavir
Protocol C4671028
Final Protocol Amendment 2, 09 Feb 2023
PFIZER CONFIDENTIAL
Page 35
PK SAMPLING SCHEMA 8 - COHORT 2: HD cohort with 1st Dose on non-HD day Monday
Study Day
Day 1 - no HD
MONDAY
Day 2 – HD
TUESDAY
Day 3 – no HD
WEDNESDAY
Day 4 – HD
THURSDAY
Day 5 - no HD
FRIDAY
PF-07321332 
(nirmatrelvir)/ritonavir 
administration
X
Xb
X
Xb
Xh
Hours after dosea
1 - 3
At end of HD
(prior to dosing)
0
0.5 - 3
4 - 8
9 - 15 
Before and during HD
0
PK blood sampling (Tasso)
Xe
[Xd]
Xd
Xe
Xe
Xe
Xd
Xd
PK blood sampling during 
HD (arterial and venous
ports)
Xc
Hematology blood sample 
(hematocrit)
Xi
Blood:Plasma Ratio 
sample (venous)
Xg
[Xg]
[Xg]
Xf, g
[Xg]
a.
Hours are in reference to the dose of PF-07321332 (nirmatrelvir)/ritonavir on each study day. The Day 1 dose should be taken at the clinic visit.
b.
On dialysis days, participants will take study intervention as soon as feasible after HD.
c.
Venous blood samples: HD staff to obtain PK blood samples from the HD filter arterial port and the venous port at 0 hr (prior to start of HD) and at 
0, 0.5, 1, 2, 3, and 4 hours post start of dialysis. 
d.
Tasso blood sample: Tasso device placed by participant, caregiver, home health provider, or other healthcare provider (as appropriate).
e.
Tasso blood samples: After dosing, Tasso device placed by participant, caregiver, home health provider, or other healthcare provider (as 
appropriate). Collect the consecutive PK samples within the prescribed windows with each sample taken a minimum of 2 hours apart.
f.
Blood:Plasma Ratio venous sample: Collected at 0 hr prior to start of HD
g.
Blood:Plasma Ratio venous sample: Collected immediately before or after a Tasso sample but no longer than 15 minutes between the samples. The 
blood:plasma ratio sample tube is divided into 1 blood sample (in a cryovial) and, after centrifugation, 1 plasma sample (in another cryovial) 
(reference the Central Lab Manual). Collect blood:plasma ratio samples on Day 1 and Day 4. If one sample is missed, it may be collected on Day 2, 
Day 3 or Day 5. Always collect a corresponding Tasso sample for each blood:plasma ratio sample.
h.
For the Day 5 in-person visit, 1) If the time of the scheduled visit is within the dosing window (± 4 hours), participants should wait to take the dose 
of PF-07321332 (nirmatrelvir)/ritonavir until the in-person visit. The dose will be taken after the pre-dose PK sample has been obtained; 2). If the 
time of the scheduled visit is not within the dosing window (± 4 hours), participants should take the dose of PF-07321332 (nirmatrelvir)/ritonavir at 
the participant’s usual time and PK samples taken per the schedule. 
i.
Hematocrit: Obtain 2 hematology blood samples (hematocrit) - one at time 0 hr (venous port sample) and one time of the last PK draw (venous port 
sample) during HD (hematocrit needed for CLd calculations).


PF-07321332 (Nirmatrelvir)/ritonavir
Protocol C4671028
Final Protocol Amendment 2, 09 Feb 2023
PFIZER CONFIDENTIAL
Page 36
PK SAMPLING SCHEMA 9 - COHORT 2: HD cohort with 1st Dose on non-HD day Tuesday
Study Day
Day 1 - no HD
TUESDAY
Day 2 – HD
WEDNESDAY
Day 3 – no HD THURSDAY
Day 4 – HD
FRIDAY
Day 5 - no HD
SATURDAY
PF-07321332 
(nirmatrelvir)/ritonavir 
administration
X
Xb
X
Xb
Xh
Hours after dosea
1 - 3
At end of HD
(prior to dosing)
0
0.5 - 3
4 - 8
9 - 15
Before and During HD
0
PK blood sampling (Tasso)
Xe
[Xd]
Xd
Xe
Xe
Xe
Xd
Xd
PK blood sampling during HD
(arterial and venous ports)
Xc
Hematology blood sample 
(hematocrit)
Xi
Blood:Plasma Ratio sample 
(venous)
Xg
[Xg]
[Xg]
Xf, g
[Xg]
a.
Hours are in reference to the dose of PF-07321332 (nirmatrelvir)/ritonavir on each study day. The Day 1 dose should be taken at the clinic visit.
b.
On dialysis days, participants will take study intervention as soon as feasible after HD.
c.
Venous blood samples: HD staff to obtain PK blood samples from the HD filter arterial port and the venous port at 0 hr (prior to start of HD) and at 
0, 0.5, 1, 2, 3, and 4 hours post start of dialysis. 
d.
Tasso blood sample: Tasso device placed by participant, caregiver, home health provider, or other healthcare provider (as appropriate).
e.
Tasso blood samples: After dosing, Tasso device placed by participant, caregiver, home health provider, or other healthcare provider (as 
appropriate). Collect the consecutive PK samples within the prescribed windows with each sample taken a minimum of 2 hours apart.
f.
Blood:Plasma Ratio venous sample: Collected at 0 hr prior to start of HD.
g.
Blood:Plasma Ratio venous sample: Collected immediately before or after a Tasso sample but no longer than 15 minutes between the samples. The 
blood:plasma ratio sample tube is divided into 1 blood sample (in a cryovial) and, after centrifugation, 1 plasma sample (in another cryovial) 
(reference the Central Lab Manual). Collect blood:plasma ratio samples on Day 1 and Day 4. If one sample is missed, it may be collected on Day 2, 
Day 3 or Day 5. Always collect a corresponding Tasso sample for each blood:plasma ratio sample.
h.
For the Day 5 in-person visit, 1) If the time of the scheduled visit is within the dosing window (± 4 hours), participants should wait to take the dose 
of PF-07321332 (nirmatrelvir)/ritonavir until the in-person visit. The dose will be taken after the pre-dose PK sample has been obtained; 2). If the 
time of the scheduled visit is not within the dosing window (± 4 hours), participants should take the dose of PF-07321332 (nirmatrelvir)/ritonavir at 
the participant’s usual time and PK samples taken per the schedule. 
i.
Hematocrit: Obtain 2 hematology blood samples (hematocrit) - one at time 0 hr (venous port sample) and one time of the last PK draw (venous port 
sample) during HD (hematocrit needed for CLd calculations).


PF-07321332 (Nirmatrelvir)/ritonavir
Protocol C4671028
Final Protocol Amendment 2, 09 Feb 2023
PFIZER CONFIDENTIAL
Page 37
PK SAMPLING SCHEMA 10 - COHORT 2: HD cohort with 1st Dose on non-HD day Wednesday
Study Day
Day 1 – no HD 
WEDNESDAY
Day 2 – HD
THURSDAY
Day 3 – no HD
FRIDAY
Day 4 - HD
SATURDAY
Day 5 - no HD
SUNDAY
PF-07321332 
(nirmatrelvir)/ritonavir 
administration
X
Xb
X
Xb
Xh
Hours after dosea
1 – 3
At end of HD
(prior to dosing)
0
0.5 – 3
4 – 8
9 – 15 
Before and During HD
0
PK blood sampling (Tasso)
Xe
[Xd]
Xd
Xe
Xe
Xe
Xd
Xd
PK blood sampling during 
HD (arterial and venous
ports)
Xc
Hematology blood sample 
(hematocrit)
Xi
Blood:Plasma Ratio sample 
(venous)
Xg
[Xg]
[Xg]
Xf, g
[Xg]
a.
Hours are in reference to the dose of PF-07321332 (nirmatrelvir)/ritonavir on each study day. The Day 1 dose should be taken at the clinic visit.
b.
On dialysis days, participants will take study intervention as soon as feasible after HD.
c.
Venous blood samples: HD staff to obtain PK blood samples from the HD filter arterial port and the venous port at 0 hr (prior to start of HD) and at 
0, 0.5, 1, 2, 3, and 4 hours post start of dialysis. 
d.
Tasso blood sample: Tasso device placed by participant, caregiver, home health provider, or other healthcare provider (as appropriate).
e.
Tasso blood samples: After dosing, Tasso device placed by participant, caregiver, home health provider, or other healthcare provider (as 
appropriate). Collect the consecutive PK samples within the prescribed windows with each sample taken a minimum of 2 hours apart.
f.
Blood:Plasma Ratio venous sample: Collected at 0 hr prior to start of HD
g.
Blood:Plasma Ratio venous sample: Collected immediately before or after a Tasso sample but no longer than 15 minutes between the samples. The 
blood:plasma ratio sample tube is divided into 1 blood sample (in a cryovial) and, after centrifugation, 1 plasma sample (in another cryovial) 
(reference the Central Lab Manual). Collect blood:plasma ratio samples on Day 1 and Day 4. If one sample is missed, it may be collected on Day 2, 
Day 3 or Day 5. Always collect a corresponding Tasso sample for each blood:plasma ratio sample.
h.
For the Day 5 in-person visit, 1) If the time of the scheduled visit is within the dosing window (± 4 hours), participants should wait to take the dose 
of PF-07321332 (nirmatrelvir)/ritonavir until the in-person visit. The dose will be taken after the pre-dose PK sample has been obtained; 2). If the 
time of the scheduled visit is not within the dosing window (± 4 hours), participants should take the dose of PF-07321332 (nirmatrelvir)/ritonavir at 
the participant’s usual time and PK samples taken per the schedule. 
i.
Hematocrit: Obtain 2 hematology blood samples (hematocrit) - one at time 0 hr (venous port sample) and one time of the last PK draw (venous port 
sample) during HD (hematocrit needed for CLd calculations).


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PK SAMPLING SCHEMA 11 - COHORT 2: HD cohort with 1st Dose on non-HD day Thursday
Study Day
Day 1 - no HD 
THURSDAY
Day 2 – HD
FRIDAY
Day 3 – no HD
SATURDAY
Day 4 - no HD
SUNDAY
Day 5 – HD
MONDAY
PF-07321332 
(nirmatrelvir)/ritonavir 
administration
X
Xb
X
X
Xb
Hours after dosea
1 - 3
At end of HD 
(prior to dosing)
0
0.5 - 3
4 - 8
9 - 15 
0
Before and During HD
PK blood sampling (Tasso)
Xe
[Xd]
Xd
Xe
Xe
Xe
Xd
Xd
PK blood sampling during 
HD (arterial and venous
ports)
Xc
Hematology blood sample 
(hematocrit)
Xi
Blood:Plasma Ratio sample 
(venous)
Xh
[Xh]
[Xh]
[Xh]
Xg, h
a.
Hours are in reference to the dose of PF-07321332 (nirmatrelvir)/ritonavir on each study day. The Day 1 dose should be taken at the clinic visit.
b.
On dialysis days, participants will take study intervention as soon as feasible after HD.
c.
Venous blood samples: HD staff to obtain PK blood samples from theHD filter arterial port and the venous port at 0 hr (prior to start of HD) and at 
0, 0.5, 1, 2, 3, and 4 hours post start of dialysis.
d.
Tasso blood sample: Tasso device placed by participant, caregiver, home health provider, or other healthcare provider (as appropriate).
e.
Tasso blood samples: After dosing, Tasso device placed by participant, caregiver, home health provider, or other healthcare provider (as 
appropriate). Collect the consecutive PK samples within the prescribed windows with each sample taken a minimum of 2 hours apart.
f.
Venous blood sample: at end of HD prior to dosing, one sample will be drawn from the venous port. 
g.
Blood:Plasma Ratio venous sample: Collected at 0 hr prior to start of HD.
h.
Blood:Plasma Ratio venous sample: Collected immediately before or after a Tasso sample but no longer than 15 minutes between the samples. The 
blood:plasma ratio sample tube is divided into 1 blood sample (in a cryovial) and, after centrifugation, 1 plasma sample (in another cryovial) 
(reference the Central Lab Manual). Collect blood:plasma ratio samples on Day 1 and Day 5. If one sample is missed, it may be collected on Day 2, 
Day 3 or Day 4. Always collect a corresponding Tasso sample for each blood:plasma ratio sample.
i.
Hematocrit: Obtain 2 hematology blood samples (hematocrit) - one at time 0 hr (venous port sample) and one time of the last PK draw (venous port 
sample) during HD (hematocrit needed for CLd calculations).


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PK SAMPLING SCHEMA 12 - COHORT 2: HD cohort with 1st Dose on non-HD day Friday
Study Day
Day 1 - no HD 
FRIDAY
Day 2 – HD
SATURDAY
Day 3 - no HD
SUNDAY
Day 4 - no HD
MONDAY
Day 5 - HD
TUESDAY
PF-07321332 
(nirmatrelvir)/ritonavir 
administration
X
Xb
X
X
Xb
Hours after dosea
1 - 3
At end of HD 
(prior to dosing)
0
0.5 - 3
4 - 8
9 - 15
0
Before and During HD
PK blood sampling (Tasso)
Xe
[Xd]
Xd
Xe
Xe
Xe
Xd
Xd
PK blood sampling during 
HD (arterial and venous
ports)
Xc
Hematology blood sample 
(hematocrit)
Xh
Blood:Plasma Ratio sample 
(venous)
Xg
[Xg]
[Xg]
[Xg]
Xf, g
a.
Hours are in reference to the dose of PF-07321332 (nirmatrelvir)/ritonavir on each study day. The Day 1 dose should be taken at the clinic visit.
b.
On dialysis days, participants will take study intervention as soon as feasible after HD.
c.
Venous blood samples: HD staff to obtain PK blood samples from the HD filter arterial port and the venous port at 0 hr (prior to start of HD) and at 
0, 0.5, 1, 2, 3, and 4 hours post start of dialysis.  
d.
Tasso blood sample: Tasso device placed by participant, caregiver, home health provider, or other healthcare provider (as appropriate).
e.
Tasso blood samples: After dosing, Tasso device placed by participant, caregiver, home health provider, or other healthcare provider (as 
appropriate). Collect the consecutive PK samples within the prescribed windows with each sample taken a minimum of 2 hours apart.
f.
Blood:Plasma Ratio venous sample: Collected at 0 hr prior to start of HD.
g.
Blood:Plasma Ratio venous sample: Collected immediately before or after a Tasso sample but no longer than 15 minutes between the samples. The 
blood:plasma ratio sample tube is divided into 1 blood sample (in a cryovial) and, after centrifugation, 1 plasma sample (in another cryovial) 
(reference the Central Lab Manual). Collect blood:plasma ratio samples on Day 1 and Day 5. If one sample is missed, it may be collected on Day 2, 
Day 3 or Day 4. Always collect a corresponding Tasso sample for each blood:plasma ratio sample.
h.
Hematocrit: Obtain 2 hematology blood samples (hematocrit) - one at time 0 hr (venous port sample) and one time of the last PK draw (venous port 
sample) during HD (hematocrit needed for CLd calculations).


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2. INTRODUCTION
PF-07321332 (nirmatrelvir), an orally administered potent and selective SARS-CoV-2 Mpro
inhibitor, is currently being investigated in participants with COVID-19 and severe renal 
impairment. 
2.1. Study Rationale 
The purpose of this study is to evaluate the safety and PK of PF-07321332 
(nirmatrelvir)/ritonavir for the treatment of adult participants with COVID-19 with severe 
renal impairment not on HD and on HD. 
The safety and efficacy of PF-07321332 (nirmatrelvir)/ritonavir in adults was demonstrated 
in Study C4671005 (EPIC-HR, NCT04960202), which enrolled non-hospitalized 
symptomatic adults with confirmed COVID-19 with at least one risk factor for progression to 
severe disease. Participants who received PF-07321332 (nirmatrelvir)/ritonavir within 5 days 
of symptom onset had an 88% (95% CI: 75%, 94%) reduction in risk of COVID-19 related 
hospitalization or death. 
On 22 December 2021, the US FDA granted Emergency Use Authorization to PF-07321332 
(nirmatrelvir) co-packaged with 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 use of PF-07321332 (nirmatrelvir)/ritonavir is 
presently not recommended in adults with severe renal impairment due to a lack of data in 
this population.2 The safety and pharmacokinetics of PF-07321332 (nirmatrelvir) has not 
been studied in adult participants with COVID-19 who require HD and there is limited 
available data in renal impairment not on HD.
2.2. Background 
In December 2019, COVID-19 was identified as a new, potentially fatal, respiratory infection 
caused by the novel coronavirus, SARS-CoV-2. The WHO declared COVID-19 a Public 
Health Emergency of International Concern on 30 January 2020 and further characterized the 
disease outbreak as a pandemic on 11 March 2020.3 As of 22 June 2022, at least 540 million 
cases have been confirmed worldwide, and at least 6.3 million deaths have occurred.4
COVID-19 manifests as a wide range of illness, from asymptomatic infection to severe 
pneumonia, ARDS, and death. Although most (approximately 80%) cases are asymptomatic 
or mild,5 patients who are hospitalized with COVID-19 may have significant morbidity and 
mortality6,7 and are at increased risk of developing complications such as severe 
inflammation associated with elevations in proinflammatory cytokines, ARDS, acute cardiac 
injury, thromboembolic events, hypercoagulability, and/or kidney injury.8-11 Moreover, other 
comorbidities, such as hypertension, obesity, and diabetes, as well as older age and male sex 
increase the risk for worse outcomes.6
Patients with COVID-19 may have pre-existing renal impairment due to CKD, which is 
known to have an estimated global prevalence of 8.5–9.8%.12 Renal impairment and renal 
replacement therapy are associated with an increased risk of infection due to comorbidities, 


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uremia, and skin barrier disruptions. Impairment of renal function is independently 
associated with an increase in susceptibility to SARS-CoV-2 infection and COVID-19 
disease and subsequent risk of adverse outcomes.13 In one large study population-based study 
in England of over 17 million adults, a history of dialysis or end-stage renal failure was 
associated with a 3 to 4-fold increase in the risk of death from COVID-19.13
There is a high unmet need for effective antiviral agents that can be used in patients with 
COVID-19 and severe renal impairment who are at high risk of progression to severe 
disease. Although there are treatments for COVID-19 which are approved under emergency 
use authorizations, there is limited data on the safety and PK of the treatments in patients 
with severe renal impairment or on HD.13-17 Remdesivir, an IV anti-viral with activity against 
SARS-CoV-2 which is approved15 for hospitalized and non-hospitalized patients with 
COVID-19 at high risk of progression to severe COVID-19 or death, is not recommended for 
patients with eGFR <30 mL/min.15 Molnupiravir, another anti-viral agent with activity 
against SARS-CoV-2, has received emergency use authorization from FDA for treatment of 
mild-to-moderate COVID-19 in adults at high risk for progression to severe COVID-1917. 
The PK of molnupiravir has not been evaluated in patients with end stage renal disease or on 
dialysis, although a significant effect on exposure is not expected. Molnupiravir reported in 
the final analysis in 1433 patients with at least one risk factor for progression of COVID-19 
showed 6.8% hospitalization or death in the molnupiravir group versus 9.7% in the placebo 
group (a 31% risk reduction).17
Currently there are 2 monoclonal antibody treatments which have received EUA for 
outpatient use in high-risk patients affected by COVID-19. Bebtelovimab and sotrovimab 
both have demonstrated activity against the SARS-CoV-2 Omicron variant. Although no 
clinical trials have been conducted for sotrovimab and bebtelovimab in renally impaired 
participants, renal impairment is not expected to affect the exposure of both of these 
agents.18,19
PF-07321332 (nirmatrelvir) is a potent and selective inhibitor of the SARS-CoV-2 Mpro and 
is being developed as an oral treatment in patients with COVID-19. An oral antiviral agent 
would be an easy and convenient method of drug administration without requiring attendance 
at a healthcare setting. Whereas mAb treatment and remdesivir need to be administered 
parenterally which will add additional burden on healthcare setting. 
This study will provide PK and safety data for PF-07321332 (nirmatrelvir)/ritonavir in 
participants with severe renal impairment not on HD and on HD. PF-07321332 (nirmatrelvir)
is co-administered with ritonavir, a strong CYP3A4 inhibitor, to achieve exposures sufficient 
to suppress viral replication through the entire dosing interval (ie, Ctrough>EC90). Ritonavir does 
not have any antiviral activity against the SARS-CoV-2 virus.
In published case series report of 15 HD patients with COVID-19, PF-07321332 
(nirmatrelvir)/ritonavir was found to be well tolerated with no SAEs.20


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2.2.1. Clinical Overview
C4671005 (NCT04960202), a Phase 2/3, randomized, double-blind, placebo-controlled study 
in non-hospitalized symptomatic adult participants with a laboratory-confirmed diagnosis of 
SARS-CoV-2 infection, included participants 18 years of age and older with at least 1 risk 
factor for progression to severe disease and with a COVID-19 symptom onset of 
≤5 days. The study excluded individuals with a history of prior COVID-19 infection or 
SARS-CoV-2 vaccination before the Day 34 visit. The primary efficacy endpoint was the 
proportion of participants with COVID-19 related hospitalization or death from any cause 
through Day 28.
In the analysis of the primary endpoint from all participants enrolled in Study C4671005, an 
89% reduction in COVID-19-related hospitalization or death from any cause compared with 
placebo in participants treated within 3 days of symptom onset was observed; 0.7% of 
participants who received PF-07321332 (nirmatrelvir)/ritonavir were hospitalized through 
Day 28 following randomization (5 of 697 hospitalized with no deaths), compared to 6.5% of 
participants who received placebo and were hospitalized or died (44 of 682 hospitalized with 
9 subsequent deaths) (p<0.0001). In a secondary endpoint, PF-07321332 
(nirmatrelvir)/ritonavir reduced the risk of hospitalization or death for any cause by 88% 
compared with placebo in participants treated within 5 days of symptom onset; 0.8% of 
patients who received PF-07321332 (nirmatrelvir)/ritonavir were hospitalized or died 
through Day 28 following randomization (8 of 1039 hospitalized with no deaths) compared 
with 6.3% of patients who received placebo (66 of 1046 hospitalized with 12 subsequent 
deaths) (p < 0.0001). Treatment with PF-07321332 (nirmatrelvir)/ritonavir was safe and well 
tolerated.
Study C4671002 (NCT05011513), is a Phase 2/3, randomized, double-blind, placebo 
controlled study in non-hospitalized symptomatic adults with low risk of progression to 
severe illness. A prespecified interim analysis of Study C4671002, which included 45% of 
the trial's planned enrollment, showed that the novel primary endpoint of self-reported, 
sustained alleviation of all symptoms for 4 consecutive days, for PF-07321332 
(nirmatrelvir)/ritonavir compared to placebo, was not met. The key secondary endpoint of 
COVID-19-related hospitalization or death from any cause through Day 28 was also 
examined at the interim analysis, showing 0.6% of those who received PF-07321332 
(nirmatrelvir)/ritonavir were hospitalized following randomization (2 of 333 hospitalized 
with no deaths), compared to 2.4% of participants who received placebo and were 
hospitalized (8 of 329 hospitalized with no deaths).
A Phase 1, open label, 2-part study (C4671011) to investigate the effect of stable mild (eGFR 
≥60 to <90 mL/min), moderate (eGFR ≥30 to <60 mL/min), or severe (eGFR <30 mL/min 
and not requiring dialysis) renal impairment on the plasma and urine PK, safety, and 
tolerability of PF-07321332 (nirmatrelvir) has been completed. PF-07321332 (nirmatrelvir)
systemic exposure increased with increasing severity of renal impairment.23
Following a single 100 mg dose of PF-07321332 (nirmatrelvir) administered orally in 
combination with ritonavir 100 mg dose given at four scheduled time points relative to the 
single dose, the adjusted geometric mean (90% CI) AUCinf, test/reference ratios for renal 


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impairment (test) compared to normal renal function (reference) were 123.8 % (99.6%, 
153.9%) for mild renal impairment, 187.4% (148.5%, 236.5%) for moderate renal 
impairment, and 304.49% (237.6%, 390.2%) for severe renal impairment. Adjusted 
geometric mean (90% CI) test/reference ratios for Cmax were 129.78% (101.9%, 165.3%) for 
mild renal impairment, 138.1% (113.2%, 168.6%) for moderate renal impairment, and 
148.0% (111.4%, 196.7%) for severe renal impairment participants. Regression plot of CL/F 
versus eGFR derived from CKD-EPI equation showed a clear trend of decreasing clearance 
with a decrease in renal function, with intercept of 1.83 (P = 0.0009) and slope of 0.05 
(P < 0.0001).
PF-07321332 (nirmatrelvir)/ritonavir was generally safe and well-tolerated in both healthy 
and renally impaired adult participants. The number of all-causality TEAEs were similar 
between the mild (1 AE), moderate (1 AE) and normal renal function (3 AEs) groups. All 
AEs in these 3 groups were mild and not considered treatment related. A greater number of 
participants in the severe renal impairment group experienced TEAEs (17 AEs experienced 
by 5 participants in the severe renally impaired group). Of these 17 AEs, 4 (dry mouth and 
dysgeusia) were considered treatment related. There were 3 SAEs occurring in 1 participant 
in the severe renally impaired group, including 1 SAE of acute kidney injury, which resulted 
in study withdrawal. None of the AEs or SAEs were considered treatment related in this 
participant. There were no clinically meaningful laboratory findings or trends observed in 
this study.
The proposed dose is being developed based on internal analysis of data on file using 
population PK modeling. This analysis demonstrated the CL was reduced by 1/3. This was 
based on PK modeling using draft data from renally impaired subjects enrolled in the C467 
program which included 4 subjects from Study C4671005. Of note, these participants did not 
experience significant safety events while on study. The data from PK modeling has 
supported the use of a reduced dose in severe renal impaired participants with COVID-19.
2.3. Benefit/Risk Assessment
More detailed information about the known and expected benefits and risks and reasonably 
expected AEs of PF-07321332 (nirmatrelvir)/ritonavir may be found in the PF-07321332 
(nirmatrelvir)/ritonavir 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: PF-07321332 
(nirmatrelvir)
Dysgeusia
In Study C4671005, dysgeusia was recorded as 
an AE by 6% of participants receiving 
PF-07321332 (nirmatrelvir)/ritonavir compared to 
<1% of participants receiving placebo
Participants may utilize recommendations to 
alleviate symptoms of dysgeusia while taking 
treatment such as peppermint post-dose. Dosing 
recommendations will be provided to the participant.
Emesis
Sporadic emesis was observed at ≥100 mg/kg/day 
of PF-07321332 (nirmatrelvir) in the 15-day NHP 
toxicology study. 
AEs will be monitored and participants may receive 
antiemetics.
Hypertension
Transient increases in systolic, diastolic and mean 
BP were observed in pre-clinical 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. 
Study Intervention: Ritonavir
Gastrointestinal disturbances (including diarrhea, 
nausea, vomiting, and abdominal pain)
Frequently reported adverse reaction in patients 
who are HIV-positive at 600 mg BID.
Lower dose of 100 mg QD is used in this study. 
There is a short duration of treatment (5 days). 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. 
In addition to ongoing review of AEs by the sponsor, 
an E-DMC will review safety data as described in
Section 10.1.5.1.
Rash (most commonly reported as erythematous 
and maculopapular, followed by pruritic)
Frequently reported adverse reaction in patients 
who are HIV-positive at 600 mg BID.
Lower dose used in this study. There will be close 
observation of AEs and monitoring through targeted 
physical exams. If needed therapeutic interventions 
per SoC may be provided.


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Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
Fatigue/Asthenia
Frequently reported adverse reaction in patients 
who are HIV-positive at 600 mg BID.
Lower dose used in this study. There will be close 
observation of AEs. Fatigue (low energy or 
tiredness) will be assessed through collection of daily 
signs and symptoms and will also be assessed 
through targeted physical examinations when 
performed during the study visits.
Study Procedures
Venipuncture will be performed during the study.
There is the risk of bleeding, bruising, hematoma 
formation, and infection at the venipuncture site.
Only appropriately qualified personnel will obtain 
the blood draw. 
Tasso device will be applied only to an upper 
extremity that does not have a functioning HD
access.
There is risk of bleeding, bruising, hematoma 
formation, and infection in the upper extremity 
and the upper extremity HD access with Tasso 
device placement.
Only participants undergoing HD and/or caregivers
of participants on HD, who have completed training 
on proper placement of Tasso device on upper 
extremities without a functioning HD access will be 
permitted to apply the Tasso device.


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2.3.2. Benefit Assessment
PF-07321332 (nirmatrelvir) has been shown to have SARS-CoV-2 antiviral activity in vitro 
and in Study C4671005 and is intended to reduce viral titers, thereby reducing the duration 
and severity of symptoms and the risk of hospitalization and mortality in SARS-CoV-2 
infected patients. Participants in Study C4671005 who received PF-07321332 
(nirmatrelvir)/ritonavir within 5 days of symptom onset had an 88% (95% CI: 75%, 94%) 
reduction in risk of COVID-19-related hospitalization or death. On this basis, the potential 
benefit to individual study participants who receive the study intervention may include a 
shorter time to clinical recovery, prevention of hospitalization, and a lower probability of 
progressing to more severe illness or death. The potential benefit of the study is that it may 
provide a new treatment option for non-hospitalized severe renal impairment patients with 
COVID-19 who are at risk of progression to severe disease. In the context of the global 
pandemic public health emergency, this treatment could play an important role in alleviating 
current pressures on health care systems globally. 
2.3.3. Overall Benefit/Risk Conclusion
Considering the current COVID-19 global pandemic and the high burden of both mortality 
and morbidity and the potential for future epidemic outbreaks, the lack of readily available 
outpatient treatment options, and the measures taken to minimize risk to participants in this 
study, the potential risks identified in association with PF-07321332 (nirmatrelvir)/ritonavir 
are justified by the anticipated benefits that may be afforded to severe renal impairment 
participants with COVID-19. 


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3. OBJECTIVES, ENDPOINTS, AND ESTIMANDS
Objectives
Endpoints
Estimands
Primary: 
Primary:
Primary:

To describe the safety and tolerability of 
PF-07321332 (nirmatrelvir)/ritonavir in 
adult participants with COVID-19 and 
severe renal impairment.
Incidence of TEAEs.
Incidence of SAEs and AEs 
leading to discontinuations.
Not Applicable.
Secondary:
Secondary:
Secondary:

To evaluate the effect of severe renal 
impairment on the PK of PF-07321332 
(nirmatrelvir) in participants not on HD.

To evaluate the effect of severe renal 
impairment on the PK of PF-07321332 
(nirmatrelvir) in participants on HD.
Plasma PF-07321332 
(nirmatrelvir) PK parameters 
including Cmax, CL/F, Vz/F, 
AUC0-tau, t½, and Ctrough 
estimated from the population 
PK model. 
Not Applicable.

To evaluate the effect of HD on the PK 
of PF-07321332 (nirmatrelvir).
HD clearance (CLd) of 
PF-07321332 (nirmatrelvir). 
Fraction of PF-07321332 
(nirmatrelvir) dose removed 
from the body by dialysis (Fd).
Not Applicable.
4. STUDY DESIGN
4.1. Overall Design
This is a Phase 1, open-label, multi-center, single arm study in approximately 
24 non-hospitalized adult participants with COVID-19 and severe renal impairment and not 
yet receiving intermittent HD (Cohort 1) and severe renal impairment receiving intermittent 
HD (Cohort 2). The following Cohorts will be enrolled: 

Cohort 1: Severe renal impairment (defined as eGFR <30 mL/min/1.73 m2) not on 
HD and mild-to-moderate COVID-19 disease with confirmed SARS-CoV-2 infection 
and initial onset of signs/symptoms attributable to COVID-19 within 5 days prior to 
the day of treatment assignment.
CCI


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
Cohort 2: Severe renal impairment on HD and mild-to-moderate COVID-19 disease 
with confirmed SARS-CoV-2 infection and initial onset of signs/symptoms 
attributable to COVID-19 within 5 days prior to the day of treatment assignment. 
All eligible participants will be assigned to receive a single dose of PF-07321332 
(nirmatrelvir)/ritonavir 300 mg/100 mg orally on Day 1 followed by PF-07321332 
(nirmatrelvir)/ritonavir 150 mg/100 mg QD from Day 2 to Day 5. Single dose PK study 
(Study C4671011) of PF-07321332 (nirmatrelvir)/ritonavir in mild, moderate, and severe 
renal impairment showed that the PF-07321332 (nirmatrelvir) exposure is approximately 
3-fold higher and CL/F is 67% lower in severe renal impairment participants relative to 
healthy volunteers. Published literature as well as internal data showed there is minimal to no 
effect of renal impairment on ritonavir PK.1, 23,24 Ritonavir 100 mg QD or BID dose has been 
used for several protease inhibitors (eg, darunavir) with small difference in dose normalized 
Ctrough of protease inhibitors. Additionally, the PK of PF-07321332 (nirmatrelvir) with 
100 mg QD of ritonavir in severe renal impairment participants is expected to be similar to 
those of healthy participants taking 100 mg BID of ritonavir. Therefore, the ritonavir dose of 
100 mg QD was selected for this study.The total study duration is up to 38 days and includes 
a 1-to 2-day screening period where participants can be screened on one day and randomized 
the next day or screened and randomized on the same day. Screening procedures can be 
performed over two days, but the participant must be randomized by the second day (Day 1) 
and begin study treatment. Therefore, Screening and Randomization can take no longer than 
2 consecutive days. After Screening, the participants takes study intervention for 5 days and 
completes the safety follow-up period through Day 34. Continued collection of ongoing 
safety information through SAE resolution will occur as applicable. 
For PK assessments in severe renal impairment participants not on HD, sparse PK samples 
will be collected on Day 1 through 5 of dosing. This should be collected using a Tasso device
and a venous blood sample as specified in the SoA.
For PK assessments in severe renal impairment participants on HD, samples will be collected 
on Days 1 through 5 of dosing with respect to the participant’s dialysis sessions during 
treatment. If at home, this should be collected using a Tasso device or may be done at an 
in-person visit, unless otherwise specified in the SoA. During HD, venous port (entering 
dialyzer) and arterial port (exiting the dialyzer) blood samples will be collected at 0, 0.5, 1, 2, 
3 and 4 hours post the start of dialysis. 
This study will use the program-level 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 for this study.
4.2. Scientific Rationale for Study Design
SARS-CoV-2 is the causative agent of COVID-19. SARS-CoV-2 is an enveloped, positive 
sense single-stranded RNA virus with a glycoprotein spike on the surface. Cell entry requires 
binding of the spike protein to the cellular receptor ACE-2 and priming of the spike 
glycoprotein by the host cell serine protease TMPRSS2.21


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Given the limited data available in severe renal impairment for COVID-19 treatment options 
and request by FDA during consideration of the EUA for PF-07321332 
(nirmatrelvir)/ritonavir to study PF-07321332 (nirmatrelvir) in this population, the study 
design is in accordance with available draft FDA guidance and takes into consideration the 
clinical course of these patients when affected by COVID-19 both on and not on HD.
The study population will be divided into a non-HD cohort and a HD cohort with severe 
renal impairment with awareness that they may be on several medications to be used with
caution when taken in conjunction with PF-07321332 (nirmatrelvir)/ritonavir. Therefore, the 
prohibited medications will be limited to those that are contraindicated per the EUA label, 
while deferring to clinical judgement by the investigator as well as consultation with the 
Sponsor for other listed medications to be used with caution.
The proposed PK sampling schedule for participants not on HD will provide flexibility 
around the participant’s schedule considering the study will be conducted in an outpatient 
setting and maintains the ability to provide close monitoring for safety. In the HD cohort, the 
PK schedule takes into consideration the schedule of intermittent HD given three times per 
week while also maintaining an appropriate dosing schedule to maintain an effective 
exposure while treating their COVID-19 infection and will inform the effect of HD on the 
PK of PF-07321332 (nirmatrelvir). 
4.2.1. Choice of Contraception/Barrier Requirements 
Human reproductive safety data are not available for PF-07321332 (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 
WOCBP (see Appendix 4).
The given study population reproductive capability is limited and the risk of reproductive 
safety may be minimized because of this. The investigator should determine the participant’s 
potential for becoming pregnant. For women who met Inclusion Criterion 1 in section 5.1 per 
the investigator’s assessment, an acceptable hormone based contraception should be used 
during the participant’s time in the study as described in Section 10.4.4.
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.
4.3. Justification for Dose
Single dose PK study (Study C4671011) of PF-07321332 (nirmatrelvir)/ritonavir in mild, 
moderate, and severe renal impairment showed that the PF-07321332 (nirmatrelvir) exposure 
is approximately 3-fold higher and CL/F is 67% lower in severe renal impairment 
participants relative to healthy volunteers. PF-07321332 (nirmatrelvir) PK data from 
Phase 2/3 study (Study C4671005) showed PF-07321332 (nirmatrelvir) exposure in mild to 
moderate COVID-19 patients with Baseline eGFR ≥45 mL/min/1.73 m2 is comparable to 
healthy adults. Population PK model-based simulations showed that the PF-07321332 


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(nirmatrelvir) single dose of 300 mg on Day 1 followed by 150 mg of PF-07321332 
(nirmatrelvir) QD on Day 2 to Day 5 with ritonavir 100 mg in severe renal impaired 
participants gives comparable exposure (AUC0-24 and Cmax) to COVID-19 patients with 
normal renal function at the 300 mg PF-07321332 (nirmatrelvir)/100 mg ritonavir BID dose 
for 5 days. Therefore, the PF-07321332 (nirmatrelvir) doses of 300 mg on Day 1 and 150 mg 
QD on Day 2 to Day 5 were selected for this study.
Ritonavir is mainly eliminated by hepatic metabolism and thus ritonavir PK is not altered in 
renal impairment participants. Published reports and internal data (C4671011 data on file) 
show ritonavir PK is comparable between normal healthy participants and severe renal 
impairment patients and only small fraction of ritonavir dose is removed by HD.1, 23, 24
Ritonavir 100 mg QD or BID dose has been used for several protease inhibitors (eg, 
darunavir) with small difference in dose normalized Ctrough of protease inhibitors.
Additionally, the PK of PF-07321332 (nirmatrelvir) with 100 mg QD of ritonavir in severe 
renal impairment participants is expected to be similar to those of healthy participants taking 
100 mg BID of ritonavir. Therefore, the ritonavir dose of 100 mg QD was selected for this 
study.
The proposed dosing regimen was studied in a non-randomized study in of 15 HD patients 
with COVID-19 and it was found to be well-tolerated with no SAEs.20
4.4. End of Study Definition
The end of the study is defined as the date of the last visit of the last participant in the study 
shown in the SoA for the last participant in the trial globally.
A participant is considered to have completed the study if they have completed all periods of 
the study, including the last visit shown in the SoA.
5. STUDY POPULATION
This study can fulfill its objectives only if appropriate participants are enrolled, including 
participants across diverse and representative racial and ethnic backgrounds. 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.


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5.1. Inclusion Criteria
Participants are eligible to be included in the study only if all of the following criteria apply:
Age and Sex:
1. Participants ≥18 years of age (or the minimum country specific age of consent if >18) 
at the time of the Screening Visit.

WOCBP may be enrolled.

WOCBP must agree to use an effective method of contraception described in 
Section 5.3. See Appendix 4 for reproductive criteria for male and female 
participants.
Disease Characteristics:
2. Mild-to-moderate COVID-19 disease as defined in Appendix 9 with confirmed 
SARS-CoV-2 infection in any specimen collected within 5 days prior to treatment 
assignment.
Note: RT-PCR is the preferred method; however, with evolving approaches to 
confirmation of SARS-CoV-2 infection, other molecular or antigen tests that detect 
viral RNA or protein are allowed. The test result must be available to confirm 
eligibility. Participants may be enrolled based on positive results of a rapid 
SARS-CoV-2 antigen test performed at screening.
3. Initial onset of signs/symptoms attributable to COVID-19 within 5 days prior to the 
day of treatment assignment. 
Other Inclusion Criteria:
4. Participants who are willing and able to comply with all scheduled visits, treatment 
plan, laboratory tests, lifestyle considerations, and other study procedures. 
Additional Inclusion Criteria for Cohort 1 (Severe Renally Impaired, and not on HD): 
5. Severe renal impairment defined as eGFR <30 mL/min/1.73m2 (using the 2021 
CKD-EPI serum creatinine only eGFR formula in Section 10.7.2.1) measured by 
clinical laboratory testing on at least 2 occasions, one of which must be within 
3 months of Screening and not receiving intermittent HD treatments. 
Additional Inclusion Criteria for Cohort 2 (Receiving HD): 
6. Receiving stable intermittent HD for at least 6 weeks prior to Screening. 


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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 or anticipated need for hospitalization within 
48 hours after randomization in the clinical opinion of the site investigator.
2. Renal transplant recipients.
3. History of severe chronic liver disease (eg, jaundice, ascites, hepatic encephalopathy, 
history of bleeding esophageal or gastric varices). No laboratory testing is needed.
4. Known HIV infection with viral load >400 copies/mL or HIV infection with CD4+ 
cell count <200/mm3.

Participants in Germany will be excluded if the screening HIV test is positive or if 
they do not consent to have an HIV test at screening.
5. Any comorbidity requiring hospitalization (excludes hospitalization for renal failure 
or HD) and/or surgery within 7 days prior to study entry, or that is considered life 
threatening within 30 days prior to study entry, as determined by the investigator.
6. History of hypersensitivity or other contraindication to any of the components of the 
study intervention, as determined by the investigator.
7. 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:
8. Current use of any medications that are highly dependent of CYP3A4 for clearance 
and which are contraindicated in combination with PF-07321332 
(nirmatrelvir)/ritonavir (Appendix 8). Participants taking lovastatin and simvastatin 
may enroll, provided that they have discontinued use at least 12 hours prior to 
initiation of PF-07321332 (nirmatrelvir)/ritonavir and refrain from use during 
treatment and for 5 days after the last dose of PF-07321332 (nirmatrelvir)/ritonavir. 
Coadministration of PF-07321332 (nirmatrelvir)/ritonavir with medications that are 
highly dependent on CYP3A4 for clearance may require dose adjustment or 
additional monitoring (See Appendix 8).
9. Use of any medications or substances that are strong inducers of CYP3A4 and that 
are contraindicated in combination with PF-07321332 (nirmatrelvir)/ritonavir without 
the appropriate washout prior to the first dose of PF-07321332 (nirmatrelvir)/ritonavir 
(see Appendix 8). The appropriate washout period for CYP3A4 inducers should be 


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determined based on the prescribing information for the concomitant medication and 
in consultation with the medical monitor. 
10. Has received or is expected to receive mAb treatment, convalescent COVID-19 
plasma, or anti-viral treatment (eg, molnupiravir, remdesivir) for the current 
SARS-CoV-2 infection (See Section 6.9).
Prior/Concurrent Clinical Study Experience:
11. Is unwilling to abstain from participating in another interventional clinical study with 
an investigational compound or device, including those for COVID-19 therapeutics, 
through the end of study. Previous administration with any investigational drug or 
vaccine within 30 days (or as determined by the local requirement) or 5 half-lives 
preceding the first dose of study intervention used in this study (whichever is longer).
12. Known prior participation in this trial or other trial involving PF-07321332 
(nirmatrelvir).
Diagnostic Assessments:
None.
Other Exclusion Criteria:
13. Females who are pregnant or breastfeeding.
14. 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 
No contraception methods are required for male participants in this study (see Appendix 4,
Section 10.4.1).
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
from the permitted list of contraception methods (see Appendix 4, Section 10.4.4) and will 
confirm that the participant has been instructed in its consistent and correct use. At time 
points indicated in the SoA, the investigator or designee will inform the participant of the 
need to use highly effective contraception consistently and correctly and document the 
conversation and the participant’s affirmation in the participant’s chart. Participants need to 
affirm their consistent and correct use of at least 1 of the selected methods of contraception, 
considering that their risk for pregnancy may have changed since the last visit. 


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In addition, the investigator or designee will instruct the participant to call immediately if the 
selected contraception method is discontinued and document the requirement to use an 
alternate protocol-specified method, including if the participant will no longer use abstinence 
as the selected contraception method, or if pregnancy is known or suspected in the participant 
or partner.
5.3.2. Other Considerations
5.3.2.1. Hemodialysis
Nausea and vomiting are commonly experienced by participants with severe CKD and can be 
exacerbated during HD treatments. Investigators shall provide guidance to study participants 
when investigational product dosing and drug absorption may be meaningfully impacted by 
nausea and/or vomiting. The investigator may refer to the IP manual for further guidance on 
alleviating nausea and/or vomiting during the treatment period. Examples of measures 
include but are not limited to taking study intervention with food which may improve 
tolerability or providing a peppermint following dosing.
Participants on HD (Cohort 2) should take their dose after end of HD on HD days.
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, eligibility details, and any SAE.
Individuals who do not meet the criteria for participation in this study (screen failure) may be 
rescreened as long as they meet eligibility criteria as outlined in Section 5. 
6. STUDY INTERVENTION(S) AND CONCOMITANT THERAPY
Study interventions are all prespecified investigational and non-investigational 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 PF-07321332 (nirmatrelvir)
300 mg with ritonavir 100 mg on Day 1 and PF-07321332 (nirmatrelvir) 150 mg with 
ritonavir 100 mg on Days 2 to Day 5.
6.1. Study Intervention(s) Administered
Day 1 of study intervention must be done in the clinic. The participant should receive the 
study intervention and the site should document that dosing and administration instructions 
were reviewed with the participant. Patients on HD (Cohort 2) should take their daily dose 
after HD. See Section 6.2.1.


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Intervention Name
PF-07321332 (nirmatrelvir)
Ritonavir 
ARM Name
(group of patients receiving a specific 
treatment (or no treatment)
PF-07321332
(nirmatrelvir)/ritonavir
PF-07321332 (nirmatrelvir)/ 
ritonavir
Type
drug
drug
Dose Formulation
tablet
capsule
Unit Dose Strength(s)
150 mg 
100 mg
Dosage Level(s)
300 mg (Day 1), 150 mg (Days 
2-5) 
100 mg 
Route of Administration
oral
oral
Use
experimental
experimental
IMP or NIMP
IMP
IMP
Sourcing
Provided centrally by the 
sponsor.
Refer to the IP manual.
Provided centrally by the 
sponsor.
Refer to the IP manual.
Packaging and Labeling
Study intervention will be 
provided in HDPE bottles. Each 
bottle will be labeled as 
required per country 
requirement and will be open-
label.
Study intervention will be 
provided in HDPE bottles. 
Each bottle will be labeled as 
required per country 
requirement and will be open-
label.
Current/Former Name(s) or Alias(es)
PF-07321332/nirmatrelvir
ritonavir
Arm Title
PF-07321332 (nirmatrelvir)/ritonavir 
(5-Days)
Arm Type
experimental 
Arm Description
Participants will receive PF-07321332/ritonavir 300 mg/100 mg 
on Day 1 followed by PF-07321332/ritonavir 150 mg/100 mg 
QD from Day 2 to Day 5.
Associated Intervention Labels
PF-07321332 (nirmatrelvir)
ritonavir


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6.1.1. Administration
Participants in both Cohort 1 and Cohort 2 will be given clear dosing instructions to take a 
single dose of PF-07321332 (nirmatrelvir)/ritonavir 300 mg/100 mg on Day 1 and 
PF-07321332 (nirmatrelvir)/ritonavir 150 mg/100 mg QD on Days 2 to 5.
Participants should take the first dose of study intervention on Day 1, during the in-clinic 
visit; that is, participants should take 2 tablets of PF-07321332 150 mg and 1 capsule of 
ritonavir 100 mg at the same time. Patients on HD (Cohort 2) should take their daily dose 
after HD.
On study Day 2, the participant selects a once daily dosing time (Day 2 dose should be taken 
no earlier than 14 hours and no later than 28 hours after the Day 1 dose). The doses on Days 
3-5 should be taken at approximately at the same time (±4 hours) as the Day 2 dose. For 
participants on HD (Cohort 2), if Day 1 dose is taken on a non-HD day, participants should 
take the Day 1 dose of study intervention during the in-clinic visit; if Day 1 dose is taken on 
an HD day, participants should take the Day 1 dose of study intervention in the clinic after 
HD. On HD days, Cohort 2 participants should take their study intervention after HD.
Participants may take the study intervention with or without food. PF-07321332 
(nirmatrelvir) and ritonavir should be taken than approximately 10 minutes or less apart, if 
feasible, but no more than 15 minutes apart. Refer to the IP manual for additional dosing and 
administration instructions.
If the participant misses a dose of PF-07321332 (nirmatrelvir)/ritonavir within 12 hours of 
the time it is usually taken, the participant should take it as soon as possible and resume the 
normal dosing schedule. If the participant misses a dose by more than 12 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.
6.2. Preparation, Handling, Storage, and Accountability
1. The investigator or designee must confirm that appropriate conditions (eg, 
temperature) have been maintained during transit for all study interventions received 
and any discrepancies are reported and resolved before use of the study intervention. 
2. Only participants enrolled in the study may receive study intervention and only 
authorized site staff may supply, prepare, and/or administer study intervention. 
3. All study interventions must be stored in a secure, environmentally controlled, and 
monitored (manual or automated recording) area in accordance with the labeled 
storage conditions with access limited to the investigator and authorized site staff. At 
a minimum, daily minimum and maximum temperatures for all site storage locations 
must be documented and available upon request. Data for nonworking days must 
indicate the minimum and maximum temperatures since previously documented upon 
return to business.


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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 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 re-dispensed 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 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 the study intervention using unique container 
numbers via an IRT system in the cartons provided, in quantities appropriate according to the 
SoA. A second staff member will verify the dispensing. The participant/caregiver should be 
instructed to maintain the product in the cartons provided throughout the course of dosing 
and return the cartons to the site per the SoA.
6.3. Assignment to Study Intervention
The study intervention to be dispensed to the participant will be assigned using an IRT 
system. The site will utilize the IRT system to assign the DU or container number(s) prior to 
the start of study intervention administration for each participant. The site will record the 
study intervention assignment on the applicable CRF, if required. 


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This is an open-label study. The investigator’s knowledge of the treatment assignment must 
not influence the decision to enroll a particular participant or affect the order in which 
participants are enrolled. 
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 an open-label study. 
6.5. Study Intervention Compliance
Participants will be issued an electronic study intervention diary device or device application
(ie, participant or caregiver completed study intervention log) and will be trained how to 
record the date and time of study intervention dosing on Day 1.
Each day, site personnel will review the electronic dosing diary data during the study 
intervention period. If any noncompliance with dosing entries is suspected or observed in the 
data, site personnel will promptly contact the participant to remind them of the relevant study 
procedures and/or entering the dosing 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 date and time of each dose 
administered in the clinic will be recorded in the electronic dosing diary. 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.
Study intervention compliance will also be assessed by delegated study personnel upon 
return of study intervention through counting returned IP and direct questioning, if 
applicable, review of the electronic study intervention diary and discussion with the 
participant. Deviation(s) from the prescribed dosage regimen should be recorded in source 
documents.
A record of the number of PF-07321332 (nirmatrelvir)/ritonavir doses 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 8.4.10):

Participants interrupting study intervention for 2 or more consecutive doses;

Participants taking either PF-07321332 (nirmatrelvir) or ritonavir alone for 2 or more
consecutive doses;

Participants who have an overall study intervention compliance <80% or >115%.


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In addition to the above listed-medication errors, any deviation from protocol-specified 
dosing (eg, missed single dose or partial dose) should be recorded as a protocol deviation,
and the investigator or designee is to counsel the participant/guardian and ensure steps are 
taken to improve compliance. The Medical Monitor should be notified immediately of 
any deviation from the prescribed dosing regimen.
6.6. Dose Modification 
Dose modification for PF-07321332 (nirmatrelvir)/ritonavir is not allowed.
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
For this study, any dose of PF-07321332 (nirmatrelvir) greater than 450 mg or ritonavir 
greater than 200 mg within a 24-hour time period will be considered an overdose.
There is no specific treatment for an overdose.
In the event of an overdose, the investigator should:
1. Contact the study medical monitor within 24 hours.
2. Closely monitor the participant for any AEs/SAEs and laboratory abnormalities as 
medically appropriate and at least until the next scheduled follow-up. 
3. Document the quantity of the excess dose as well as the duration of the overdose in 
the CRF.
4. Overdose is reportable to Pfizer Safety only when associated with an SAE.
5. Obtain a blood sample for PK analysis within 1 day from the date of the last dose of 
study intervention if requested by the study medical monitor (determined on a 
case-by-case basis). 
Decisions regarding dose interruptions or modifications will be made by the investigator in 
consultation with the study medical monitor as needed based on the clinical evaluation of the 
participant.
6.9. Prior and Concomitant Therapy
Contraceptives that meet the requirements of this study are allowed to be used in participants 
who are WOCBP (see Appendix 4).


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6.9.1. Permitted During the Study
All participants may receive SoC therapy for COVID-19, in addition to study intervention,
unless listed as prohibited medication (see Appendix 8) or as defined in Section 5.2. SoC
therapy is defined as any therapy that is approved and used as indicated by the local
regulatory authorities (including approvals for emergency use, compassionate use, or through
similar regulatory guidance), or any therapy as recommended by a relevant national (or a
reputable international) scientific body (eg, WHO, ECDC, CDC, NIH). Sites should consult
with the sponsor if a new SoC option becomes available after study initiation. Investigator
should ensure that any recommended SoC therapy is not a strong inducer of CYP3A4 or
highly dependent on CYP3A4 for clearance.
For participants taking phosphate binders, a minimum of 2 hours between administration of 
study drug and phosphate binders should be applied.
6.9.2. Prohibited in the study
Participants must not receive convalescent COVID-19 plasma treatment for COVID-19, 
antiviral treatment (eg, molnupiravir, remdesivir), or mAb for the treatment of COVID-19, 
during the study period.
PF-07321332 (nirmatrelvir)/ritonavir are inhibitors of CYP3A4. Therefore, medications 
highly dependent on CYP3A4 for clearance and which are contraindicated in combination 
with PF-07321332 (nirmatrelvir)/ritonavir (see Appendix 8) are prohibited during study 
intervention (from Day 1 and prior to the first dose of study intervention, if clinically 
appropriate).
Participants taking lovastatin and simvastatin should discontinue use at least 12 hours prior to 
initiation of PF-07321332 (nirmatrelvir)/ritonavir and refrain from use during treatment and 
for 5 days after the last dose of PF-07321332 (nirmatrelvir)/ritonavir. 
Coadministration of PF-07321332 (nirmatrelvir)/ritonavir with medications that are highly 
dependent on CYP3A4 for clearance may require dose adjustment or additional monitoring. 
Investigators should reference Appendix 8 for a list of these medications and consult the 
Pfizer medical monitor for guidance on coadministration with PF-07321332 
(nirmatrelvir)/ritonavir. 
Medications or substances that are highly dependent on CYP3A4 for clearance or are strong 
inducers of CYP3A4 and that are contraindicated in combination with PF-07321332 
(nirmatrelvir)/ritonavir must be discontinued for an appropriate washout period prior to the 
first dose of PF-07321332 (nirmatrelvir)/ritonavir and are prohibited for the duration of the 
study intervention period and for 4 days after the last dose of PF-07321332 
(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; a minimum washout period of 28 days prior to 
dosing of study intervention is required. 


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7. DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL
7.1. Discontinuation of Study Intervention
It may be necessary for a participant to permanently discontinue study intervention. Reasons 
for permanent discontinuation of study intervention include the following.

AE (including Grade 3 severity or greater and considered by the investigator to be 
related to study intervention);

SAE considered by the investigator to be related to the study intervention;

Requirement for prohibited concomitant medication;

Death;

Pregnancy;

Study terminated by sponsor;

Withdrawal by participant or legally authorized representative;
Note that discontinuation of study intervention does not represent withdrawal from the study. 
If study intervention is permanently discontinued, the participant will remain in the study to 
be evaluated for all subsequent scheduled assessments. See the SoA for data to be collected 
at the time of discontinuation of study intervention and follow-up for any further evaluations 
that need to be completed. 
In the event a participant is hospitalized, study intervention may continue to be administered,
as feasible, and based on medical judgement of the investigator.
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.
7.2. Participant Discontinuation/Withdrawal From the Study 
A participant may withdraw from the study at any time at their own request. Reasons for 
discontinuation from the study include the following:

Refused further study procedures;

Lost to follow-up;

Death;

Study terminated by sponsor.


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At the time of discontinuing from the study, if possible, an early discontinuation visit should 
be conducted. See the SoA for assessments to be collected at the time of study 
discontinuation and follow-up and for any further evaluations that need to be completed.
The early discontinuation visit applies only to participants who are enrolled/randomized and 
then are prematurely withdrawn from the study. Participants should be questioned regarding 
their reason for withdrawal. 
If a participant withdraws from the study, they may request destruction of any remaining 
samples taken and not tested, and the investigator must document any such requests in the 
site study records and notify the sponsor accordingly.
If the participant withdraws from the study and also withdraws consent (see Section 7.2.1) 
for disclosure of future information, no further evaluations will be performed and no 
additional data will be collected. The sponsor may retain and continue to use any data 
collected before such withdrawal of consent.
7.2.1. Withdrawal of Consent 
Participants who request to discontinue receipt of study intervention will remain in the study 
and must continue to be followed for protocol-specified follow-up procedures. The only 
exception to this is when a participant specifically withdraws consent for any further contact 
with them or persons previously authorized by the participant to provide this information. 
Participants should notify the investigator in writing of the decision to withdraw consent 
from future follow-up, whenever possible. The withdrawal of consent should be explained in 
detail in the medical records by the investigator, as to whether the withdrawal is only from 
further receipt of study intervention or also from study procedures and/or posttreatment study 
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 


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address or local equivalent methods). These contact attempts should be documented 
in the participant’s medical record;

Should the participant continue to be unreachable, the participant will be considered 
to have withdrawn from the study. 
8. STUDY ASSESSMENTS AND PROCEDURES
8.1. Administrative and Baseline Procedures
The investigator (or an appropriate delegate at the investigator site) must obtain a signed and 
dated ICD before performing any study-specific procedures. 
Study procedures and their timing are summarized in the SoA. Protocol waivers or 
exemptions are not allowed.
Safety issues should be discussed with the sponsor immediately upon occurrence or 
awareness to determine whether the participant should continue or discontinue study 
intervention.
Adherence to the study design requirements, including those specified in the SoA, is essential 
and required for study conduct.
All screening evaluations must be completed and reviewed to confirm that potential 
participants meet all eligibility criteria. The investigator will maintain a screening log to 
record details of all participants screened and to confirm eligibility or record reasons for 
screening failure, as applicable.
Procedures conducted as part of the participant’s routine clinical management (eg, eGFR) 
and obtained before signing of the ICD may be utilized for screening or baseline purposes 
provided the procedures met the protocol-specified criteria and were performed within the 
time frame defined in the SoA.
In the event a participant is hospitalized, study assessments should be performed as feasible.
Procedures not performed due to hospitalizations would not be considered protocol
deviations.
Every effort should be made to ensure that protocol-required tests and procedures are 
completed as described. However, it is anticipated that from time to time there may be 
circumstances outside the control of the investigator that 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.


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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 
120 mL for Cohort 1 and approximately 150 mL for Cohort 2 over approximately 36 days. 
The actual collection times of blood sampling may change. Additional blood samples may be 
taken for safety assessments at times specified by Pfizer, provided the total volume taken 
during the study does not exceed 550 mL during any period of 56 consecutive days.
8.1.1. Tasso sample training and collection
Participants (and/or caregivers) completing Tasso M20 device training will use the Tasso 
M20 device at home to collect PK samples during the times specified in the PK schema.
Samples collected at the site that are not specified to be arterial port or venous port samples 
for HD participants (Cohort 2) will also be simultaneously collected by site staff using the 
Tasso device and venous sample blood draw. At Screening (or during the Screening Period) 
participants and/or caregivers will be instructed on administration of the Tasso M20 device 
and will demonstrate their understanding by self-collecting or a caregiver collecting a sample 
on site using this device. This sample is for training purposes and no testing will be 
performed on it. Participants unwilling or unable to complete Tasso training and applied 
demonstration of the tool, may utilize support from a caregiver to administer the Tasso 
device. If the site finds the participant (or caregiver) is willing and able to correctly 
administer the device, the participant will enter the study and go home with sufficient 
quantities of the Tasso device as well as all required study materials per protocol. The site 
will document participant’s and/or caregiver’s training in source and confirm the participant 
has continued the required Tasso sample collection on Day 2 at home via a telehealth visit. 
Additional site support and training may be required for participants. 
If a participant (or caregiver) is unwilling or cannot demonstrate proficiency collecting the 
sample using the Tasso device, then the site must document the participant as a screen failure 
based on the inclusion criteria in Section 5 unless the participant has the option to use a home 
healthcare provider as described in Section 8.1.4.
8.1.2. Medical History
Medical history in addition to COVID-19 disease history and demographics will be collected 
at screening. Smoking status will be collected. Complete medication history of all 
prescription or nonprescription drugs (including vaccinations), adjunctive therapeutic 
procedures (non-drug treatments and procedures), and dietary and herbal supplements taken 
within 30 days prior to the planned first dose will be collected. All doses of COVID-19 
vaccinations administered at any time before study participation will be collected.
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 


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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. See Section 8.4.

Review and record any new concomitant medications or changes in concomitant 
medications since the last contact.

Review and record any new adjunctive therapeutic procedures (non-drug treatments 
and procedures) or changes in adjunctive therapeutic procedures 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. See Appendix 4. 

Review and record any COVID-19 related hospitalizations and emergency 
department visits which have occurred since the last visit.

Study participants must be reminded to promptly notify site staff about any change in 
their health status.

Any other activities listed as per the SoA.
8.1.4. Home Health Visits
A home health care service 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.

Review and record any new concomitant medications or changes in concomitant 
medications since the last contact.

Review and record any new adjunctive therapeutic procedures (non-drug treatments 
and procedures) or changes in adjunctive therapeutic procedures since the last 
contact.

Review and record any COVID-19 related hospitalizations and emergency 
department visits which have occurred since the last visit.


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
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, PK, and biomarker samples in accordance with the SoA.

Perform a targeted PE per the SoA.

Collect Vital Signs per the SoA.

Any other activities per the SoA
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. COVID-19-Related Medical Visit Details
Details of participants’ COVID-19-related medical visits (ie, hospitalization and emergency 
room visits) will be collected during study visits, including level of care (ICU status) and 
dates of utilization, including admission and discharge, as applicable. 
COVID-19-related hospitalization is defined as admission to inpatient care for the treatment 
of clinical manifestations of COVID-19 of any duration. Participants who are waiting in an 
emergency department or other hospital unit for an inpatient bed to become available are 
considered hospitalized provided that a decision to admit to inpatient care has occurred. The 
definition of hospitalizations also 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.
8.3. 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 Examinations
A targeted physical examination will include, at a minimum, general appearance, abdominal 
exam including assessment of ascites, distension, and organomegaly, lungs and 
cardiovascular systems. 
Investigators should pay special attention to clinical signs related to any new or previous 
serious illnesses. 
CCI


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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. Height and Weight
Height and weight will be measured and recorded as source data at screening. Height may be 
self-reported.
On HD treatment days, record the pre- and post- dialysis weight on the appropriate CRF. 
Refer to CRF completion guidelines.
8.3.3. Vital Signs
Temperature, PR, respiratory rate, and oxygen saturation rate will be assessed in all 
participants as specified in the SoA. Temperature should be measured using the same method 
for all study visits. 
Blood pressure and PR measurements will be assessed in a supine or seated position with 
their feet on the floor when possible with a completely automated device. Manual techniques 
will be used only if an automated device is not available.
Blood pressure and PR measurements should be preceded by at least 5 minutes of rest in a 
semi-supine or sitting position for the participant in a quiet setting without distractions (eg, 
television, cell phones).
On HD treatment days record the last available BP measurement in the appropriate CRF. 
Refer to the CRF completion guidelines.
Vital signs are to be taken before blood collection for laboratory tests.
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.
8.3.4. Clinical Safety Laboratory Assessments 
See Appendix 2 for the list of clinical safety laboratory tests to be performed and the SoA for 
the timing and frequency. All protocol-required laboratory assessments, as defined in 
Appendix 2, must be conducted in accordance with the laboratory manual and the SoA. 
Unscheduled clinical laboratory measurements may be obtained at any time during the study 
to assess any perceived safety issues.
Laboratory safety parameters will be graded according to DAIDS Table for Grading the 
Severity of Adult and Pediatric Adverse Events, version 2.1.22 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 


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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.
8.3.5. Pregnancy Testing 
Local urine testing using the central lab-provided test (locally purchased test is acceptable 
after Day 1 if the participant and/or home health staff does not have one provided by the 
central lab) will be standard for the protocol unless serum testing is required by local 
regulation or IRB/EC or the participant is anuric. Pregnancy tests (β-hCG) must have a 
sensitivity of at least 25 mIU/mL. A negative urine or serum (β-hCG) pregnancy test must be 
confirmed at screening or Day 1 prior to treatment for ALL women of childbearing potential 
(WOCBP). Following a negative pregnancy test result at screening, appropriate contraception 
must be commenced. Pregnancy tests will also be done whenever 1 menstrual cycle is missed 
during the active treatment period (or when potential pregnancy is otherwise suspected). 
Pregnancy tests may also be repeated if requested by IRBs/ ECs or if required by local 
regulations.
8.3.5.1. At-Home Pregnancy Testing
If a participant requiring pregnancy testing cannot visit a local laboratory or have a central 
lab-provided pregnancy test, 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 home pregnancy test kit will be provided by the central 
lab. The pregnancy test outcome should be documented in the participant’s source 
documents/medical records and relevant data recorded on the CRF. If the pregnancy test is 
positive, the EDP should be reported (Section 8.4.5.1). 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 


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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/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.
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.


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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.
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.


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


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
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 or participant’s partner, the investigator must report 
this information to Pfizer Safety using the PSSA and an EDP Supplemental Form, 
regardless of whether an SAE has occurred. Details of the pregnancy will be collected 
after the start of study intervention and until a minimum of 28 calendar days after the 
last administration of study intervention.

If EDP occurs in the setting of environmental exposure, the investigator must report 
information to Pfizer Safety using the PSSA and EDP Supplemental Form. Since the 
exposure information does not pertain to the participant enrolled in the study, the 
information is not recorded on a CRF; however, a copy of the completed PSSA is 
maintained in the investigator site file.
Follow-up is conducted to obtain general information on the pregnancy and its outcome for 
all EDP reports with an unknown outcome. The investigator will follow the pregnancy until 
completion (or until pregnancy termination) and notify Pfizer Safety of the outcome as a 
follow-up to the initial EDP Supplemental Form. In the case of a live birth, the structural 
integrity of the neonate can be assessed at the time of birth. In the event of a termination, the 
reason(s) for termination should be specified and, if clinically possible, the structural 
integrity of the terminated fetus should be assessed by gross visual inspection (unless pre-
procedure 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. 


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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 
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 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 PSSA must be maintained in the investigator site file.


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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.  
The investigator must report signs, symptoms, and/or clinical sequelae resulting from lack of 
efficacy. Lack of efficacy or failure of expected pharmacological action in an approved 
indication constitutes an SAE and should be reported to Pfizer Safety. 
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 
intervention by the wrong participant, or at the wrong time, or at the wrong dosage strength.
Medication errors are recorded and reported as follows:
Recorded on the 
Medication Error Page 
of the CRF
Recorded on the 
Adverse Event Page 
of the CRF
Reported 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;


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
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.

See Section 6.5 for potential errors related to study intervention compliance not listed 
above.
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 the PSSA only 
when associated with an SAE.
8.5. Pharmacokinetics 
8.5.1. Non-Hemodialysis 
Participants assigned to Cohort 1 will begin study intervention on Day 1 and the PK samples 
collected will follow the PK Sampling Schema in Section 1.3.
8.5.2. Hemodialysis 
Participants assigned to Cohort 2 will begin study intervention either on a HD treatment day 
or non-HD treatment day. The day of the participant’s first IP dose, either on an HD day or
on a non-HD day (ie, Treatment Day 1) will determine the subsequent PK sample schedule as 
described in the PK Sampling Schema. 
Participants beginning IP administration on an HD treatment day (ie, Treatment Day 1) will 
have PK samples collected per the PK Sampling schema in Section 1.3 including samples 
drawn from HD lines before and during HD treatment days. Obtain blood samples for 
hematology (hematocrit) at time 0 (venous port sample) and time of the last PK draw
(venous port sample) on dialysis, to be used for dialysis clearance (CLd) calculations. Time 0 
is defined as the time period prior to the start of the HD blood pump.
If the participant is assigned to begin IP treatment (ie, Treatment Day 1) on a non-HD day, 
the participant will have samples collected per the PK Sampling Schema in Section 1.3.
Obtain blood samples for hematology (hematocrit) at time 0 (venous port sample) and time 
of the last PK draw (venous port sample) on dialysis, to be used for dialysis clearance (CLd) 
calculations. Time 0 is defined as the time period prior to the start of the HD blood pump.
Additional details regarding the HD treatment will be captured in the database (refer to CRF 
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8.5.3. PK Samples for Analysis of PF-07321332 (nirmatrelvir) and Ritonavir
PK samples for measurement of PF-07321332 (nirmatrelvir) and ritonavir plasma
concentrations will be collected, using Tasso M20 device for dried blood. If Tasso device is 
not available or unable to function properly, then  a venous blood sample must be drawn.
For plasma samples, a blood sample of approximately 4 mL, to provide approximately 
1.5 mL plasma, will be collected for measurement of plasma concentrations of PF-07321332 
(nirmatrelvir) and ritonavir as specified in the SoA. For Tasso sampling, approximately
100 µL of blood is collected. Instructions for the collection, handling, and recording of 
biological samples will be provided in the laboratory manual or by the sponsor. The date and 
time (12-hour clock time) of collection for each sample will be recorded on the sample 
requistion forms that are submitted to the laboratories.
The ritonavir concentration will be measured using Tasso samples collected and/or venous 
blood sample collected and will be reported as plasma concentration listings only (no PK 
analysis of ritonavir data).
If a participant cannot attend a clinic visit, PK samples may be collected via home health 
visit, self-collected or caregiver-collected using the Tasso M20 device to collect whole blood 
microsamples to measure PF-07321332 (nirmatrelvir) and ritonavir concentrations.
The actual times may change, but the number of samples will remain the same. All efforts 
will be made to obtain the samples per the PK sampling times in Section 1.3 relative to 
dosing.
Both Tasso sample and venous blood samples will be used to evaluate the PK of 
PF-07321332 (nirmatrelvir) and ritonavir. Samples collected for analyses of PF-07321332 
(nirmatrelvir) and ritonavir concentrations may also be used to evaluate safety or efficacy 
aspects related to concerns arising during or after the study, for metabolite identification 
and/or evaluation of the bioanalytical method
.
Genetic analyses will not be performed on these plasma samples unless consent for this was 
included in the informed consent. Participant confidentiality will be maintained.
Samples collected for measurement of plasma concentrations of PF-07321332 (nirmatrelvir)
and ritonavir will be analyzed using a validated analytical method in compliance with 
applicable SOPs. Potential metabolites may be analyzed with
validated
methods.
The PK samples must be processed and shipped as indicated in the instructions provided to 
the investigator site to maintain sample integrity. Any deviations from the PK sample 
handling procedure (eg, sample collection and processing steps, interim storage or shipping 
conditions, etc), including any actions taken, must be documented and reported to the 
sponsor. On a case-by-case basis, the sponsor may decide whether sample integrity has been 
compromised.
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8.5.4. Blood to Plasma Ratio Analysis of PF-07321332 (nirmatrelvir) and Ritonavir
As specified in the SoA, exploratory PK venous blood samples of approximately 4 mL each 
for the measurement of PF-07321332 (nirmatrelvir) and ritonavir concentrations will be 
collected to evaluate microsampling PK approach using the Tasso® M20 device. These 
venous blood samples will be collected at 2 time points immediately either before or after 
Tasso sample collection but no more than 15 minutes apart between the Tasso and venous 
blood samples. Venous blood samples of approximately 4 mL will be collected, a portion of 
it will be aliquotted for blood and the remaining blood will be centrifuged to harvest plasma 
in K2EDTA for nirmatrelvir and ritonavir blood/plasma ratio measurements. 
Instructions for the collection and handling of biological samples will be provided in the 
laboratory manual or by the sponsor. The actual date and time (24‑hour clock time) of each 
sample will be recorded.
Samples collected for measurement of plasma concentrations of PF-07321332 (nirmatrelvir)
and ritonavir will be analyzed using a validated analytical method in compliance with 
applicable SOPs.
8.5.5. Electronic diary (eDiary)
All participants will be provided an electronic handheld device (eDiary) or will download the 
eDiary application on their own device to record times of study intervention administration. 
All dosing times must be entered into the eDiary by the participant (or caregiver) 
within 24 hours of taking the dose of study intervention.
Participants will receive daily reminders to complete eDiary entries on their own (or by 
caregiver) as specified on the SoA. The eDiary should be completed at approximately the 
same time every day.
Compliance will be monitored daily during treatment by the site staff and by the sponsor. If a 
participant experiences any issues with the Tasso M20 device, electronic diary entry, or study 
intervention, they should contact the site immediately for appropriate mitigating actions. 
Noted issues with compliance will be escalated to the sponsor as per the agreed upon 
electronic diary review plan.
8.6. Genetics
8.6.1. Specified Genetics (Not Applicable)
Specified genetics are not included 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.


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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 laboratory manual.
8.7. Biomarkers
Collection of samples for biomarker research is also part of this study.
The following samples discussed in this section for biomarker research are required and will 
be collected from all participants in this study as specified in the SoA:

A 6 mL blood sample optimized for plasma may be utilized for proteomics and 
immunologic studies.
8.7.1. Viral Load Assessments
Residual SARS-CoV-2 RNA 
concentration samples may be utilized for viral sequencing to assess for signs of viral 
evolution and evaluation of potential genetic viral variants (eg, 3CL gene) SARS CoV-2 
infectivity assays, and additional molecular analysis. 
Residuals of all samples may be stored and used for additional analyses related to COVID-19 
and/or the mechanism of action of PF-07321332 (nirmatrelvir)/ritonavir. Storage and 
shipping instructions will be in accordance with the laboratory manual.
8.7.2. Specified Protein Research 
8.7.2.1. Specified Biomarker Research (Plasma)
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 
studies and/or analysis of SARS-CoV-2 by RT-PCR. Residuals of all samples may be stored 
and used for additional analyses related to COVID-19 and/or the mechanism of action of PF-
07321332 (nirmatrelvir)/ritonavir. Storage and shipping instructions will be in accordance 
with the laboratory manual.
8.7.3. 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
Retained Research Samples will be collected as local regulations and IRB/ECs allow 
according to the SoA.  
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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
8.8. Immunogenicity Assessments
Immunogenicity assessments are not included in this study.
8.9. Health Economics
Medical resource utilization will be evaluated in this study (see Section 8.2.1).
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
As this is a single-arm study, there will be no treatment comparisons, and all analyses will be 
descriptive.
9.2. Analysis Sets
For purposes of analysis, the following analysis sets are defined:
Participant Analysis Set
Description
Enrolled 
"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 assignment to study intervention. A participant 
will be considered enrolled if the informed consent is not 
withdrawn prior to participating in any study activity after 
screening. Potential participants who are screened for the 
purpose of determining eligibility for the study, but do not 
participate in the study, are not considered enrolled, unless 
otherwise specified by the protocol. 
SAS
All participants assigned to study intervention and who 
take at least 1 dose of study intervention. Participants will 
be analyzed according to the product they actually 
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Defined Analysis Set
Description
PK Concentration
The PK concentration population is 
defined as all participants assigned to 
investigational product and treated who 
have at least 1 concentration measured.
PK Parameter
The PK parameter analysis population is 
defined as all participants assigned to 
investigational product and treated who 
have at least 1 of the PK parameters of 
interest measured. 
9.3. Statistical Analyses
The SAP will be developed and finalized before any analyses are performed and will 
describe the analyses and procedures for accounting for missing, unused, and spurious data. 
This section is a summary of the planned statistical analyses of the primary and secondary 
endpoints.
9.3.1. General Considerations
Descriptive statistics for all endpoints by each cohort and visit will be provided. 
The number of participants screened, intervention assigned in treatment phase, completing 
the study drug administration, and completing the study will be summarized. 
The reason for all discontinuations will be summarized by each cohort. 
Baseline demographic and other characteristics will be tabulated for the SAS and 
summarized by each cohort. Quantitative variables will be described by standard descriptive 
statistics (mean, standard deviation, minimum, and maximum), and qualitative variables will 
be summarized by frequency tables with number and proportion in each category (with the 
corresponding sample sizes). 
For continuous endpoints, change from baseline over time will be summarized for each 
cohort and overall. 
For binary endpoints, proportion of participants with the event will be summarized for each 
cohort. 
For categorical endpoints, proportion of participants for each category will be summarized 
for each cohort. 
9.3.2. Primary Endpoints Analyses
TEAEs will be summarized with the number and percent of participants in the SAS through 
Day 34 for two cohorts and overall. 


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The incidence of SAEs and AEs leading to discontinuation will be summarized in the SAS 
through Day 34 for two cohorts and overall.
9.3.3. Secondary Endpoints Analyses
PF-07321332 (nirmatrelvir) plasma concentration data will be analyzed using a population 
PK analysis approach (nonlinear mixed effects models). Pharmacokinetic parameters 
including CL/F, Cmax, Cmin, AUC0-tau will be provided for PF-07321332 (nirmatrelvir) based 
on the final population PK model. A stand-alone population PK modeling and simulation 
analysis plan will be prepared and the results will be reported in a stand-alone report, outside 
the clinical study report. 
PK parameters including AUC0-tau, Cmax, Ctrough, CL/F and Vz/F will be estimated from the 
population PK model by each cohort. HD clearance (CLd) and fraction of dose (Fd) of PF-
07321332 (nirmatrelvir) removed from the body by dialysis will be calculated for Cohort 2 
(participants on HD). 
Individual PF-07321332 (nirmatrelvir) plasma concentration profiles, using the PK analysis 
set for Cohorts 1 to 2, will be presented graphically using actual sample collection time on 
both linear and semilogarithmic scales, showing all participants on a single plot for each 
cohort. Median concentration time profiles will be presented on both linear and 
semilogarithmic scales using nominal sampling time. Additional graphical presentations of 
PK data may be included at the discretion of the PK scientist.
In addition, the PF-07321332 (nirmatrelvir) plasma concentrations, participant 
demographics, and disease status data will be combined with data from appropriate previous 
clinical studies in adult participants for a population PK analysis. The actual dosing and 
plasma sampling times will be used for the analysis. A stand-alone population PK modeling 
and simulation analysis plan will be prepared and the results will be reported in a stand-alone 
report, outside the clinical study report. Pharmacokinetic parameters including CL/F, Cmax, 
Cmin, AUC0-tau will be provided for PF-07321332 (nirmatrelvir) based on the final population 
PK model.
A listing of PF-07321332 (nirmatrelvir) plasma concentrations at the nominal sampling time 
by participant and cohort will be provided. For each Cohort 1 and 2, the plasma 
concentration will be summarized by nominal sampling time using appropriate descriptive 
statistics (eg, number of participants/samples, mean, SD, minimum, median, maximum, 
geometric mean, and coefficient of variation). 
For summary statistics by sampling time, the nominal PK sampling time will be used. For 
individual participant plots by time, the actual PK sampling time will be used. Box and 
whisker plots for individual participant parameters (AUCinf and Cmax) will be constructed by 
each cohort and overlaid with geometric means.
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9.3.5. Other Safety Analyses
All safety analyses will be performed on the safety population.
AEs, BP, PR, and safety laboratory data will be reviewed and summarized on an ongoing 
basis during the study to evaluate the safety of participants. Any clinical laboratory, BP, and 
PR abnormalities of potential clinical concern will be described. Safety data will be presented 
in tabular and/or graphical format and summarized descriptively, where appropriate.
Medical history and physical examination collected during the course of the study will be 
considered source data and will not be required to be reported, unless otherwise noted. 
However, any untoward findings identified on physical and/or neurological examinations 
conducted during the active collection period will be captured as AEs, if those findings meet 
the definition of an AE. Data collected at screening that are used for inclusion/exclusion 
criteria, such as laboratory data, and vital signs, will be considered source data, and will not 
be required to be reported, unless otherwise noted. Demographic data collected at screening 
will be reported. 
9.4. Interim Analyses
No interim analysis will be conducted for this study. As this is an open-label, unblinded 
study, the sponsor may conduct reviews of the data during the study for the purpose of safety 
assessment, facilitating PK/PD modeling, and/or supporting clinical development.
9.5. Sample Size Determination
The sample size of 12 evaluable participants per cohort is considered to provide a suitable 
estimate of precision of PK parameters of PF-07321332 (nirmatrelvir) in severe renal 
impairment participants on HD and not on HD, as this provided 40% precision (the width of 
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90% confidence interval) for AUCinf and Cmax. To ensure sufficient PK data for analysis, any 
participant with insufficient PK samples for analysis may be replaced.  
To identify an adequate sample size for the PK, we assessed the precision of estimating the 
PK parameter using different sample sizes, as defined by the width of the resultant 
confidence intervals represented as a percentage of the mean value of the PK parameter. 
Currently, no PK data is available in severe renal impairment following multiple doses of 
PF-07321332 (nirmatrelvir); therefore, we used single dose PK data of PF-07321332 
(nirmatrelvir) in severe renal impairment adults not on dialysis (Table 1) to determine the CV 
estimates for PF-07321332 (nirmatrelvir) PK parameters. As illustrated in Table 1, the CV 
estimates for PF-07321332 (nirmatrelvir) AUCinf and Cmax range from 33% to 38% (ie, 0.33 
to 0.38).
Table 1.
PF-07321332 (nirmatrelvir) PK Parameters Following Single Dose of PF-
07321332 (nirmatrelvir)/Ritonavir 100 mg/100 mg in Severe Renal 
Impairment Patients
PK Parameter (units)
PF-07321332 (nirmatrelvir)
(N=8)
Cmax (ng/mL)
2369 (38)
AUCinf (ng*hr/mL)
44040 (33)
Tmax (hr)
3.00 (1.00-6.05)
t1/2 (hr)
13.37 ± 3.3225
Values are presented as geometric mean (geometric % CV) except median (range) for Tmax and arithmetic 
mean ± SD for t½.
Since we anticipate that study participants may experience more variability in PK parameters 
than the available data given the wider range of multiple doses, precision is described with an 
anticipated CV of 0.2, 0.3, or 0.4. 
Table 2 below shows the upper and lower confidence limits and 90% CI width for the mean 
PK parameter (eg, AUC, t½, or Cmax), presented as a percentage of the mean, for different N 
and CV. With a sample size of 12 evaluable patients and a CV equal to 0.4, the 90% CI will 
range from 79.3% – 120.7 % of the mean, and the corresponding CI width will be 41.4% of 
the mean. This rather tight CI would indicate whether or not the study findings reveal a 
higher than 40% difference from the PK parameter in a severe renal impaired population. 
Table 2.
Percentile Range and Width of 90% Confidence Intervals for the Mean 
PK Parameter
N
CV=0.2
CV=0.3
CV=0.4
Range
Width
Range
Width
Range
Width
8
86.6-113.4%
26.8%
79.9-120.1%
40.2%
73.2-126.8%
53.6%
10
88.5-111.5%
23.1%
82.7-117.3%
34.6%
76.9-123.1%
46.2%
12
89.6-110.4%
20.7%
84.5-115.5%
31.1%
79.3-120.7%
41.4%
14
90.5-109.5%
19.0%
85.8-114.2%
28.4%
81.1 -119.0%
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10. SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS
10.1. Appendix 1: Regulatory, Ethical, and Study Oversight Considerations
10.1.1. Regulatory and Ethical Considerations
This study will be conducted in accordance with the protocol and with the following:

Consensus ethical principles derived from international guidelines, including the 
Declaration of Helsinki and CIOMS International Ethical Guidelines;

Applicable ICH GCP guidelines;

Applicable laws and regulations, including applicable privacy laws.
The protocol, protocol amendments, ICD, SRSD(s), and other relevant documents (eg, 
advertisements) must be reviewed and approved by the sponsor, submitted to an IRB/EC by 
the investigator, and reviewed and approved by the IRB/EC before the study is initiated.
Any amendments to the protocol will require IRB/EC approval before implementation of 
changes made to the study design, except for changes necessary to eliminate an immediate 
hazard to study participants.
Protocols and any substantial amendments to the protocol will require health authority 
approval prior to initiation except for changes necessary to eliminate an immediate hazard to 
study participants.
The investigator will be responsible for the following:

Providing written summaries of the status of the study to the IRB/EC annually or 
more frequently in accordance with the requirements, policies, and procedures 
established by the IRB/EC;

Notifying the IRB/EC of SAEs or other significant safety findings as required by 
IRB/EC procedures;

Providing oversight of the conduct of the study at the site and adherence to 
requirements of 21 CFR, ICH GCP guidelines, the IRB/EC, European regulation 
536/2014 for clinical studies, European Medical Device Regulation 2017/745 for 
clinical device research, and all other applicable local regulations.
10.1.1.1. Reporting of Safety Issues and Serious Breaches of the Protocol or ICH GCP
In the event of any prohibition or restriction imposed (ie, clinical hold) by an applicable 
regulatory authority in any area of the world, or if the investigator is aware of any new 
information that might influence the evaluation of the benefits and risks of the study 
intervention, Pfizer should be informed immediately. 


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In addition, the investigator will inform Pfizer immediately of any urgent safety measures 
taken by the investigator to protect the study participants against any immediate hazard, and 
of any serious breaches of this protocol or of the ICH GCP guidelines that the investigator 
becomes aware of.
10.1.2. Financial Disclosure
Investigators and sub-investigators will provide the sponsor with sufficient, accurate 
financial information as requested to allow the sponsor to submit complete and accurate 
financial certification or disclosure statements to the appropriate regulatory authorities. 
Investigators are responsible for providing information on financial interests during the 
course of the study and for 1 year after completion of the study.
10.1.3. Informed Consent/Assent 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.


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The medical record must include a statement that written informed consent was obtained 
before the participant was enrolled in the study and the date on which the written consent was 
obtained. The authorized person obtaining the informed consent must also sign the ICD.
Participants or 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).
Participants who are rescreened are required to sign a new ICD.
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 and/or paper
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.
Information technology systems used to collect, process, and store study-related data are 
secured by technical and organizational security measures designed to protect such data 
against accidental or unlawful loss, alteration, or unauthorized disclosure or access.
The sponsor maintains standard operating procedures on how to respond in the event of 
unauthorized access, use, or disclosure of sponsor information or systems.
10.1.5. Committees Structure
10.1.5.1. Data Monitoring Committee 
This study will use the program-level E-DMC which is independent of the study team and 
includes only external members, and is responsible for the ongoing monitoring of the 


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efficacy and safety of participants in the program’s studies according to the E-DMC charter. 
This study is not assessing efficacy and assessing only safety. The E-DMC charter describes 
the role of the E-DMC in more detail for this study. The recommendations made by the 
E-DMC will be forwarded to the appropriate authorized Pfizer personnel for review and final 
decision as appropriate. Pfizer will communicate such decisions, which may include 
summaries of aggregate analyses of endpoint events of safety data, as well as those that are 
not endpoints, 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 
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.


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Data sharing
Pfizer provides researchers secure access to participant-level data or full CSRs for the 
purposes of “bona-fide scientific research” that contributes to the scientific understanding of 
the disease, target, or compound class. Pfizer will make data from these trials available 
24 months after study completion. Participant-level data will be anonymized in accordance 
with applicable privacy laws and regulations. CSRs will have personally identifiable 
information anonymized.
Data requests are considered from qualified researchers with the appropriate competencies to 
perform the proposed analyses. Research teams must include a biostatistician. Data will not 
be provided to applicants with significant conflicts of interest, including individuals 
requesting access for commercial/competitive or legal purposes.
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 and/or paper form and are password protected to prevent access by unauthorized 
third parties.
The investigator must permit study-related monitoring, audits, IRB/EC review, and 
regulatory agency inspections and provide direct access to source data documents. This 
verification may also occur after study completion. It is important that the investigator(s) and 
their relevant personnel are available during the monitoring visits and possible audits or 
inspections and that sufficient time is devoted to the process.
Monitoring details describing strategy, including definition of study-critical data items and 
processes (eg, risk-based initiatives in operations and quality such as risk management and 
mitigation strategies and analytical risk-based monitoring), methods, responsibilities, and 
requirements, including handling of noncompliance issues and monitoring techniques 
(central, virtual, or on-site monitoring), are provided in the data management plan and 
monitoring plan maintained and utilized by the sponsor or designee. 
The sponsor or designee is responsible for the data management of this study, including 
quality checking of the data.
Records and documents, including signed ICDs, pertaining to the conduct of this study must 
be retained by the investigator for 15 years after study completion unless local regulations or 
institutional policies require a longer retention period. No records may be destroyed during 


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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.
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 on which the clinical study will be open for recruitment of 
participants.


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The first act of recruitment is the date of the first participant’s first visit and will be the study 
start date.
The sponsor designee reserves the right to close the study site or terminate the study at any 
time for any reason at the sole discretion of the sponsor, including (but not limited to) 
regulatory authority decision, change in opinion of the IRB/EC, or change in benefit-risk 
assessment. Study sites will be closed upon study completion. A study site is considered 
closed when all required documents and study supplies have been collected and a study-site 
closure visit has been performed.
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.

Sites may be closed early if the enrollment is completed earlier than anticipated in 
one country but ongoing in other countries.
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 3.
Protocol-Required Safety Laboratory Assessments
Hematology
Chemistry
Other
Additional Tests 
Hemoglobin
Hematocrit
RBC count
Platelet count
WBC count
Total neutrophils 
(Abs)
Eosinophils (Abs)
Monocytes (Abs)
Basophils (Abs)
Lymphocytes (Abs)
Urea and creatinine
CystatinC and eGFR
Glucose 
Calcium
Sodium
Potassium
Chloride
Total CO2 (bicarbonate)
AST, ALT
Total bilirubin
Alkaline phosphatase
Albumin
Total protein
Pregnancy test 
(β-hCG)a
SARS-CoV-2 serology 
(IgG and IgM)
HIV Testing b
For suspected DICI/DIKI: 
Creatinine (Scr) 
CystatinC (Scys) 
eGFR (Scr only and combined 
Scr+Scys) 
Spot (dipstick) UACR
Needed for Hy’s Law
AST, ALT (repeat)
Total bilirubin (repeat)
Albumin 
Alkaline phosphatase (repeat)
Direct bilirubin
Indirect bilirubin
Creatine kinase
GGT
PT/INR
Total bile acids
Acetaminophen drug and/or 
protein adduct levels
Hepatitis serology
a.
Local urine testing using the central lab-provided test (locally purchased test is acceptable after Day 1 if 
the participant and/or home health staff does not have one provided by the central lab) will be standard 
for the protocol unless serum testing is required by local regulation or IRB/EC or the participant is 
anuric. A negative urine or serum (β-hCG) pregnancy test must be confirmed at screening and prior to 
dispensing treatment for ALL WOCBP.
b.
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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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 
(3) exposure to the study intervention under study during pregnancy or breastfeeding, and 
occupational exposure. 


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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
Report Form to Pfizer 
Safety Within 24 Hours of 
Awareness
SAE
All
All
Nonserious AE
All
None
Exposure to the study 
intervention under study 
during pregnancy or 
breastfeeding 
All AEs or SAEs associated 
with 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 and EDP Supplemental Form; 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.

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.


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
There may be instances when copies of medical records for certain cases are 
requested by Pfizer Safety. In this case, all participant identifiers, with the 
exception of the participant number, will be redacted on the copies of the medical 
records before submission to Pfizer Safety.

The investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information. Whenever possible, the diagnosis (not 
the individual signs/symptoms) will be documented as the AE or SAE.
Assessment of Intensity
The investigator will make an assessment of intensity for each AE and SAE reported 
during the study and assign it to 1 of the following categories, which are based on the 
Division of AIDS (DAIDS) Table for Grading the Severity of Adult and Pediatric Adverse 
Events, 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.

The investigator will also consult the IB and/or product information, for marketed 
products, in their assessment.


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
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.

If the electronic system is unavailable, then the site will use the paper SAE DCT 
(see next section) to report the event within 24 hours.

The site will enter the SAE data into the electronic DCT (eg, eSAE or 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 
10.4.1. Male Participant Reproductive Inclusion Criteria
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.
10.4.2. Female Participant Reproductive Inclusion Criteria
The criteria below are part of Inclusion Criterion 1 (Age and Sex; Section 5.1) and specify 
the reproductive requirements for including female participants. Refer to Section 10.4.4 for a 
complete list of contraceptive methods permitted in the study. 
A female participant is eligible to participate if she is not pregnant or breastfeeding and at 
least 1 of the following conditions applies:

Is not a WOCBP (see definition in Section 10.4.3).
OR

Is a WOCBP and agrees to use an acceptable contraceptive method: intrauterine 
device (IUD), dual barrier method, partner vasectomy, or abstinence, 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). The investigator should evaluate the effectiveness of the 
contraceptive method in relationship to the first dose of study intervention.
Because ritonavir may reduce the effect of estradiol-containing contraceptives when agents 
are co-administered, a barrier method or other nonhormonal method of contraception must 
also be used if the participant is using estradiol-containing contraceptives during the 5 days 
of PF-07321332 (nirmatrelvir)/ritonavir treatment and until one menstrual cycle after 
stopping study intervention.
The investigator is responsible for review of medical history, menstrual history, and recent 
sexual activity to decrease the risk for inclusion of a woman with an early undetected 
pregnancy. 
10.4.3. Woman of Childbearing Potential
A woman is considered fertile following menarche and until becoming postmenopausal 
unless permanently sterile (see below).
If fertility is unclear (eg, amenorrhea in adolescents or athletes) and a menstrual cycle cannot 
be confirmed before the first dose of study intervention, additional evaluation should be 
considered.


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Women in the following categories are not considered WOCBP:
1. Premenopausal female with 1 of the following: 

Documented hysterectomy;

Documented bilateral salpingectomy;

Documented bilateral oophorectomy.
For individuals with permanent infertility due to a medical cause other than the above (eg, 
mullerian agenesis, androgen insensitivity), investigator discretion should be applied to 
determining study entry.
Note: Documentation for any of the above categories can come from the site personnel’s 
review of the participant’s medical records, medical examination, or medical history 
interview. The method of documentation should be recorded in the participant’s medical 
record for the study.
2. Postmenopausal female:

A postmenopausal state is defined as no menses for 12 months without an 
alternative medical cause. In addition:

A female on HRT and whose menopausal status is in doubt will be required to 
use one of the highly effective non-estrogen 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.

A negative urine pregnancy test must be confirmed at screening or Day 1 prior 
to dispensing treatment for all women unless they are 50 years or older with 
no menses for 12 months.
10.4.4. Contraception Methods
Contraceptive use by men or women should be consistent with local availability/regulations 
regarding the use of contraceptive methods for those participating in clinical trials.
The following contraceptive methods are appropriate for this study:
Highly Effective Methods That Have Low User Dependency 
1. Implantable progestogen-only hormone contraception associated with inhibition of 
ovulation.
2. Intrauterine device.


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3. Intrauterine hormone-releasing system.
4. Bilateral tubal occlusion.
5. Vasectomized partner:

Vasectomized partner is a highly effective contraceptive method provided that the 
partner is the sole sexual partner of the WOCBP and the absence of sperm has 
been confirmed. If not, an additional highly effective method of contraception 
should be used. The spermatogenesis cycle is approximately 90 days.
Sexual Abstinence
6. 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 (not highly effective) may be used concomitantly with option 6 
above for the study include any of the following:

Male or female condom, with or without spermicide;

Cervical cap, diaphragm, or sponge with spermicide;

A combination of male condom with either cervical cap, diaphragm, or sponge 
with spermicide (double-barrier methods).


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10.5. Appendix 5: Genetics
Use/Analysis of DNA

Genetic variation may impact a participant’s response to study intervention, 
susceptibility to, and severity and progression of disease. Therefore, where local 
regulations and IRBs/ECs allow, a blood sample will be collected for DNA analysis.

The scope of the genetic research may be narrow (eg, 1 or more candidate genes) or 
broad (eg, the entire genome), as appropriate to the scientific question under 
investigation.

The samples may be analyzed as part of a multistudy assessment of genetic factors 
involved in the response to PF-07321332 (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.”
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: Kidney Safety Monitoring Guidelines
10.7.1. Laboratory Assessment of Change in Kidney Function and Detection of Kidney 
Injury
Standard kidney safety monitoring requires assessment of baseline and postbaseline serum 
creatinine (Scr measurement to eGFR [Scr-based eGFR] or [eCrCl]). Baseline and 
postbaseline Scys makes it feasible to distinguish AKI from other causes of Scr increase. If 
Scr increase is confirmed after baseline, then reflex measurement of Scys is indicated to 
estimate the combined Scr-Scys eGFR calculation (for adults only).
Regardless of whether kidney function monitoring tests are required as a routine safety 
monitoring procedure in the study, if the investigator or sponsor deems it necessary to further 
assess kidney safety and quantify kidney function, then these test results should be managed 
and followed per standard of care.
10.7.2. Age-Specific Kidney Function Calculation Recommendations
Sites will use the provided calculator to calculate eGFR: https://www.mdcalc.com/ckd-epi-
equations-glomerular-filtration-rate-gfr
10.7.2.1. Adults (18 Years and Above)—2021 CKD-EPI Equations
2021 CKD-
EPI          
Scr Only
Scr
(mg/dL)
Scys
(mg/L)
Recommended eGFR Equation
Female
if ≤0.7
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
2021 CKD-
EPI          
Scr-Scys 
Combined
Scr
(mg/dL)
Scys
(mg/L)
Recommended eGFR Equation
Female
if ≤0.7
if ≤0.8
eGFR = 130 × (Scr/0.7)-0.219  × (Scys/0.8)-0.323  ×
(0.9961)Age
Female
if ≤0.7
if > 0.8
eGFR = 130 × (Scr/0.7)-0.219  × (Scys/0.8)-0.778  ×
(0.9961)Age
Female
if > 0.7
if ≤0.8
eGFR = 130 × (Scr/0.7)-0.544  × (Scys/0.8)-0.323  ×
(0.9961)Age
Female
if > 0.7
if > 0.8
eGFR = 130 × (Scr/0.7)-0.544  × (Scys/0.8)-0.778  ×
(0.9961)Age
Male
if ≤0.9
if ≤0.8
eGFR = 135 × (Scr/0.9)-0.144  × (Scys/0.8)-0.323  ×
(0.9961)Age
Male
if ≤0.9
if > 0.8
eGFR = 135 × (Scr/0.9)-0.144  × (Scys/0.8)-0.778  ×
(0.9961)Age
Male
if > 0.9
if ≤0.8
eGFR = 135 × (Scr/0.9)-0.544  ×  (Scys/0.8)-0.323  ×
(0.9961)Age
Male
if > 0.9
if > 0.8
eGFR = 135 × (Scr/0.9)-0.544  ×  (Scys/0.8)-0.778  ×
(0.9961)Age
Inker LA et al. N Engl J Med. 2021;385:1737-49.


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10.7.3. Adverse Event Grading for Kidney Safety Laboratory Abnormalities
AE grading for decline in kidney function (ie, eGFR or eCrCl) will be according to KDIGO
criteria.


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10.8. Appendix 8: Concomitant Medications That May Result in DDI  
PF-07321332 (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 PF-07321332 
(nirmatrelvir)/ritonavir without the appropriate washout prior to the first dose of 
PF-07321332 (nirmatrelvir)/ritonavir are prohibited. 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; a minimum washout 
period of 28 days prior to dosing of study intervention is required. PF-07321332 
(nirmatrelvir)/ritonavir are inhibitors of CYP3A4. Therefore, medications highly dependent 
on CYP3A4 for clearance and which are contraindicated in combination with PF-07321332 
(nirmatrelvir)/ritonavir are prohibited during study intervention (from Day 1 and prior to the 
first dose of study intervention to Day 5, if clinically appropriate).
Participants taking lovastatin and simvastatin should discontinue use at least 12 hours prior to 
initiation of PF-07321332 (nirmatrelvir)/ritonavir and refrain from use during treatment and 
for 5 days after the last dose of PF-07321332 (nirmatrelvir)/ritonavir. 
Medications or substances that are highly dependent on CYP3A4 for clearance or are strong 
inducers of CYP3A4 and that are contraindicated in combination with PF-07321332 
(nirmatrelvir)/ritonavir must be discontinued for an appropriate washout period prior to the 
first dose of PF-07321332 (nirmatrelvir)/ritonavir and are prohibited for the duration of the 
study intervention period and for 4 days after the last dose of PF-07321332 
(nirmatrelvir)/ritonavir.
A non-exhaustive list of prohibited and precautionary medications is provided below in 
Table 4. If a medication is not listed as contraindicated, it should not automatically be 
assumed it is safe to co-administer. Appropriately qualified site staff will review all 
concomitant medications to determine if they are prohibited. Investigators should consult the 
ritonavir product label and the product label for any other medication used during the study
for information regarding medication that is prohibited for concomitant use and consult with 
the Sponsor medical monitor as appropriate to maintain participant safety.
The Pfizer study team is to be notified of any prohibited medications taken during the study. 
After consulting with the sponsor, the investigator will make a judgement on the ongoing 
participation of any participant with prohibited medication use during the study.
This list of drugs prohibited for potential DDI concerns with the 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 study intervention, availability of new information in literature on the DDI potential of 
other drugs). 
This is not an all-inclusive list. Site staff should consult with the sponsor or designee with 
any questions regarding potential DDI.


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Table 4.
Established and Other Potentially Significant Drug Interactions
Drug Class 
Drugs within Class
Effect on 
Concentration
Clinical Comments
Alpha 
1-adrenoreceptor 
antagonist
alfuzosin
↑ alfuzosin
Co-administration contraindicated 
due to potential hypotension.
Analgesics 
pethidine, 
propoxyphene
↑ pethidine
↑ propoxyphene
Co-administration contraindicated 
due to potential for serious 
respiratory depression or 
hematologic abnormalities.
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 
arrhythmia.
Antiarrhythmics
bepridil,
lidocaine (systemic)
↑ antiarrhythmic
Caution is warranted and 
therapeutic concentration 
monitoring is recommended for 
antiarrhythmics if available.
Anticancer drugs
apalutamide
↓ PF-07321332 
(nirmatrelvir)/ritonavir
Co-administration contraindicated 
due to potential loss of virologic 
response and possible resistance.
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
↑↓ warfarin
↑ rivaroxaban
Closely monitor INR if
co-administration with warfarin is 
necessary.
Increased bleeding risk with 
rivaroxaban. Avoid concomitant 
use.


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Table 4.
Established and Other Potentially Significant Drug Interactions
Drug Class 
Drugs within Class
Effect on 
Concentration
Clinical Comments
dabigatran
↑ dabigatran
Increased bleeding risk with 
Dabigatran. Avoid concomitant use 
with dabigatran.
Anticonvulsants
carbamazepine,
phenobarbital,
phenytoin
↓PF-07321332 
(nirmatrelvir)/ritonavir
↑ carbamazepine
↓ phenobarbital
↓ phenytoin
Co-administration contraindicated 
due to potential loss of virologic 
response and possible resistance.
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
↑PF-07321332 
(nirmatrelvir)/ritonavir
Avoid concomitant use of 
voriconazole.
Refer to ketoconazole, 
isavuconazonium sulfate, and 
itraconazole product labels for 
further information.
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.


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Table 4.
Established and Other Potentially Significant Drug Interactions
Drug Class 
Drugs within Class
Effect on 
Concentration
Clinical Comments
Anti-HIV protease 
inhibitors
amprenavir,
atazanavir,
darunavir,
fosamprenavir,
indinavir,
nelfinavir,
saquinavir,
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 PF-07321332
(nirmatrelvir)/ritonavir or protease 
inhibitor adverse events with 
concomitant use of these protease 
inhibitors.
Anti-HIV
didanosine,
delavirdine,
efavirenz,
maraviroc,
nevirapine,
raltegravir,
zidovudine
bictegravir/ 
emtricitabine/ 
tenofovir
↑ didanosine 
↑ efavirenz
↑ maraviroc
↓ raltegravir 
↓ 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.
Antimycobacterial
rifampin
↓ PF-07321332 
(nirmatrelvir)/ritonavir
Co-administration contraindicated 
due to potential loss of virologic 
response and possible resistance. 
Alternate antimycobacterial drugs 
such as rifabutin should be 
considered.
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
lurasidone, 
pimozide,
clozapine
↑ lurasidone
↑ pimozide
↑ clozapine
Co-administration contraindicated 
due to serious and/or 
life-threatening reactions such as 
cardiac arrhythmias.


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Table 4.
Established and Other Potentially Significant Drug Interactions
Drug Class 
Drugs within Class
Effect on 
Concentration
Clinical Comments
Antipsychotics
quetiapine
↑ quetiapine
If co-administration is necessary, 
reduce quetiapine dose and 
monitor for quetiapine-associated 
adverse reactions. Refer to the 
quetiapine prescribing information 
for recommendations.
Calcium channel 
blockers
amlodipine, 
diltiazem,
felodipine,
nicardipine,
nifedipine
↑ 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 
PF-07321332 
(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 PF-07321332 
(nirmatrelvir)/ritonavir with 
digoxin, with appropriate 
monitoring of serum digoxin 
levels. 
Refer to the digoxin product label 
for further information.
Endothelin receptor
Antagonists
bosentan
↑ bosentan
Discontinue use of bosentan at 
least 36 hours prior to initiation of 
PF-07321332 
(nirmatrelvir)/ritonavir. 
Refer to the bosentan product label 
for further information.
Ergot derivatives
dihydroergotamine,
ergotamine,
methylergonovine
↑ dihydroergotamine
↑ ergotamine
↑ methylergonovine
Co-administration contraindicated 
due to potential for acute ergot 
toxicity characterized by 
vasospasm and ischemia of the 
extremities and other tissues 
including the central nervous 
system.


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Table 4.
Established and Other Potentially Significant Drug Interactions
Drug Class 
Drugs within Class
Effect on 
Concentration
Clinical Comments
Hepatitis C direct 
acting antivirals
elbasvir/grazoprevir,
glecaprevir/pibrenta
svir
ombitasvir/paritapre
vir/ritonavir and 
dasabuvir
sofosbuvir/velpatasv
ir/voxilaprevir
↑ antiviral 
Increased grazoprevir 
concentrations can result in ALT 
elevations.
It is not recommended to 
co-administer ritonavir with 
glecaprevir/pibrentasvir. 
Refer to the 
ombitasvir/paritaprevir/ritonavir 
and dasabuvir label for further 
information.
Refer to the 
sofosbuvir/velpatasvir/voxilaprevir 
product label for further 
information.
Patients on ritonavir-containing 
HCV regimens should continue 
their treatment as indicated. 
Monitor for increased 
PF-07321332 
(nirmatrelvir)/ritonavir or HCV 
drug adverse events with 
concomitant use.
Herbal products
St. John’s Wort 
(hypericum 
perforatum)
↓ PF-07321332 
(nirmatrelvir)/ritonavir
Co-administration contraindicated 
due to potential loss of virologic 
response and possible resistance 
[see Contraindications (4)].
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 PF-07321332 
(nirmatrelvir)/ritonavir and refrain 
from use during treatment and for 
5 days after the last dose of 
PF-07321332 
(nirmatrelvir)/ritonavir.
HMG-CoA 
reductase inhibitors
atorvastatin,
rosuvastatin
↑ atorvastatin
↑ rosuvastatin
Consider temporary 
discontinuation of atorvastatin and 
rosuvastatin during treatment with 


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Table 4.
Established and Other Potentially Significant Drug Interactions
Drug Class 
Drugs within Class
Effect on 
Concentration
Clinical Comments
PF-07321332 
(nirmatrelvir)/ritonavir..
Hormonal 
contraceptive
ethinyl estradiol
↓ ethinyl estradiol
An additional, non-hormonal 
method of contraception should be 
considered during the 5 days of 
PF-07321332 
(nirmatrelvir)/ritonavir treatment 
and until one menstrual cycle after 
stopping PF-07321332 
(nirmatrelvir)/ritonavir.
Immunosuppressan
ts
cyclosporine,
tacrolimus,
sirolimus
↑ cyclosporine
↑ tacrolimus
↑ sirolimus
Therapeutic concentration 
monitoring is recommended for 
immunosuppressants.
Avoid use of PF-07321332 
(nirmatrelvir)/ritonavir when close 
monitoring of immunosuppressant 
serum concentrations is not 
feasible.
Avoid concomitant use of 
sirolimus and PF-07321332 
(nirmatrelvir)/ritonavir.
If co-administered, refer to 
individual product label for 
immunosuppressant for further 
information.
Long-acting 
beta-adrenoceptor 
agonist
salmeterol
↑ salmeterol
Co-administration is not 
recommended. The combination 
may result in increased risk of 
cardiovascular adverse events 
associated with salmeterol, 
including QT prolongation, 
palpitations, and sinus tachycardia. 
Narcotic analgesics
fentanyl
methadone
↑ fentanyl
↓ methadone
Careful monitoring of therapeutic 
and adverse effects (including 
potentially fatal respiratory 
depression) is recommended when 
fentanyl is concomitantly 
administered with PF-07321332 
(nirmatrelvir)/ritonavir. 
Monitor methadone-maintained 
patients closely for evidence of 
withdrawal effects and adjust the 
methadone dose accordingly.


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Table 4.
Established and Other Potentially Significant Drug Interactions
Drug Class 
Drugs within Class
Effect on 
Concentration
Clinical Comments
PDE5 inhibitor
sildenafil (Revatio®) 
when used for 
pulmonary arterial 
hypertension 
↑ sildenafil
Co-administration 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.
Sedative/hypnotics
midazolam 
(administered 
parenterally)
↑ midazolam
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.
Systemic 
corticosteroids
betamethasone,
budesonide,
ciclesonide,
dexamethasone,
fluticasone,
methylprednisolone,
mometasone,
prednisone,
triamcinolone
↑ corticosteroid
Increased risk for Cushing’s 
syndrome and adrenal suppression. 
Alternative corticosteroids 
including beclomethasone and 
prednisolone should be considered.


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10.9. Appendix 9: Country-Specific Requirements
10.9.1. Germany
Local HIV testing at screening will be performed for participants in Germany as required by 
the German HA (See Appendix 2).


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10.10. Appendix 10: Definition of COVID-19 Severity
The severity of a COVID-19 infection for this study is classified using the below criteria 
developed by NIH (Clinical Spectrum | COVID-19 Treatment Guidelines [nih.gov]):

Asymptomatic or Presymptomatic Infection:
o
Individuals who test positive for SARS-CoV-2 using a virologic test (ie, a 
NAAT or an antigen test) but who have no symptoms that are consistent with 
COVID-19.

Mild Illness:
o
Individuals who have any of the various signs and symptoms of COVID-19 
(eg, fever, cough, sore throat, malaise, headache, muscle pain, nausea, 
vomiting, diarrhea, loss of taste and smell) but who do not have shortness of 
breath, dyspnea, or abnormal chest imaging.

Moderate Illness:
o
Individuals who show evidence of lower respiratory disease during clinical 
assessment or imaging and who have an oxygen saturation (SpO2) ≥94% on 
room air at sea level.

Severe Illness:
o
Individuals who have SpO2 <94% on room air at sea level, a ratio of arterial 
partial pressure of oxygen to fraction of inspired oxygen (PaO2/FiO2) <300 
mm Hg, a respiratory rate >30 breaths/min, or lung infiltrates >50%.

Critical Illness:
o
Individuals who have respiratory failure, septic shock, and/or multiple organ 
dysfunction.


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10.11. Appendix 11: Protocol Amendment History
Amendment 1 (23 Jun 2022) 
Overall Rationale for the Amendment: To update from BID to QD dosing schedule;
clearly delineate PK sample collection schemas for Cohort 1 and for Cohort 2 when HD is 
given on specific days; clarify that the Tasso device is the preferred method of PK sampling; 
and clarify eDiary data collection and other study procedures.
Section # and 
Name
Description of 
Change
Brief Rationale
Substantial or 
Nonsubstantial
1. Protocol 
Summary 
4. Study Design
6. Study 
Intervention(s) 
and Concomitant 
Therapy
Nirmatrelvir/ritonavir 
100 mg /100 mg Q12 
hr dose on Days 1-5 
changed to a single 
dose on Day 1 of 
PF-07321332 
(nirmatrelvir)/ritonavir 
300 mg/100 mg 
followed by 
PF-07321332 
(nirmatrelvir)/ritonavir 
150 mg/100 mg QD 
on Days 2-5.
Considering the 
uncertainty in safety in 
this vulnerable 
population, higher 
exposure with BID 
dosing regimen is 
concerning. Population 
PK model-based 
simulations showed 
that 300 mg PF-
07321332 
(nirmatrelvir) on Day 
1 and 150 mg of 
PF-07321332 
(nirmatrelvir) QD on 
Day 2 to Day 5 with 
100 mg ritonavir gives 
comparable exposure 
to COVID-19 patients 
with normal renal 
function at the 300 mg 
PF-07321332 
(nirmatrelvir)/100 mg 
ritonavir BID dose for 
5 days.
Substantial (impacts 
scientific value/ 
conduct/management 
of the trial).
1.2 Schema
Revised for QD 
dosing.
Revised for QD 
dosing.
Substantial (impacts 
scientific value/ 
conduct/management 
of the trial.
1.3 SoA
6. Study 
Intervention(s) 
and Concomitant 
Therapy
Revised dosing 
windows to allow for 
Day 1-Day 2 to be no 
earlier than 14 hours 
and no later than 28 
hours after the Day 1 
Revised for QD 
dosing.
Substantial (impacts 
scientific value/ 
conduct/management 
of the trial.


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Section # and 
Name
Description of 
Change
Brief Rationale
Substantial or 
Nonsubstantial
dose and for the 
remaining doses (Days 
3-5) to be taken at 
approximately the 
same time (±4 hours) 
as the Day 2 dose.
1.3 PK Sampling 
Schemas
Additional PK 
sampling tables were 
added for Cohort 2. 
Tables were added to 
for both cohorts to 
show the different PK 
collection scenarios as 
related to dosing and 
HD.
Substantial (impacts 
scientific value/ 
conduct/management 
of the trial).
8.4. AEs, SAEs, 
and Other Safety 
Reporting
10.3. Adverse 
Events: 
Definitions and 
Procedures for 
Recording, 
Evaluating, 
Follow Up, and 
Reporting
Revised CT SAE 
Report Form to PSSA.
This study will use the 
PSSA tool for 
reporting SAEs.
Nonsubstantial
1. Inclusion 
Criteria
5. Study 
Population
10.4.1 Male 
Participant 
Reproductive 
Inclusion 
Criteria
Inclusion criterion 1 
revised: deletion of 
requirement for male 
contraception.
Exposure to females 
through seminal fluid 
will be sufficiently 
low and therefore 
precludes the need for 
male contraception.
Nonsubstantial
1.1. Synopsis
5. Study 
population
Exclusion criterion 3 
revised.
Simplification of 
chronic liver disease 
criteria. This update 
includes removal of 
need for INR testing at 
screening.
Nonsubstantial
1.1. Synopsis
5. Study 
population
Exclusion criterion 4 
revised.
HIV medications are 
not prohibited but will 
be reviewed during 
concomitant 
medication review per 
Nonsubstantial


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Section # and 
Name
Description of 
Change
Brief Rationale
Substantial or 
Nonsubstantial
Screening procedures 
and Appendix 8.
6.5. Study 
Intervention 
Compliance
Updated definitions of 
medication errors.
Revised for QD 
dosing.
Nonsubstantial
1.3. Schedule of 
Activities
Added maximum time 
between dosing of the 
two study 
interventions as 15 
minutes.
To allow additional 
time between taking 
the study 
interventions.
Nonsubstantial
1.3 SoA
8.1.1. Tasso 
Sample Training 
and Collection
Tasso device 
instruction.
Clarification that use 
of Tasso device is the 
preferred method of 
PK sampling. If Tasso 
device is not available 
or unable to function 
properly, only then is a 
venous draw 
permitted.
Nonsubstantial
8.1.4. Home 
Health Visits
Addition of the 
procedure to review 
and record COVID-19 
related 
hospitalizations.
Correction of an 
important end point 
omission.
Nonsubstantial
1.3 SoA
8.5.4 Electronic 
diary
Clarification of eDiary 
use and addition of 
investigative site 
compliance check.
Clarification of eDiary 
use and requirement of 
compliance check by 
the investigative site.
Nonsubstantial
9.5. Sample Size 
Determination
Added that 
participants may be 
prelaced.
To ensure sufficient 
PK data for analysis, 
any participant with 
insufficient PK 
samples for analysis 
may be replaced.
Nonsubstantial
1. Protocol Title, 
Rationale, 
Inclusion Criteria
Minor word changes, 
administrative.
Clarification.
Nonsubstantial
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Section # and 
Name
Description of 
Change
Brief Rationale
Substantial or 
Nonsubstantial
8.7 Biomarkers
Table 4, 
Appendix 10
Throughout the 
protocol
Electronic diary will 
not be used to collect 
PK sample times.
PK collection times 
will be captured on the 
sample requisition 
forms that are 
submitted to the 
laboratories.
Nonsubstantial
Throughout the 
protocol
Changed 
“nirmatrelvir” to 
“PF-07321332 
(nirmatrelvir)”.
To be consistent with 
study drug bottle 
labeling.
Nonsubstantial


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10.12. Appendix 12: Abbreviations
The following is a list of abbreviations that may be used in the protocol. 
Abbreviation
Term
Abs
absolute
ADL
activity/activities of daily living
AE
adverse event
AKI
acute kidney injury
ALT
alanine aminotransferase
ARDS
acute respiratory distress syndrome
AST
aspartate aminotransferase
AUC
area under the plasma concentration-time curve
AUC0-tau
AUC over a dosing interval
AUCinf
AUC from time 0 extrapolated to infinite time
AxMP
auxiliary medicinal product
BID
twice daily
BP
blood pressure
CDC
Centers for Disease Control and Prevention
CFR
Code of Federal Regulations
CI
confidence interval
CIOMS
Council for International Organizations of Medical Sciences
CK
creatine kinase
CKD
chronic kidney disease
CKD-EPI
chronic kidney disease epidemiology 
CL/F
apparent oral clearance
CLd
hemodialysis clearance
Cmax
maximum plasma concentration
Cmin
minimum plasma concentration
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
Ctrough
Pre-dose trough concentration
CV
coefficient of variation
CYP
cytochrome P450
DAIDS
Division of AIDS
DCT
data collection tool
DDI
drug-drug interaction 
DICI
drug-induced creatinine increase
DIKI
drug-induced kidney injury


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Abbreviation
Term
DILI
drug-induced liver injury
DU
dispensable unit
EC
ethics committee
EC90
90% effective concentration
ECC
emergency contact card
ECDC
European Centre for Disease Prevention and Control
ECG
electrocardiogram or electrocardiography
eCrCl
estimated creatinine clearance
eCRF
electronic case report form
EDB
exposure during breastfeeding
eDiary
electronic diary
E-DMC
External Data Monitoring Committee
EDP
exposure during pregnancy
eGFR
estimated glomerular filtration rate
ET
early termination
EU
European Union
EUA
Emergence Use Authorization
EudraCT
European Union Drug Regulating Authorities Clinical Trials 
(European Clinical Trials Database)
Fd
fraction of drug removed from the body
FDA
Food and Drug Administration
GCP
Good Clinical Practice
GGT
gamma-glutamyl transferase
HA
health authority
HCP
healthcare provider
HCV
hepatitis C virus
HD
hemodialysis
HIV
human immunodeficiency virus
HMG-CoA
3-hydroxy-3-methylglutaryl coenzyme A
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
IgG
immunoglobulin G
IgM
immunoglobulin M
IMP
investigational medicinal product
IND
Investigational New Drug
INR
international normalized ratio
IP
investigational product
IPAL
Investigational Product Accountability Log
IPM
investigational product manual


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Abbreviation
Term
IRB
Institutional Review Board
IRT
Interactive Response Technology
IUD
intrauterine device
IV
intravenous
KDIGO
Kidney Disease: Improving Global Outcomes
LFT
liver function test
mAb
monoclonal antibody
Mpro
main protease
MQI
medically qualified individual
N
number of
NA
not applicable
NAAT
nucleic acid amplification test
NHP
non-human primates
NIH
National Institutes of Health
NIMP
non-investigational medicinal product
NOAEL
no adverse event observed level
NP
nasopharyngeal
PaO2/FiO2
ratio of arterial partial pressure of oxygen to fraction of inspired 
oxygen
PDE5
phosphodiesterase type 5
PE
physical examination
PK
pharmacokinetic(s)
PopCL
population clearance
PR
pulse rate
PSSA
Pfizer's Serious Adverse Event Submission Assistant
PT
prothrombin time
QD
daily
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
SAS
safety analysis set
Scr
serum creatinine
Scys
serum cystatin C
SD
standard deviation
SoA
schedule of activities
SoC
standard of care
SOP
standard operating procedure
SpO2
oxygen saturation
SRSD
Single Reference Safety Document
SUSAR
Suspected Unexpected Serious Adverse Reaction


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Abbreviation
Term
T bili
total bilirubin
t½
terminal half-life
TB
tuberculosis 
TEAE
treatment-emergent adverse event
Tmax
maximum plasma concentration 
UACR
urine albumin/creatinine ratio
UADE
unanticipated adverse device effect
ULN
upper limit of normal
US
United States
Vz/F
apparent volume of distribution
WBC
white blood cell
WHO
World Health Organization
WOCBP
woman/women of childbearing potential
-hCG
-human chorionic gonadotropin


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11. REFERENCES
1.
NORVIR prescribing information. Available from: 
https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/209512lbl.pdf. Accessed 22 
June 2022.
2.
FACT SHEET FOR HEALTHCARE PROVIDERS: EMERGENCY USE 
AUTHORIZATION FOR PAXLOVID (fda.gov) Accessed on: 16 February 2022.
3.
Coronavirus disease (COVID-19) pandemic, WHO/Europe. Available from:
https://www.euro.who.int/en/health-topics/health-emergencies/coronavirus-covid-
19/novel-coronavirus-2019-ncov. Accessed: 17 January 2022.
4.
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: 22 June 2022.
5.
Wu Z, McGoogan JM. Characteristics of and Important Lessons From the Coronavirus 
Disease 2019 (COVID-19) Outbreak in China: Summary of a Report of 72314 Cases 
From the Chinese Center for Disease Control and Prevention. JAMA. 
2020;323(13):1239-42.
6.
Docherty AB, Harrison EM, Green CA, et al. Features of 20,133 UK patients in hospital 
with covid-19 using the ISARIC WHO Clinical Characterisation Protocol: prospective 
observational cohort study. BMJ. 2020;369:m1985.
7.
Richardson S, Hirsch JS, Narasimhan M, et al. Presenting Characteristics,
Comorbidities, and Outcomes Among 5700 Patients Hospitalized With COVID-19 in
the New York City Area. JAMA. 2020;323(20):2052-59.
8.
Chen T, Wu D, Chen H, et al. Clinical characteristics of 113 deceased patients with 
coronavirus disease 2019: retrospective study. BMJ. 2020;368:m1091.
9.
Cummings MJ, Baldwin MR, Abrams D, et al. Epidemiology, clinical course, and 
outcomes of critically ill adults with COVID-19 in New York City: a prospective cohort 
study. Lancet. 2020;395(10239):1763-70.
10. Mehta P, McAuley DF, Brown M, et al. COVID-19: consider cytokine storm syndromes 
and immunosuppression. Lancet. 2020;395(10229):1033-34.
11. Wang D, Hu B, Hu C, et al. Clinical Characteristics of 138 Hospitalized Patients With 
2019 Novel Coronavirus-Infected Pneumonia in Wuhan, China. JAMA. 
2020;323(11):1061-69.
12. Bikbov B, Purcell C, Levey A, et al. Global, regional, and national burden of chronic 
kidney disease, 1990–2017: a systematic analysis for the Global Burden of Disease 
Study 2017. Lancet. 2020;395(10225):709–33.


PF-07321332 (Nirmatrelvir)/ritonavir
Protocol C4671028
Final Protocol Amendment 2, 09 Feb 2023
PFIZER CONFIDENTIAL
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13. Williamson EJ, Walker AJ, Bhaskaran K, et al. Factors associated with COVID-19-
related death using OpenSAFELY. Nature. 2020; 584(7821): 430–36.
14. Carlson N, Nelveg-Kristensen K-E, Freese Ballegaard E, et al.  Increased vulnerability 
to COVID-19 in chronic kidney disease. J Intern Med. 2021: 290(1):166-78.
15. VEKLURY (remdesivir). US Prescribing Information (USPI); 
https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/214787Orig1s000lbl.pdf. 
Accessed 22 June 2022.
16. FACT SHEET FOR HEALTHCARE PROVIDERS: EMERGENCY USE 
AUTHORIZATION FOR PAXLOVID (fda.gov) Accessed: 16 February 2022.
17. US Food and Drug Administration. Molnupiravir EUA Fact Sheet. FACT SHEET FOR 
HEALTHCARE PROVIDERS: EMERGENCY USE AUTHORIZATION FOR 
MOLNUPIRAVIR (fda.gov) Accessed: 16 February 2022.
18. Fact Sheet for Healthcare Providers: Emergency Use Authorization for Bebtelovimab 
(fda.gov) Accessed: 16 February 2022.
19. Sotrovimab EUA: Sotrovimab | Emergency Use Authorization (EUA) Information for 
HCPs. Available from: https://www.sotrovimab.com/. Accessed: 16 February 2022. 
20. Brown PA, McGuinty M, Argyropoulos C, Clark EG, Colantonio D, Giguere P, 
Hiremath S. Early experience with modified dose nirmatrelvir/ritonavir in dialysis 
patients with coronavirus disease-2019. May 2022. Available from: 
https://doi.org/10.1101/2022.05.18.22275234. Accessed 16 June 2022.
21. Matusiak M, Schurch CM. Expression of SARS-CoV-2 entry receptors in the respiratory 
tract of healthy individuals, smokers and asthmatics. Respir Res. 2020;21(1):252
22. 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: 18 
March 2022.
23. C4671011 Clinical Study Report. A Phase 1, Non-Randomized, Open-Label Study to 
Assess the Pharmacokinetics, Safety and Tolerability of PF-07321332 Boosted With 
Ritonavir in Adult Participants With Renal Impairment and in Healthy Participants With 
Normal Renal Function. 19 November 2021.
24. Shuster D, Menon R, Ding B, et al. Effects of chronic kidney disease stage 4, end-stage 
renal disease, or dialysis on the plasma concentrations of ombitasvir, paritaprevir, 
ritonavir, and dasabuvir in patients with chronic HCV infection: pharmacokinetic 
analysis of the phase 3 RUBY-I and RUBY-II trials. Eur J Clin Pharmacol.
2019;75(2)207-16.

SAP_001.pdf: 
Nirmatrelvir (PF-07321332)/ritonavir
Protocol C4671028 Amendment 1, 23 June 2022
Statistical Analysis Plan
PFIZER CONFIDENTIAL 
Page 1
Protocol C4671028
A PHASE 1, OPEN-LABEL, NON-RANDOMIZED STUDY TO 
INVESTIGATE THE SAFETY AND PK FOLLOWING MULTIPLE 
ORAL DOSES OF PF-07321332 (NIRMATRELVIR)/RITONAVIR IN 
ADULT PARTICIPANTS WITH COVID-19 AND SEVERE RENAL 
IMPAIRMENT EITHER ON HEMODIALYSIS OR NOT ON
HEMODIALYSIS
Statistical Analysis Plan 
(SAP)
Version:
1.0
Date:
19 August 2022


Nirmatrelvir (PF-07321332)/ritonavir
Protocol C4671028 Amendment 1, 23 June 2022
Statistical Analysis Plan
PFIZER CONFIDENTIAL 
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TABLE OF CONTENTS
LIST OF TABLES.....................................................................................................................4
LIST OF FIGURES ...................................................................................................................4
APPENDICES ...........................................................................................................................4
1. VERSION HISTORY............................................................................................................5
2. INTRODUCTION .................................................................................................................5
2.1. Modifications to the Analysis Plan Described in the Protocol..................................5
2.2. Study Objectives, Endpoints, and Estimands............................................................5
2.2.1. Primary Estimand(s).....................................................................................6
2.2.2. Secondary Estimand(s).................................................................................6
2.2.3. Additional Estimand(s).................................................................................6
2.3. Study Design .............................................................................................................6
2.4. Sample Size Determination.......................................................................................7
3. ENDPOINTS AND BASELINE VARIABLES:  DEFINITIONS AND  
CONVENTIONS ..................................................................................................................8
3.1. Primary Endpoint ......................................................................................................8
3.2. Secondary Endpoint(s) ..............................................................................................8
3.4. Baseline Variables.....................................................................................................9
3.5. Safety Endpoints .......................................................................................................9
3.5.1. Adverse Events .............................................................................................9
3.5.2. Medical History ..........................................................................................10
3.5.3. Height and Weight......................................................................................10
3.5.4. Laboratory Data..........................................................................................10
3.5.5. Vital Signs ..................................................................................................10
4. ANALYSIS SETS (POPULATIONS FOR ANALYSIS)...................................................10
5. GENERAL METHODOLOGY AND CONVENTIONS....................................................11
5.1. Hypotheses and Decision Rules ..............................................................................11
5.2. General Methods .....................................................................................................11
5.2.1. Analyses for Binary Endpoints...................................................................11
5.2.2. Analyses for Continuous Endpoints ...........................................................11
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Statistical Analysis Plan
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5.2.3. Analyses for Categorical Endpoints ...........................................................11
5.3. Methods to Manage Missing Data and Non-Quantifiable Data..............................12
6. ANALYSES AND SUMMARIES ......................................................................................12
6.1. Primary Endpoint ....................................................................................................12
6.1.1. Primary Endpoint/Estimand Analysis.........................................................12
6.1.1.1. Main Analysis ...........................................................................12
6.1.1.2. Sensitivity/Supplementary Analysis .........................................12
6.2. Secondary Endpoint(s) ............................................................................................13
6.2.1. Plasma nirmatrelvir PK parameters: CL/F, Vz/F, AUC0-tau, Cmax, t1/2
and Ctrough.........................................................................................................13
6.2.2. HD clearance (CLd) of PF-07321332 (nirmatrelvir) ..................................13
6.2.3. Fraction of PF-07321332 (nirmatrelvir) dose removed from the body 
by dialysis (Fd).................................................................................................13
 
6.4. Subset Analyses.......................................................................................................15
6.5. Baseline and Other Summaries and Analyses.........................................................15
6.5.1. Baseline Summaries....................................................................................15
6.5.2. Study Conduct and Participant Disposition................................................15
6.5.3. Study Treatment Exposure .........................................................................15
6.5.4. Concomitant Medications and Nondrug Treatments..................................15
6.5.5. Vaccination.................................................................................................16
6.6. Safety Summaries and Analyses .............................................................................16
6.6.1. Adverse Events ...........................................................................................16
6.6.2. Laboratory Data..........................................................................................16
6.6.3. Vital Signs ..................................................................................................17
6.6.4. Electrocardiograms.....................................................................................17
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Statistical Analysis Plan
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6.6.5. Physical Examination .................................................................................17
7. INTERIM ANALYSES.......................................................................................................17
8. REFERENCES ....................................................................................................................17
9. APPENDICES .....................................................................................................................18
LIST OF TABLES
Table 1.
Summary of Changes..................................................................................5
Table 2. 
Objectives and Endpoints ...........................................................................5
Table 3.
PF-07321332 (nirmatrelvir) PK Parameters Following Single Dose 
of PF-07321332 (nirmatrelvir) /Ritonavir 100 mg/100 mg in Severe 
Renal Impairment Patients..........................................................................8
Table 4.
Percentile Range and Width of 90% Confidence Intervals for the 
Mean PK Parameter....................................................................................8
Table 5. 
Post-Baseline Vital Signs Categories .......................................................17
Table 6.
Protocol-Required Safety Laboratory Assessments .................................20
LIST OF FIGURES
Figure 1.
Study Design...............................................................................................7
APPENDICES
Appendix 1. Summary of PK Concentration Analyses ...........................................................18
Appendix 2. Data Derivation Details.......................................................................................19
Appendix 2.1. Definition and Use of Visit Windows in Reporting.........................................19
Appendix 2.2. Endpoint Derivations .......................................................................................19
Appendix 2.3. Definition of Protocol Deviations That Relate to Statistical 
Analyses/Populations................................................................................19
Appendix 3. Clinical Laboratory Tests....................................................................................20
Appendix 4. List of Abbreviations...........................................................................................21


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1. VERSION HISTORY
Table 1.
Summary of Changes
Version/
Date
Associated
Protocol 
Amendme
nt
Rationale
Specific Changes
1.0
1.0
SAP original version
For the entire document, text in Italic format will represent language copied directly from 
protocol.
2. INTRODUCTION
The purpose of this study is to evaluate the safety and PK of PF-07321332
(nirmatrelvir)/ritonavir in adults with severe renal impairment and COVID-19. Eligible
participants include those with severe renal impairment (defined as eGFR <30 mL/min/1.73 
m2) and not yet receiving HD (Cohort 1) and individuals receiving HD (Cohort 2).
2.1. Modifications to the Analysis Plan Described in the Protocol
Not applicable.
2.2. Study Objectives, Endpoints, and Estimands
Table 2.
Objectives and Endpoints
Objectives
Endpoints
Estimands
Primary: 
Primary:
Primary:
To describe the safety and tolerability of 
nirmatrelvir/ritonavir in adult 
participants with COVID-19 and severe 
renal impairment.
Incidence of TEAEs.
Incidence of SAEs and AEs leading to 
discontinuations.
Not Applicable.
Secondary:
Secondary:
Secondary:
To evaluate the effect of severe renal 
impairment on the PK of nirmatrelvir in 
participants not on HD.
To evaluate the effect of severe renal 
impairment on the PK of nirmatrelvir in 
participants on HD.
Plasma nirmatrelvir PK parameters 
including Cmax, CL/F, Vz/F, AUC0-tau,
t½, and Ctrough estimated from the 
population PK model. 
Not Applicable.
To evaluate the effect of HD on the PK 
of nirmatrelvir.
HD clearance (CLd) of nirmatrelvir. 
Fraction of nirmatrelvir dose removed 
from the body by dialysis (Fd)
Not Applicable.
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2.2.1. Primary Estimand(s)
Not applicable.
2.2.2. Secondary Estimand(s)
Not applicable.
2.2.3. Additional Estimand(s)
Not applicable.
2.3. Study Design
This is a Phase 1, open-label study to evaluate the effect of severe renal impairment on the 
PK of nirmatrelvir/ritonavir and the safety and tolerability of nirmatrelvir/ritonavir in adult 
participants with COVID-19 and severe renal impairment and not yet receiving intermittent 
hemodialysis (Cohort 1) and severe renal impairment receiving intermittent hemodialysis 
(Cohort 2). The study will be conducted in 2 parallel cohorts. Cohort 1 will enroll eligible 
participants with severe renal impairment (defined as eGFR <30 mL/min/1.73 m2) not on 
hemodialysis. Cohort 2 will enroll eligible participants with severe renal impairment on 
hemodialysis. All eligible participants will be assigned to receive a single dose of PF-
07321332 (nirmatrelvir)/ritonavir 300 mg/100 mg orally on Day 1 followed by PF-07321332
(nirmatrelvir)/ritonavir 150 mg/100 mg QD from Day 2 to Day 5.
Approximately 24 participants (12 participants in Cohort 1 and 12 participants in Cohort 2) 
will be assigned to study intervention. 
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Figure 1.
Study Design
2.4. Sample Size Determination
The 12 evaluable participants per cohort is considered sufficient to provide a suitable 
estimate of precision of PK parameters of nirmatrelvir in severe renal impairment 
participants on HD and not on HD, in which provides approximately 40% precision (the 
width of 90% confidence interval) for AUCinf and Cmax. To ensure sufficient PK data for 
analysis, any participant with insufficient PK samples for analysis may be replaced.  
To identify an adequate sample size for PK, we assessed the precision of estimating the PK 
parameter using different sample sizes, as defined by the width of the resultant confidence 
intervals represented as a percentage of the mean value of the PK parameter. Currently, no 
PK data is available in severe renal impairment following multiple doses of nirmatrelvir;
therefore, a single dose PK data of nirmatrelvir in severe renal impairment adults not on 
dialysis (Table 3) was used to determine the CV estimates for nirmatrelvir PK parameters. 
The CV estimates in Table 3, for nirmatrelvir AUCinf and Cmax range from 33% to 38% (ie, 
0.33 to 0.38).


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Table 3.
PF-07321332 (nirmatrelvir) PK Parameters Following Single Dose of PF-
07321332 (nirmatrelvir) /Ritonavir 100 mg/100 mg in Severe Renal 
Impairment Patients
PK Parameter (units)
Nirmatrelvir
(N=8)
Cmax (ng/mL)
2369 (38)
AUCinf (ng*hr/mL)
44040 (33)
Tmax (hr)
3.00 (1.00-6.05)
t1/2 (hr)
13.37 ± 3.3225
Values are presented as geometric mean (geometric % CV) except median (range) for Tmax
and arithmetic mean ± SD for t½.
The study participants may experience more variability in PK parameters than the available 
data given the wider range of multiple doses, thus a precision is described with an anticipated 
CV of 0.2, 0.3, or 0.4. 
Table 4 below shows the upper and lower confidence limits and 90% CI width for the mean 
PK parameter (eg, AUC, t½, or Cmax), presented as a percentage of the mean, for different N 
and CV. With a sample size of 12 evaluable participants and a CV equal to 0.4, the 90% CI 
will range from 79.3% – 120.7 % of the mean, and the corresponding CI width will be 41.4% 
of the mean. The PK parameter will be estimated with a tight 95% CI in the a severe renal 
impaired population.
Table 4.
Percentile Range and Width of 90% Confidence Intervals for the Mean 
PK Parameter
N
CV=0.2
CV=0.3
CV=0.4
Range
Width
Range
Width
Range
Width
8
86.6-113.4%
26.8%
79.9-120.1%
40.2%
73.2-126.8%
53.6%
10
88.5-111.5%
23.1%
82.7-117.3%
34.6%
76.9-123.1%
46.2%
12
89.6-110.4%
20.7%
84.5-115.5%
31.1%
79.3-120.7%
41.4%
14
90.5-109.5%
19.0%
85.8-114.2%
28.4%
81.1 -119.0%
37.9%
3. ENDPOINTS AND BASELINE VARIABLES: DEFINITIONS AND 
CONVENTIONS
3.1. Primary Endpoint
Incidence of TEAEs
Incidence of SAEs and AEs leading to discontinuations.
3.2. Secondary Endpoint(s)
Plasma PF-07321332 (nirmatrelvir) PK parameters including Cmax, CL/F, Vz/F,


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AUC0-tau, t½, and Ctrough estimated from the population PK model.
HD clearance (CLd) of PF-07321332 (nirmatrelvir).
Fraction of PF-07321332 (nirmatrelvir) dose removed from the body by dialysis (Fd).
3.4. Baseline Variables
Baseline visit is set up according to study days of Day -1 to Day 1. Only non-missing results 
that are prior to the first dose intervention will be considered as Baseline data. The variables 
for baseline include vital signs, labs (hematology, chemistry, and additional tests), COVID-19
vaccination status, SARS-CoV-2 serology, SARS-CoV-2 RNA, and prior medications. For 
SARS-CoV-2 RNA concentration data, the Baseline data is on Day 1.
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 adverse event is considered a Treatment-
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Emergent Adverse Event (TEAE) if the event started on or after the study medication start 
date and time. 
3.5.2. Medical History
Medical history in addition to COVID-19 disease history and demographics will be collected 
at screening. Smoking status will be collected. Medication history of prescription or 
nonprescription drugs (including vaccinations), and dietary and herbal supplements taken 
within 30 days prior to the planned first dose will be collected. All doses of COVID-19
vaccinations administered at any time before study participation will be collected and 
summarized.
3.5.3. Height and Weight
Height and weight will be measured and recorded at screening.
3.5.4. Laboratory Data
The Appendix 3 lists clinical safety laboratory tests to be performed and the protocol SoA for 
the timing and frequency.
3.5.5. Vital Signs
Vital signs measure include temperature, pulse rate, respiratory rate, oxygen saturation level, 
and blood pressure.
4. ANALYSIS SETS (POPULATIONS FOR ANALYSIS)
Data for all participants will be assessed to determine if participants meet the criteria for 
inclusion in each analysis population.
Participant Analysis Set
Description
Enrolled 
"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 
assignment to study intervention. A participant will be 
considered enrolled if the informed consent is not withdrawn 
prior to participating in any study activity after screening. 
Potential participants who are screened for the purpose of 
determining eligibility for the study, but do not participate in 
the study, are not considered enrolled, unless otherwise 
specified by the protocol. 
SAS
All participants assigned to study intervention and who take at 
least 1 dose of study intervention. Participants will be analyzed 
according to the product they actually received.


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Defined Analysis Set
Description
PK Concentration
The PK concentration population is defined as 
all participants assigned to investigational 
product and treated who have at least 1 
concentration measured.
PK Parameter
The PK parameter analysis population is 
defined as all participants assigned to 
investigational product and treated who have 
at least 1 of the PK parameters of interest 
measured. 
5. GENERAL METHODOLOGY AND CONVENTIONS
5.1. Hypotheses and Decision Rules
This is single arm study and has no statistical hypotheses tested and no formal decision rules 
for interpreting the study results. All analyses will be descriptive.
5.2. General Methods
Descriptive statistics for all endpoints will be provided by cohort and time point.  For most 
summary tables, unless stated otherwise, cohorts will be presented both separately and 
combined.  
5.2.1. Analyses for Binary Endpoints
For binary endpoints, number and proportion of participants with the event of interest (with 
corresponding sample size) will be summarized for each cohort and overall. 
5.2.2. Analyses for Continuous Endpoints
For continuous endpoints, values and/or changes from baseline over time, as applicable, will 
be summarized for each cohort and overall. Standard descriptive statistics (n, mean, standard 
deviation, median, interquartile range, minimum, and maximum) will be utilized.
5.2.3. Analyses for Categorical Endpoints
For categorical endpoints, number and proportion of participants for each category (with 
corresponding sample size) will be summarized for each cohort and overall. 


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5.3. Methods to Manage Missing Data and Non-Quantifiable Data
In summary tables of concentration data by cohort, visit day and time, statistics will be 
calculated having set concentrations to missing if one of the following applies:
A concentration has been collected as ND (not done) or NS (no sample), or
A deviation in sampling time is of sufficient concern or a concentration has been 
flagged anomalous by the pharmacokineticist.  In such cases, data for all participants 
will be assessed to determine if samples meet the criteria for exclusion from analysis 
prior to releasing the database, and classifications will be documented per standard 
operating procedures.
SARS-CoV-2 RNA < LLOQ is imputed as 1.7 = log10(50) for non-missing results.
As all analyses are descriptive, missing endpoint data will result in a summary where the N 
for that endpoint (and time point) is smaller than the total N of the corresponding analysis 
set. No imputation of the missing data will be performed.
Missing PK concentration values will generally be handled as described above.  Non-missing 
concentrations that are below the limit of quantitation will be reported as such in listings and 
imputed as zero for summary tables and figures.  
Additional details for handling missing data in the population PK modeling will be described in a 
population modeling analysis plan.
Missing safety data such as dates or severities of adverse events will be handled using 
standard algorithms in accordance with CDISC and CaPS standards.  
6. ANALYSES AND SUMMARIES
6.1. Primary Endpoint
6.1.1. Primary Endpoint/Estimand Analysis
6.1.1.1. Main Analysis
Incidence of TEAEs through Day 34, SAEs, and AEs leading to discontinuation will be 
summarized with number and percent of participants in the SAS for each cohort, and overall, 
in accordance with CDISC and CaPS standards.
6.1.1.2. Sensitivity/Supplementary Analysis
Not applicable.


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6.2. Secondary Endpoint(s)
6.2.1. Plasma nirmatrelvir PK parameters: CL/F, Vz/F, AUC0-tau, Cmax, t1/2 and Ctrough
Nonlinear mixed effect modeling will be performed using the PK concentration analysis set 
(see Section 4) to evaluate pharmacokinetic parameters of nirmatrelvir (CL/F, Vz/F, AUC0-
tau, Cmax, t1/2 and Ctrough). The detailed procedures for the population PK analysis, 
including the model implementation and evaluation will be described in a population 
modeling analysis plan. Also, the results of the analysis will be summarized in a 
population modeling and analysis report, separate from the clinical study report.
Plasma concentrations of nirmatrelvir from venous or Tasso samples will be summarized 
using the PK concentration analysis set.  A listing of plasma concentrations at the 
nominal sampling time by participant, method of blood collection, and cohort will be 
provided.  A listing of deviations from the nominal sampling time will also be provided.  
For each cohort, and overall, the plasma concentrations will be summarized by nominal 
sampling time using appropriate descriptive statistics (eg, number of 
participants/samples, number of concentrations at or above the lower limit of 
quantification (NALQ), mean, SD, minimum, median, maximum, and coefficient of 
variation).
Individual nirmatrelvir plasma concentration profiles (ie, concentration vs. time data) will 
be presented graphically by cohort (ie, spaghetti plots) using actual sample collection 
time on both linear and semilogarithmic scales. Median concentration time profiles will 
be presented by cohort on both linear and semilogarithmic scales using nominal sampling 
time.  Additional graphical presentations of PK data may be included at the discretion of 
the PK scientist.
6.2.2. HD clearance (CLd) of PF-07321332 (nirmatrelvir)
Hemodialysis clearance (CLd) of nirmatrelvir will be calculated using the following relationship: 
CLd = [(Cin – Cout) / Cin] × [Qb × (1 – HCT)] 
where Cin and Cout are plasma concentrations measured in blood samples entering and exiting the 
dialyzer, respectively; Qb and HCT are blood flow rate entering the dialyzer and hematocrit 
measured at each collection time, respectively. Individual time point CLd values obtained using 
this method will be used to calculate an average subject CLd.
6.2.3. Fraction of PF-07321332 (nirmatrelvir) dose removed from the body by dialysis 
(Fd)
Fraction of nirmatrelvir dose removed from the body by dialysis (Fd) will be calculated as follow: 
Fd = 100% × Ad / Dose 


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where Ad is the amount of drug removed by the dialysis and is calculated as follows: 
Ad = CLd × AUCt0-t1
where for AUCt0-t1 , t0 marks the start time and t1 the termination of the hemodialysis session.
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6.4. Subset Analyses
Not applicable.
6.5. Baseline and Other Summaries and Analyses
6.5.1. Baseline Summaries
Baseline demographic and other characteristics described in 3.4 will be tabulated for the SAS 
and summarized by cohort, and overall.  Quantitative variables will be described by standard 
descriptive statistics (N, mean, standard deviation, median, minimum, and maximum), and 
qualitative variables will be summarized by number and proportion in each category. 
Demographic data collected at screening will be reported.
6.5.2. Study Conduct and Participant Disposition
The number of participants screened, assigned to study treatment, completing study 
treatment, and completing the study will be summarized.  The reasons for discontinuation 
will be summarized by cohort.
6.5.3. Study Treatment Exposure
The number of doses of the study treatment received and the percentage compliance will be 
summarized.
6.5.4. Concomitant Medications and Nondrug Treatments
Concomitant medications and non-drug treatments will be summarized by cohort in 
accordance with CDISC and CaPS standards.
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The types of vaccines received will be summarized for number and percent of participants for 
each vaccine type overall and each cohort.
6.5.5. Vaccination
Vaccination data will be collected in con-med data set (ADCM), the variable MCAT 
represents the type of vaccine (i.e., Pfizer, J&J and others). For participant who have more 
than one dose of vaccine, there are more than one record in the ADCM data set. So the 
number of doses can be derived from the record.
The number of doses received will be summarized for number and percent of subject for each 
vaccine dose overall and each cohort.
6.6. Safety Summaries and Analyses
All safety analyses will be performed on the safety population, ie, Safety Analysis Set (SAS).
Safety summaries and analyses will utilize CDISC and CaPS standards.
6.6.1. Adverse Events
As this study has only one treatment, the 3-tier approach to adverse event reporting will not 
be utilized.  For each AE, the number and percent incidence will be summarized by cohort, 
but the incidence will not be formally compared among cohorts.  No p-values or confidence 
intervals will be generated and therefore, no multiplicity adjustment will be used.  AEs will 
be arranged alphabetically within system organ class in the summary tables.
It should be recognized that most studies are not designed to reliably demonstrate a causal 
relationship between the use of a pharmaceutical product and an adverse event or a group of 
adverse events. Except for select events in unique situations, studies do not employ formal 
adjudication procedures for the purpose of event classification. As such, safety analysis is 
generally considered as an exploratory analysis and its purpose is to generate hypotheses for 
further investigation. 
6.6.2. Laboratory Data
Lab data and the corresponding changes from baseline will be summarized over time (Day 1, 
5) by cohort, and overall using standard descriptive statistics.  Any abnormalities of potential 
clinical concern according to the criteria specified by the Pfizer reporting standards will be 
described.  Data will be presented in tabular and/or graphical format, as appropriate.
Data collected at screening that are used for inclusion/exclusion criteria will be considered 
source data, and will not be required to be reported, unless otherwise noted.


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6.6.3. Vital Signs
SBP, DBP, pulse rate, respiratory rate, oral temperature, and SpO2 will be summarized over 
time (Day 1, 5, 14, 34) by cohort, and overall using standard descriptive statistics.  Any
abnormalities of potential clinical concern (see Table 5) will be described.  Data will be 
presented in tabular and/or graphical format, as appropriate.
Table 5.
Post-Baseline Vital Signs Categories
Parameter (units)
Criteria
Systolic Blood Pressure (mmHg)
Value < 90
Diastolic Blood Pressure (mmHg)
Value < 50
Pulse Rate (bpm)
Value < 40
Value > 120
6.6.4. Electrocardiograms
Not applicable.
6.6.5. Physical Examination
Medical history and physical examination collected during the course of the study will be 
considered source data and will not be required to be reported, unless otherwise noted.
However, any untoward findings identified on physical and/or neurological examinations 
conducted during the active collection period will be captured as AEs, if those findings meet 
the definition of an AE.
7. INTERIM ANALYSES
No interim analysis will be conducted for this study.
As this is an open-label, unblinded study, the sponsor may conduct reviews of the data during 
the study for the purpose of safety assessment, facilitating PK/PD modeling, and/or 
supporting clinical development.
8. REFERENCES
None.


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9. APPENDICES
Appendix 1. Summary of PK Concentration Analyses
Endpoint
Analysis Type
Population
Data Inclusion and 
Rules for Handling 
Intercurrent Events 
and Missing Data 
Analysis Model
PK 
concentration
Summary (nominal 
sampling time)
PK 
concentration 
analysis set
Missing data will not be 
imputed.  
Concentrations BLQ 
imputed as zero.
Descriptive stats for 
overall, Cohort 1 and 
Cohort 2
Figure – Individual 
concentration vs. 
time profiles 
(actual sampling 
time)
PK 
concentration 
analysis set
Missing data will not be 
imputed.  
Concentrations BLQ 
imputed as zero.
Spaghetti plots for 
Cohort 1, Cohort 2
Figure – Median 
concentration vs. 
time profile 
(nominal sampling 
time)
PK 
concentration 
analysis set
Missing data will not be 
imputed.  
Concentrations BLQ 
imputed as zero.
Summary plots for 
Cohort 1 and Cohort 2
Listing (nominal 
sampling time)
PK 
concentration 
analysis set
Concentrations BLQ 
reported as such.
Listing by cohort, 
participant, nominal 
sampling time; 
includes method of 
blood collection, 
actual sampling time, 
and deviation from 
nominal sampling time


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Appendix 2. Data Derivation Details
Appendix 2.1. Definition and Use of Visit Windows in Reporting
Reporting will be based on nominal visits.  When categorizing dated assessments under 
nominal times for the purpose of reporting, the protocol-defined visit windows will be 
utilized (see the protocol schedule of activities).  Unplanned visits will be listed, but 
generally not summarized, except in the case of lab abnormalities and vital sign categories 
summary tables.
Appendix 2.2. Endpoint Derivations
See the Analysis and Reporting Plan for any relevant endpoint derivations.
Appendix 2.3. Definition of Protocol Deviations That Relate to Statistical 
Analyses/Populations
Protocol deviations that may result in exclusion of specific data points (eg, PK 
concentrations) from analysis include deviations related to:
Compliance, missed doses, dosing/administration errors.
Prohibited concomitant medications.
Participant conditions affecting drug metabolism such as hepatic impairment.
PK samples not done or not properly collected, stored, or handled.


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Appendix 3. Clinical Laboratory Tests
The following safety laboratory tests will be performed at times defined in the SoA section of 
this protocol. Unscheduled clinical laboratory measurements may be obtained at any time 
during the study to assess any perceived safety issues.
Table 6.
Protocol-Required Safety Laboratory Assessments
Hematology
Chemistry
Other
Additional Tests 
Hemoglobin
Hematocrit
RBC count
Platelet count
WBC count
Total neutrophils
(Abs)
Eosinophils (Abs)
Monocytes (Abs)
Basophils (Abs)
Lymphocytes 
(Abs)
Urea and creatinine
eGFR
Glucose
Calcium
Sodium
Potassium
Chloride
Total CO2 
(bicarbonate)
AST, ALT
Total bilirubin
Alkaline phosphatase
Albumin
Total protein
Pregnancy test
-hCG)a
SARS-CoV-2
serology
(IgG and IgM)
For suspected DICI/DIKI: 
Creatinine (Scr) 
Needed for Hy’s Law
AST, ALT (repeat)
Total bilirubin (repeat)
Albumin 
Alkaline phosphatase (repeat)
Direct bilirubin
Indirect bilirubin
Creatine kinase
GGT
PT/INR
Total bile acids
Acetaminophen drug and/or protein 
adduct levels
Hepatitis serology
a.
Local urine testing using the central lab-provided test (locally purchased test is acceptable after Day 1 if
the participant and/or home health staff does not have one provided by the central lab) will be standard
for the protocol unless serum testing is required by local regulation or IRB/EC or the participant is
-hCG) pregnancy test must be confirmed at screening and prior to
dispensing treatment for ALL WOCBP.


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Appendix 4. List of Abbreviations
Abbreviation
Term
Abs
Absolute
AE
adverse event
AUC
area under the curve
AUC0-tau
AUC over a dosing interval
AUCinf
AUC from time 0 extrapolated to infinite time
BLQ
below the limit of quantitation
BP
blood pressure
CaPS
CDISC aligned Pfizer Standards
CDISC
Clinical Data Interchange Standards Consortium
CI
confidence interval
CLd
hemodialysis clearance
CL/F
apparent oral clearance
Cmax
maximum observed concentration
Cmin
minimum plasma concentration
COVID-19
coronavirus disease 2019
CRF
case report form
CSR
clinical study report
Ctrough
Pre-dose trough concentration
CV
Coefficient of variation
DMC
data monitoring committee
EC
Ethics committee
ECG
electrocardiogram
E-DMC
external data monitoring committee 
eDiary
Electronic diary
ET
early termination
Fd
fraction of drug removed from the body
FDA
Food and Drug Administration
GCP
Good Clinical Practice
HD
hemodialysis
ICD
informed consent document
IRB
Institutional Review Board
LLOQ
lower limit of quantitation
LOD
limit of detection
MedDRA
Medical Dictionary for Regulatory Activities
N/A
not applicable
NALQ
Number of concentrations at or above the lower limit of quantification
NP
nasopharyngeal
PK
pharmacokinetic(s)
PR
pulse rate


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Abbreviation
Term
PT
preferred term
RR
relative risk
RT-PCR
real time polymerase chain reaction
SAE
serious adverse event
SAP
statistical analysis plan
SAS
Safety analysis set
SARS-CoV-2
severe acute respiratory syndrome coronavirus 2
SD
standard deviation
SGS
Statistical Guidance Standards
SOP
standard operating procedure
SoA
schedule of activities
SpO2
oxygen saturation
TEAE
treatment emergent adverse event
ULN
upper limit of normal
WHO 
World Health Organization
WHODD
World Health Organization Drug Dictionary


PFIZER INTERNAL USE ONLY 
                             
 
CLINICAL AND MEDICAL CONTROLLED DOCUMENT (CMCD)  
REQUIRED FORM 
Identifier  
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Effective Date  
DMB02-GSOP-
RF01 
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STATISTICAL ANALYSIS PLAN 
APPROVAL SIGNATURE FORM 
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NOTE: This form is used to document the approval of a Statistical Analysis Plan (SAP) and 
any subsequent amendment of the SAP. 
 
SAP Title: 
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following example: A### Statistical 
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Name and Title of Person Submitting 
form: (SAP Author)
Date Submitted: (dd-Mmm-yyyy) 
25-AUG-2022
Approval indicates that the SAP provides analysis specifications consistent with the 
analysis outlined in the protocol and meets the standards and requirements used for 
programming of tables, listings and figures.
SAP Approver’s 
Name: 
SAP Approver’s 
Title: 
Signature:  
Date: (dd-Mmm-
yyyy)
PPD
PPD
PPD
PPD