Clinical trial NCT05525910
Conditions: Biological Availability Healthy Participants
Keywords: Coronavirus disease 2019 (COVID-19) Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Nirmatrelvir Paxlovid
Sponsor: Pfizer
Start date: 2022-08-31; Completion date: 2022-11-07
Enrollment: 15 participants; Allocation: RANDOMIZED; Intervention model: CROSSOVER

Brief summary:
The purpose of this study is to estimate the relative bioavailability of nirmatrelvir/ritonavir of 4 different FDC tablet formulations relative to the commercial tablet formulation under fasted conditions in healthy adult participants.

Detailed description:

Arms: arm 1: Nirmatrelvir and ritonavir tablets arm 2: Nirmatrelvir/ ritonavir test tablets arm 3: Nirmatrelvir/ ritonavir test tablets arm 4: Nirmatrelvir/ ritonavir test tablets arm 5: Nirmatrelvir/ ritonavir test tablets
Interventions: intervention 1: Nirmatrelvir/ ritonavir intervention 2: Nirmatrelvir/ritonavir intervention 3: Nirmatrelvir/ritonavir intervention 4: Nirmatrelvir/ ritonavir intervention 5: Nirmatrelvir/ ritonavir
Intervention descriptions: intervention 1: Single oral dose of nirmatrelvir/ritonavir tablets under fasted condition intervention 2: Single oral dose of nirmatrelvir/ritonavir tablets under fasted condition intervention 3: Single oral dose of nirmatrelvir/ritonavir tablets under fasted condition intervention 4: Single oral dose of nirmatrelvir/ritonavir tablets under fasted condition intervention 5: Single oral dose of nirmatrelvir/ritonavir tablets under fasted condition

Protocol documents:
Prot_000.pdf: 
Nirmatrelvir (PF-07321332)/ritonavir
Protocol C4671023
Final Protocol Amendment 1, 18 August 2022
PFIZER CONFIDENTIAL
Page 1
A PHASE 1, OPEN-LABEL, RANDOMIZED, SINGLE DOSE, CROSSOVER STUDY 
TO ESTIMATE THE RELATIVE BIOAVAILABILITY OF NIRMATRELVIR AND 
RITONAVIR FOLLOWING ORAL ADMINISTRATION OF 4 DIFFERENT FIXED 
DOSE COMBINATION TABLET FORMULATIONS RELATIVE TO THE 
COMMERCIAL TABLET FORMULATION IN HEALTHY ADULT 
PARTICIPANTS UNDER FASTED CONDITIONS
Study Intervention Number:
PF-07321332
Study Intervention Name:
nirmatrelvir and ritonavir
US IND Number:
153517
EudraCT Number:
NA
ClinicalTrials.gov ID: 
NA
Pediatric Investigational Plan Number:
NA
Protocol Number:
C4671023
Phase:
1
Brief Title: A Phase 1 Relative Bioavailability Study of Nirmatrelvir/Ritonavir 4
Different Fixed Dose Combination Tablets Relative to the Commercial Tablets in 
Healthy Participants
This document and accompanying materials contain confidential information belonging to Pfizer. Except as 
otherwise agreed to in writing, by accepting or reviewing these documents, you agree to hold this 
information in confidence and not copy or disclose it to others (except where required by applicable law) or 
use it for unauthorized purposes. In the event of any actual or suspected breach of this obligation, Pfizer 
must be promptly notified.


Nirmatrelvir (PF-07321332)/ritonavir
Protocol C4671023
Final Protocol Amendment 1, 18 August 2022
PFIZER CONFIDENTIAL
Page 2
Document History
Document
Version Date
Ammendment 1
18 August 2022
Original protocol
29 June 2022
This amendment incorporates all revisions to date, including amendments made at the 
request of country health authorities and IRBs/ECs and any global protocol administrative 
change letter(s). 
Protocol Amendment Summary of Changes Table
Amendment 1 (18 August 2022)
Overall Rationale for the Amendment: This study is being amended to
 
 
 
  
Section # and Name
Description of Change
Brief Rationale
Substantial or 
Nonsubstantial

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
 
 
 
 
 
 
 
 

 
 
 
 
 

Section 9.2 (Analysis 
Sets);
Revisions made on PK 
concentration set and PK 
parameter set.
Updates based on 
newly added 
objective and 
endpoint.
Substantial
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Nirmatrelvir (PF-07321332)/ritonavir
Protocol C4671023
Final Protocol Amendment 1, 18 August 2022
PFIZER CONFIDENTIAL
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Section # and Name
Description of Change
Brief Rationale
Substantial or 
Nonsubstantial

Section 9.3.1 
(Pharmacokinetic 
Analyses);
Added statement about salivary 
PK parameters.

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Nirmatrelvir (PF-07321332)/ritonavir
Protocol C4671023
Final Protocol Amendment 1, 18 August 2022
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 ...............................................................................................................22
2.1. Study Rationale .......................................................................................................22
2.2. Background .............................................................................................................22
2.2.1. Nonclinical Pharmacology..........................................................................22
2.2.2. Nonclinical Pharmacokinetics and Metabolism .........................................22
2.2.3. Nonclinical Safety ......................................................................................23
2.2.4. Clinical Overview.......................................................................................23
2.2.4.1. Safety Overview........................................................................24
2.2.4.2. Summary of Nirmatrelvir Pharmacokinetics in Human............25
2.3. Benefit/Risk Assessment.........................................................................................26
2.3.1. Risk Assessment.........................................................................................27
3. OBJECTIVES AND ENDPOINTS.....................................................................................28
4. STUDY DESIGN.................................................................................................................29
4.1. Overall Design.........................................................................................................29
4.2. Scientific Rationale for Study Design.....................................................................31
4.2.1. Choice of Contraception/Barrier Requirements .........................................31
4.2.2. Collection of Retained Research Samples..................................................31
4.3. Justification for Dose ..............................................................................................31
4.4. End of Study Definition ..........................................................................................32
5. STUDY POPULATION......................................................................................................32
5.1. Inclusion Criteria.....................................................................................................32
5.2. Exclusion Criteria....................................................................................................33
5.3. Lifestyle Considerations..........................................................................................36
5.3.1. Contraception..............................................................................................36
5.3.2. Meals and Dietary Restrictions...................................................................36


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Protocol C4671023
Final Protocol Amendment 1, 18 August 2022
PFIZER CONFIDENTIAL
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5.3.3. Caffeine, Alcohol, and Tobacco .................................................................37
5.3.4. Activity .......................................................................................................37
5.4. Screen Failures ........................................................................................................37
6. STUDY INTERVENTION(S) AND CONCOMITANT THERAPY.................................37
6.1. Study Intervention(s) Administered........................................................................38
6.1.1. Administration............................................................................................39
6.2. Preparation, Handling, Storage, and Accountability...............................................39
6.2.1. Preparation and Dispensing........................................................................40
6.3. Assignment to Study Intervention...........................................................................41
6.4. Blinding...................................................................................................................41
6.5. Study Intervention Compliance...............................................................................41
6.6. Dose Modification...................................................................................................41
6.7. Continued Access to Study Intervention After the End of the Study......................41
6.8. Treatment of Overdose............................................................................................41
6.9. Prior and Concomitant Therapy..............................................................................42
6.9.1. Rescue Medicine.........................................................................................43
7. DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL...........................................................................43
7.1. Discontinuation of Study Intervention ....................................................................43
7.1.1. ECG Changes..............................................................................................43
7.1.2. Potential Cases of Acute Kidney Injury .....................................................43
7.1.3. Stopping Rules............................................................................................44
7.2. Participant Discontinuation/Withdrawal From the Study.......................................44
7.2.1. Withdrawal of Consent...............................................................................45
7.3. Lost to Follow-up....................................................................................................45
8. STUDY ASSESSMENTS AND PROCEDURES...............................................................46
8.1. Administrative Procedures ......................................................................................46
8.2. Efficacy Assessments..............................................................................................47
8.3. Safety Assessments .................................................................................................47
8.3.1. Physical Examinations................................................................................47
8.3.2. Vital Signs ..................................................................................................48
8.3.2.1. Blood Pressure and Pulse Rate..................................................48


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Final Protocol Amendment 1, 18 August 2022
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8.3.2.2. Temperature ..............................................................................48
8.3.3. Electrocardiograms.....................................................................................48
8.3.4. Clinical Safety Laboratory Assessments ....................................................49
8.3.5. COVID-19 Specific Assessments...............................................................50
8.3.6. Pregnancy Testing ......................................................................................50
8.4. Adverse Events, Serious Adverse Events, and Other Safety Reporting .................50
8.4.1. Time Period and Frequency for Collecting AE and SAE Information.......51
8.4.1.1. Reporting SAEs to Pfizer Safety...............................................51
8.4.1.2. Recording Nonserious AEs and SAEs on the CRF...................51
8.4.2. Method of Detecting AEs and SAEs ..........................................................52
8.4.3. Follow-Up of AEs and SAEs......................................................................52
8.4.4. Regulatory Reporting Requirements for SAEs...........................................52
8.4.5. Environmental Exposure, Exposure During Pregnancy or 
Breastfeeding, and Occupational Exposure.....................................................53
8.4.5.1. Exposure During Pregnancy......................................................53
8.4.5.2. Exposure During Breastfeeding ................................................55
8.4.5.3. Occupational Exposure .............................................................55
8.4.6. Cardiovascular and Death Events...............................................................55
8.4.7. Disease-Related Events and/or Disease-Related Outcomes Not 
Qualifying as AEs or SAEs..............................................................................55
8.4.8. Adverse Events of Special Interest.............................................................55
8.4.8.1. Lack of Efficacy........................................................................56
8.4.9. Medical Device Deficiencies......................................................................56
8.4.9.1. Time Period for Detecting Medical Device Deficiencies .........56
8.4.9.2. Follow-Up of Medical Device Deficiencies..............................56
8.4.9.3. Prompt Reporting of Device Deficiencies to the Sponsor ........56
8.4.9.4. Regulatory Reporting Requirements for Device 
Deficiencies .......................................................................................56
8.4.10. Medication Errors.....................................................................................56
8.5. Pharmacokinetics ....................................................................................................57
8.5.1. Plasma for Analysis of Nirmatrelvir and Ritonavir....................................57
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8.6. Genetics...................................................................................................................59
8.6.1. Specified Genetics ......................................................................................59
8.6.2. Retained Research Samples for Genetics ...................................................59
8.7. Biomarkers ..............................................................................................................59
8.7.1. Specified Gene Expression (RNA) Research .............................................59
8.7.2. Specified Protein Research.........................................................................59
8.7.3. Specified Metabolomic Research ...............................................................60
8.7.4. Retained Research Samples for Biomarkers...............................................60
8.8. Immunogenicity Assessments.................................................................................60
8.9. Health Economics ...................................................................................................60
9. STATISTICAL CONSIDERATIONS ................................................................................60
9.1. Statistical Hypotheses .............................................................................................61
9.2. Analysis Sets ...........................................................................................................61
9.3. Statistical Analyses .................................................................................................61
9.3.1. Pharmacokinetic Analyses..........................................................................61
9.3.1.1. Derivation of Pharmacokinetic Parameters...............................61
9.3.2. Statistical Methods for PK Data .................................................................62
9.3.3. Other Safety Analyses ................................................................................63
9.3.4. Other Analyse(s).........................................................................................63
9.3.4.1. Biomarker Assessment..............................................................63
9.4. Interim Analyses .....................................................................................................63
9.5. Sample Size Determination.....................................................................................63
10. SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS..........................................................................................................65
10.1. Appendix 1: Regulatory, Ethical, and Study Oversight Considerations...............65
10.1.1. Regulatory and Ethical Considerations ....................................................65
10.1.1.1. Reporting of Safety Issues and Serious Breaches of the 
Protocol or ICH GCP.........................................................................65
10.1.2. Financial Disclosure .................................................................................66
10.1.3. Informed Consent Process ........................................................................66
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10.1.4. Data Protection .........................................................................................67
10.1.5. Committees Structure ...............................................................................67
10.1.5.1. Data Monitoring Committee ...................................................67
10.1.6. Dissemination of Clinical Study Data ......................................................67
10.1.7. Data Quality Assurance ............................................................................69
10.1.8. Source Documents....................................................................................70
10.1.9. Study and Site Start and Closure ..............................................................70
10.1.10. Publication Policy...................................................................................71
10.1.11. Sponsor’s Medically Qualified Individual..............................................72
10.2. Appendix 2: Clinical Laboratory Tests .................................................................73
10.3. Appendix 3: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-Up, and Reporting .....................................................................74
10.3.1. Definition of AE .......................................................................................74
10.3.2. Definition of an SAE ................................................................................75
10.3.3. Recording/Reporting and Follow-Up of AEs and/or SAEs During 
the Active Collection Period............................................................................76
10.3.4. Reporting of SAEs....................................................................................80
10.4. Appendix 4: Contraceptive and Barrier Guidance ................................................81
10.4.1. Male Participant Reproductive Inclusion Criteria....................................81
10.4.2. Female Participant Reproductive Inclusion Criteria.................................81
10.4.3. Woman of Childbearing Potential ............................................................81
10.4.4. Contraception Methods.............................................................................82
10.5. Appendix 5: Genetics............................................................................................84
10.6. Appendix 6: Liver Safety: Suggested Actions and Follow-Up Assessments .......85
10.7. Appendix 7: Kidney Safety: Monitoring Guidelines ............................................87
10.7.1. Laboratory Assessment of Change in Kidney Function and 
Detection of Kidney Injury..............................................................................87
10.7.2. Age-Specific Kidney Function Calculation Recommendations...............87
10.7.2.1. Adults (18 Years and Above)—2021 CKD-EPI 
Equations ...........................................................................................87
10.7.3. Adverse Event Grading for Kidney Safety Laboratory 
Abnormalities...................................................................................................87
10.8. Appendix 8: ECG Findings of Potential Clinical Concern ...................................88


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Protocol C4671023
Final Protocol Amendment 1, 18 August 2022
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10.10. Appendix 10: Abbreviations ...............................................................................99
11. REFERENCES ................................................................................................................103
LIST OF TABLES
Table 1.
Randomized Treatment Sequences...........................................................30
Table 2.
Plasma Nirmatrelvir and Ritonavir PK Parameters Definitions...............62
Table 3.
Protocol-Required Safety Laboratory Assessments .................................73
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Protocol C4671023
Final Protocol Amendment 1, 18 August 2022
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1. PROTOCOL SUMMARY 
1.1. Synopsis 
Protocol Title: A Phase 1, Open-Label, Randomized, Single Dose, Crossover Study to 
Estimate the Relative Bioavailability of Nirmatrelvir and Ritonavir Following Oral 
Administration of 4 Different Fixed Dose Combination Tablet Formulations Relative to The 
Commercial Tablet Formulation in Healthy Adult Participants Under Fasted Conditions
Brief Title: A Phase 1 Relative Bioavailability Study of Nirmatrelvir/Ritonavir 4 Different
Fixed Dose Combination Tablets Relative to the Commercial Tablets in Healthy Participants.
Regulatory Agency Identification Number(s):
US IND Number:
153517
EudraCT Number:
NA
ClinicalTrials.gov ID: 
NA
Pediatric Investigational Plan Number:
NA
Protocol Number:
C4671023
Phase:
1
Rationale:
Nirmatrelvir is a potent and selective inhibitor of the SARS-CoV-2 Mpro that is currently 
being developed as an oral treatment of COVID-19. Ritonavir is a strong CYP3A4 inhibitor 
being used to inhibit the metabolism of nirmatrelvir in order to increase plasma 
concentrations of nirmatrelvir to values that are efficacious. The clinical development 
program for nirmatrelvir includes 12 completed clinical studies: 8 Phase 1 studies in healthy 
participants (C4671001, C4671008, C4671012, C4671013, C4671014, C4671015, C4671019
and C4671024), 1 Phase 1 study in renal impairment participants (C4671011), 1 Phase 1
study in hepatic impairment participants (C4671010) and 2 Phase 2/3 pivotal studies in 
COVID-19 patients (C4671005 and C4671006).
The 4 different test formulations are designed to evaluate the effect of nirmatrelvir drug 
loading and disintegrant level on the performance of FDC tablets relative to the commercial 
product. The purpose of this study is to estimate the rBA of nirmatrelvir/ritonavir of 4
different FDC tablet formulations relative to the commercial tablet formulation under fasted 
conditions in healthy adult participants. 
 
 
 
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Final Protocol Amendment 1, 18 August 2022
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Objectives and Endpoints:
Objectives
Endpoints
Primary: 
Primary: 

To estimate the rBA of the nirmatrelvir/ritonavir 
300/100 mg (2 × 150/50 mg) FDC tablets Test 
formulation 1 (low disintegrant) compared to the 
nirmatrelvir/ritonavir 300 (2 × 150)/100 mg 
commercial tablets under fasted conditions 
(reference).    

To estimate the rBA of the nirmatrelvir/ritonavir 
300/100 mg (2 × 150/50 mg) FDC tablets Test
formulation 2 (high disintegrant) compared to the 
nirmatrelvir/ritonavir 300 (2 × 150)/100 mg 
commercial tablets under fasted conditions 
(reference).

To estimate the rBA of the nirmatrelvir/ritonavir 
300/100 mg (2 × 150/50 mg) FDC tablets Test 
formulation 3 (high drug load) compared to the 
nirmatrelvir/ritonavir 300 (2 × 150)/100 mg 
commercial tablets under fasted conditions 
(reference).

To estimate the rBA of the nirmatrelvir/ritonavir 
300/100 mg (3 × 100/33.3 mg ) FDC tablets Test
formulation 4 compared to the 
nirmatrelvir/ritonavir 300 (2 × 150)/100 mg
commercial tablets under fasted conditions 
(reference).

The test/reference ratios for AUCinf (if data 
permits), AUClast, and Cmax of nirmatrelvir and 
ritonavir.
Secondary: 
Secondary: 

To evaluate the safety and tolerability of 
nirmatrelvir/ritonavir in healthy participants.

Assessment of TEAEs, clinical laboratory 
abnormalities, vital signs, PEs, and 12-lead 
ECGs.
Overall Design:
This is a Phase 1, open-label, single-dose, randomized, crossover study in healthy adult 
participants to estimate rBA of nirmatrelvir/ritonavir 300/100 mg of 4 different FDC Test 
formulations compared to the nirmatrelvir/ritonavir 300/100 mg commercial tablets
(Reference formulation) under fasted conditions. The study will also assess the safety and
tolerability of nirmatrelvir/ritonavir FDC and commercial tablet formulations in healthy adult 
participants.
 
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Nirmatrelvir (PF-07321332)/ritonavir
Protocol C4671023
Final Protocol Amendment 1, 18 August 2022
PFIZER CONFIDENTIAL
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The study will consist of 5 treatments: 

Single oral dose of nirmatrelvir/ritonavir 300 (2 × 150)/100 mg commercial tablets 
(Treatment A)

Single oral dose of nirmatrelvir/ritonavir 300/100 mg (2 × 150/50 mg) FDC tablets
Test formulation 1 (Treatment B; nirmatrelvir/ritonavir 150/50 mg, low disintegrant), 

Single oral dose of nirmatrelvir/ritonavir 300/100 mg (2 × 150/50 mg) FDC tablets 
Test formulation 2 (Treatment C; nirmatrelvir/ritonavir 150/50 mg, high disintegrant)

Single oral dose of nirmatrelvir/ritonavir 300/100 mg (2 × 150/50 mg) FDC tablets 
Test formulation 3 (Treatment D; nirmatrelvir/ritonavir 150/50 mg, high drug load).

Single oral dose of nirmatrelvir/ritonavir 300/100 mg (3 × 100/33.3 mg) FDC tablets 
Test formulation 4 (Treatment E; nirmatrelvir/ritonavir 100/33.3 mg), 
All treatments will be administered under fasted condition. Between each treatment, a 
minimum of 4 days washout is proposed to minimize any residual nirmatrelvir and ritonavir
concentrations prior to start of the next treatment.
Approximately 15 healthy male and/or female participants will be enrolled and randomized
to the study. Participants who discontinue from the study for non-safety reasons may be 
replaced at the sponsor’s discretion in collaboration with the investigator.
Healthy participants will be screened to determine eligibility within 28 days prior to study 
treatment. Medical history and results of PEs, vital signs, 12-lead ECGs, and clinical 
laboratory evaluations will determine eligibility. Eligible participants will be admitted to the 
PCRU on Day -1 and will be confined in the PCRU until discharge on Day 4 of Period 4.
On Day 1 of each period, participants will receive a single oral dose of study intervention 
nirmatrelvir/ritonavir 300/100 mg as per the randomization schedule. Study treatments will 
be administered with approximately 240 mL of ambient temperature water under fasted
conditions (overnight fast and no food until 4 hours after dosing). Serial PK samples will be 
collected up to 72 hours post dose.
 
Participants will be discharged from the PCRU on Day 
4 of Period 4, following completion of all assessments.
If a participant has any clinically significant, study-related abnormalities at the conclusion of 
a scheduled inpatient portion of the study, the Pfizer medical monitor (or designated 
representative) should be notified and the participant may be asked to remain in the PCRU
until such abnormalities are deemed not clinically significant, or it is safe for outpatient 
follow-up.
A safety follow-up call will be made to participants approximately 28 to 35 days from 
administration of the final dose of study intervention.
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Number of Participants:
Approximately 15 healthy male and/or female participants will be enrolled and randomized 
to 1 of 5 possible treatment sequences to ensure at least 12 participants will complete the 
study. 
Note: "Enrolled" means a participant's, or their legally authorized representative’s, agreement 
to participate in a clinical study following completion of the informed consent process and 
randomization. A participant will be considered enrolled if the informed consent is not 
withdrawn prior to participating in any study activity. Potential participants who are screened 
for the purpose of determining eligibility for the study, but do not participate in the study, are 
not considered enrolled, unless otherwise specified by the protocol.
Study Population:
Key inclusion and exclusion criteria are listed below:
Inclusion Criteria
Participants must meet the following key inclusion criteria to be eligible for enrollment into 
the study:
1. Male and female participants who are overtly healthy as determined by medical 
evaluation including medical history, PE, laboratory tests, vital signs and standard 
12-lead ECGs.
Exclusion Criteria
Participants with any of the following characteristics/conditions will be excluded:
1. Positive test result for SARS-CoV-2 infection on Day -1.
2. Participants who have received a COVID-19 vaccine within 7 days before screening 
or admission, or who are to be vaccinated with a COVID-19 vaccine at any time 
during the study confinement period.
Study Arms and Duration
The study will consist of 5 treatments. Each enrolled participant will participate in 4 study 
periods to receive 4 different treatments according to the sequence determined by 
randomization: 

Treatment A: Single oral dose of nirmatrelvir/ritonavir 300 (2 × 150)/100 mg 
commercial tablets under fasted conditions (Reference) 

Treatment B: Single oral dose of nirmatrelvir/ritonavir 300/100 mg (2 × 150/50 mg)
FDC tablets Test formulation 1 (low disintegrant) under fasted conditions (Test 1) 


Nirmatrelvir (PF-07321332)/ritonavir
Protocol C4671023
Final Protocol Amendment 1, 18 August 2022
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
Treatment C: Single oral dose of nirmatrelvir/ritonavir 300/100 mg (2 × 150/50 mg)
FDC tablets Test formulation 2 (high disintegrant) under fasted conditions (Test 2)

Treatment D: Single oral dose of nirmatrelvir/ritonavir 300/100 mg (2 × 150/50 mg)
FDC tablets Test formulation 3 (high drug loading) under fasted conditions (Test 3)

Treatment E: Single oral dose of nirmatrelvir/ritonavir 300/100 mg (3 × 100/33.3 mg)
FDC tablets Test formulation 4 under fasted conditions (Test 4) 
Participants will be randomly assigned to 1 of 5 sequences as below:
Treatment Sequence
S
Period 1
Period 2
Period 3
Period 4
Sequence 1 (N =3)
Treatment A
Treatment B
Treatment C
Treatment D
Sequence 2 (N =3)
Treatment B
Treatment C
Treatment D
Treatment E
Sequence 3 (N =3)
Treatment C
Treatment D
Treatment E
Treatment A
Sequence 4 (N =3)
Treatment D
Treatment E
Treatment A
Treatment B
Sequence 5 (N =3)
Treatment E
Treatment A
Treatment B
Treatment C
Between each treatment, a minimum of 4 days washout is proposed to minimize any residual 
nirmatrelvir and ritonavir concentrations prior to start of the next treatment. Participants will 
be discharged on Day 4 of Period 4, following completion of all assessments. 
The total planned duration of participation from the Screening visit to the last follow-up 
phone call, is approximately 12 weeks.


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Study Intervention(s)
Intervention Name
Nirmatrelvir
Ritonavir
Nirmatrelvir/ 
ritonavir
Nirmatrelvir/ 
ritonavir
Nirmatrelvir/ 
ritonavir
Nirmatrelvir/ 
ritonavir
Arm Name
(group of 
participants receiving 
a specific treatment 
or no treatment)
nirmatrelvir/ 
ritonavir 
commercial 
tablets 
nirmatrelvir
/ ritonavir 
commercial 
tablets 
nirmatrelvir/ 
ritonavir 
FDC tablets 
Test 
formulation 
1
nirmatrelvir/ 
ritonavir 
FDC tablets 
Test 
formulation 
2
nirmatrelvir/ 
ritonavir 
FDC tablets 
Test 
formulation 3
nirmatrelvir/ 
ritonavir FDC 
tablets Test 
formulation 4
Unit Dose Strength(s)
150 mg
100 mg 
150/50 mg
150/50 mg
150/50 mg
100/33.3 mg 
Route of 
Administration
Oral
Oral
Oral
Oral
Oral
Oral
Use
Reference
Reference 
Test 1
Test 2
Test 3
Test 4
IMP or NIMP/AxMP
IMP
NIMP
IMP
IMP
IMP
IMP
Study Arm(s)
Arm Title
Nirmatrelvir/ 
ritonavir 
commercial tablets
Nirmatrelvir/ 
ritonavir FDC 
tablets Test 
formulation 1
Nirmatrelvir/ 
ritonavir FDC 
tablets Test 
formulation 2
Nirmatrelvir/ 
ritonavir FDC 
tablets Test 
formulation 3
Nirmatrelvir/ 
ritonavir FDC 
tablets Test 
formulation 4
Arm Type
Reference
Experimental
Experimental 
Experimental
Experimental 
Arm 
Description
Single oral dose of 
nirmatrelvir/ 
ritonavir 300 
(2 × 150)/100 mg 
commercial tablets 
under fasted 
conditions 
(Reference)
Single oral dose 
of nirmatrelvir 
/ritonavir 
300/100 mg 
(2 x 150/50 mg) 
FDC tablets Test 
formulation 1 
(low disintegrant)
under fasted 
conditions (Test 
1)
Single oral dose 
of nirmatrelvir/ 
ritonavir 
300/100 mg 
(2 x 150/50 mg) 
FDC tablets Test 
formulation 2 
(high
disintegrant) 
under fasted 
conditions (Test 
2)
Single oral dose 
of nirmatrelvir/ 
ritonavir 
300/100 mg 
(2 x 150/50 mg) 
FDC tablets Test 
formulation 3 
(high drug 
loading) under 
fasted conditions 
(Test 3)
Single oral dose 
of nirmatrelvir/ 
ritonavir 
300/100 mg 
(3 x 100/33.3 mg) 
FDC tablets Test 
formulation 4
under fasted 
conditions (Test 
4)
Statistical Methods:
Natural log transformed AUCinf (if data permits), AUClast and Cmax for nirmatrelvir and 
ritonavir will be analyzed using a mixed effect model with sequence, period and treatment as 
fixed effects and participant within a sequence as a random effect.


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Sample Size Determination
Total of 15 participants will be enrolled, so that each treatment sequence will have 3
participants. A sample size of 15 participants will be sufficient to provide a reliable estimate 
of rBA and intrasubject variability of nirmatrelvir and ritonavir. Participants who withdraw
from the study or discontinue treatment, or whose PK samples are considered to be 
nonevaluable with respect to the primary PK objective may be replaced at the discretion of 
the investigator upon consultation with the sponsor.
Pharmacokinetics Analysis
The PK concentration analysis set is defined as all participants who take at least 1 dose of 
study intervention and in whom at least 1 plasma concentration value is reported.
The PK parameter analysis set is defined as all participants who take at least 1 dose of study 
intervention and in whom at least 1 of the plasma PK parameters of primary interest are 
reported.
Plasma PK parameters of nirmatrelvir and ritonavir will be derived (as data permits) from the 
concentration-time data using standard noncompartmental methods. Actual PK sampling 
times will be used in the derivation of nirmatrelvir and ritonavir PK parameters when 
available, otherwise nominal times will be used. The nirmatrelvir and ritonavir plasma PK 
parameters will be summarized descriptively by treatment and Day. Plasma concentrations 
will be listed and summarized descriptively by treatment, and nominal PK sampling time.
Individual participant and summary profiles (mean and median plots) of the plasma 
concentration time data will be plotted using actual and nominal times, respectively. 
To estimate relative bioavailability, natural log transformed AUCinf (if data permits), AUClast
and Cmax values of nirmatrelvir and ritonavir will be analyzed using a mixed effect model 
with sequence, period and treatment as fixed effect and participant within sequence as a 
random effect. Estimates of the adjusted mean differences (Test-Reference) and 
corresponding 90% CIs will be obtained from the model. The adjusted mean differences and 
90% CIs for the differences will be exponentiated to provide estimates of the ratio of 
adjusted geometric means (Test/Reference) and 90% CI for the ratios.
Safety Analysis
AEs, ECGs, 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, 
ECG, 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.


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Ethical Considerations:
Nirmatrelvir is not expected to provide any clinical benefit to healthy participants in this 
study. This study is designed primarily to further the understanding of human PK, 
metabolism, and elimination of nirmatrelvir.

Participants will be expected to commit time and may experience some discomfort 
while undergoing study assessments.

Participants must agree to use appropriate contraception methods.
1.2. Schema
Not Applicable.


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1.3. Schedule of Activities
The SoA table provides an overview of the protocol visits and procedures. Refer to the STUDY ASSESSMENTS AND 
PROCEDURES section of the protocol for detailed information on each procedure and assessment required for compliance with the 
protocol. 
The investigator may schedule visits (unplanned visits) in addition to those listed in the SoA table, in order to conduct evaluations or 
assessments required to protect the well-being of the participant. 
SoA:
Visit Identifier
Abbreviations used in this table may be 
found in Appendix 10
Screeninga
Period 1
Period 2 & 3
Period 4
Follow-Up
Early 
Termination/
Discontinuation
Days Relative to Day 1
Days
-28 to -2
Day -1
1
2
3
4
1
2
3
4
1
2
3
4
28-35 
Daysb
Informed consent
X
CRU Confinementc
X











X
Inclusion/exclusion criteria
X
X
Medical/medication history (update)d
X
X
Demographye
X
PEf
X
X
Safety laboratoryg
X
X
X
X
FSHh
X
Urine drug testingi
X
X
Serology: HBsAg, HBsAb, HBcAb, 
HCVAb, and HIVj
X
Pregnancy test (WOCBP only)
X
X
X
X
Contraception checkk
X
X
X
12-lead ECG (single)l
X
Xm
X
X
Vital signs (BP/PR)n
X
X
X
X
X
X
COVID-19 questionnaireo
X
X
COVID-19 testingp
X
X
Nirmatrelvir/ritonavir dosingq
X
X
X


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Visit Identifier
Abbreviations used in this table may be 
found in Appendix 10
Screeninga
Period 1
Period 2 & 3
Period 4
Follow-Up
Early 
Termination/
Discontinuation
Days Relative to Day 1
Days
-28 to -2
Day -1
1
2
3
4
1
2
3
4
1
2
3
4
28-35 
Daysb
PK Blood Sampling for nirmatrelvir and
ritonavirs
X
X
X
X
X
X
X
X
X
X
X
X
X
Blood/Plasma ratio sample for 
nirmatrelvir and ritonavir
X
X
X
 
Retained Research Sample for Genetics 
(Prep D1)v
X
 
Serious and nonserious AE monitoring
X













X
X
Concomitant treatments
X
X
X










X
X
CRU discharge
X
a.
Screening will be performed within 28 days prior to the first dose of nirmatrelvir/ritonavir. 
b.
Follow-up contact may occur via telephone contact and must occur 28 to 35 days from administration of the final dose of study intervention.
c.
Participants will be admitted to the CRU on Day -1. Participants will be discharged on Period 4 Day 4 following the final assessments.
d.
Medical history will include a history of prior illegal drug, alcohol, and tobacco use, as well as blood donation within prior 60 days. Medical history will be recorded at 
Screening and updated on Period 1 Day -1. 
e.
Demographics will include participant race, ethnicity, age, and gender during the Screening visit. 
f.
PE will be performed by trained medical personnel at the investigator site at Screening or Period 1 Day -1 only (height and weight must be obtained at Screening to obtain 
BMI for eligibility criteria). A brief PE may be performed at other designated time points at the discretion of the investigator. 
g.
Safety laboratory assessments including urinalysis, hematology, chemistry and coagulation will be performed at Screening, Period 1 Day -1, Period 4 Day 4, and early 
termination/discontinuation if applicable. All the safety laboratory samples must be collected following at least a 4-hour fast. Additional safety laboratory assessments may 
be performed at any time at the discretion of the investigator.
h.
For confirmation of postmenopausal (amenorrheic for at least 12 consecutive months) female participants.
i.
Urine drug (mandatory) and alcohol breath test (at discretion of investigator) will be performed at Screening and on Period 1 Day -1. These tests may be performed at any 
other time at the discretion of the investigator.
j.
HBsAb will be tested if HBsAg and/or HBcAb are positive.
k.
The investigator or his/her designee will discuss with the participant the need to use highly effective contraception consistently and correctly according to contraception 
guidelines.
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Visit Identifier
Abbreviations used in this table may be 
found in Appendix 10
Screeninga
Period 1
Period 2 & 3
Period 4
Follow-Up
Early 
Termination/
Discontinuation
Days Relative to Day 1
Days
-28 to -2
Day -1
1
2
3
4
1
2
3
4
1
2
3
4
28-35 
Daysb
l.
Single 12-lead ECG readings approximately will be taken at specified time point. All ECG assessments will be made after at least a 5-minute rest in a supine position and 
prior to any blood draws or vital sign measurements.
m.
This will be done predose of Period 1 Day 1.
n.
Single supine BP and PR will be performed following at least a 5-minute rest in a supine position, at specified time point. BP, and PR assessments will be performed after 
collection of ECGs and prior to collection of blood draws if scheduled at the same time. Vital signs will be done at Screening, predose of Period 1 Day 1, and 2 hours and 6 
hours post dose on Day 1 of each treatment period and also on Day 4 of Period 4. 
o.
COVID-19 related signs and symptoms as per local procedures. 
p.
The testing for COVID-19 pathogen by RT-PCR will be performed as per local procedures.
q.
Nirmatrelvir/ritonavir will be administered orally after overnight fasting on Day 1 of each treatment period. There will be at least a 4 day washout between each dose.
r.
 
 
s.
One (approximately 4 mL) blood sample for PK analysis of nirmatrelvir and ritonavir will be taken at the designated time points. See PK sampling schema in table below.
t.
 
 
v.
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. These samples will be collected in Period 1 only.
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Pharmacokinetic Sampling Schema
Visit Identifier
Treatment Period 1 to 4
Study Day
Day 1
Day 2
Day 3
Day 4
Planned Hours Post Dose 
0
0.5
1
1.5
2
2.5
3
4
6
8
12
16
24
48
72
PK blood sampling for nirmatrelvir and 
ritonavir
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
 
Blood/Plasma ratio sampleb
X
X
 
a.
b.
Blood sample for blood/plasma ration analysis of nirmatrelvir and ritonavir will be collected for Treatment A and B only.
c.
 
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2. INTRODUCTION
Nirmatrelvir is a potent and selective inhibitor of the SARS-CoV-2 Mpro that is currently 
being developed as an oral treatment of COVID-19. Ritonavir is a strong CYP3A4 inhibitor 
being used to inhibit the metabolism of nirmatrelvir in order to increase plasma 
concentrations of nirmatrelvir to values that are efficacious. 
2.1. Study Rationale 
The purpose of this study is to estimate the rBA of nirmatrelvir/ritonavir of 4 different FDC
tablet formulations relative to the commercial tablet formulation under fasted conditions in 
healthy adult participants. The study will also assess the safety and tolerability, of 
nirmatrelvir/ritonavir of FDC and commercial tablet formulations in healthy adult 
participants.
 
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 2020.1
Nirmatrelvir is an orally bioavailable 3CLpro inhibitor shown to be effective against 
SARS-CoV-2 3CLpro (Ki = 0.00311 µM) in a biochemical enzymatic assay. Nirmatrelvir is 
being developed as an oral treatment in patients with COVID-19 infection.
Ritonavir is a strong CYP3A4 inhibitor being used to inhibit the metabolism of nirmatrelvir
in order to increase plasma concentrations of nirmatrelvir to values that are efficacious. 
Ritonavir is not expected to have any pharmacological impact on the SARS-CoV-2 virus and 
its elimination. Ritonavir is being used only as a PK boosting agent.
The clinical development program for nirmatrelvir includes 12 completed clinical studies: 8
Phase 1 studies in healthy participants (C4671001, C4671008, C4671019, C4671024, 
C4671012, C4671013, C4671014 and C4671015), 1 Phase 1 study in renal impairment 
participants (C4671011), 1 Phase 1 study in hepatic impairment participants (C4671010) and 
2 Phase 2/3 pivotal studies in COVID-19 patients (C4671005 and C4671006).
2.2.1. Nonclinical Pharmacology
Details of the nonclinical pharmacology of nirmatrelvir can be found in the current IB2.
2.2.2. Nonclinical Pharmacokinetics and Metabolism
Hepatic CYP3A enzymes were identified as the main pathway for clearance of nirmatrelvir
in vitro in liver microsomes (mouse, rat, hamster, rabbit, monkey, and human), hepatocytes 
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(rat, monkey, and human), and in vivo in rat and monkey after repeat oral dosing.
 
 
Additional information of the nonclinical PK and metabolism of nirmatrelvir is available in 
the current IB2.
2.2.3. Nonclinical Safety
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Further details of the nonclinical safety program are provided in the current IB2.
2.2.4. Clinical Overview
Safety, tolerability and PK of nirmatrelvir studies in healthy adult participants (C4671001, 
C4671008, C4671019, C4671024, C4671012, C4671013, C4671014 and C4671015), as well 
as in renal impairment participants (C4671011) and hepatic impairment participants 
(C4671010). The relative bioavailability and food effect were evaluated in 2 phase 1 studies
(C4671001 and C4671019) in healthy participants. Efficacy and safety of nirmatrelvir were
evaluated in interventional Phase 2/3 pivotal studies in COVID-19 patients (C4671005 and
C4671006). 
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Included in this Clinical Overview are summaries of the results of Study C4671001,
C4671019 and C4671005.
 
 
 
 
 
 
 
 
2.2.4.1. Safety Overview
In the completed Phase 1 studies in healthy participants and Phase 2/3 study in participants 
with a laboratory-confirmed diagnosis of SARS-CoV-2 infection, nirmatrelvir/ritonavir was 
generally safe and well-tolerated.
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Further details on the clinical safety information with nirmatrelvir are provided in the current 
IB2.
2.2.4.2. Summary of Nirmatrelvir Pharmacokinetics in Human
Study C4671001- FIH
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Further details on the clinical PK of nirmatrelvir are provided in the current IB2.
Study C4671019-Food Effects
 
 
 
 
 
 
 
 
 
 
2.3. Benefit/Risk Assessment
Nirmatrelvir is not expected to provide any clinical benefit to healthy participants in this 
study. This study is designed primarily to further the understanding of human PK, 
metabolism, and elimination of nirmatrelvir.
Based on data from Study C4671001, C4671019 and C4671005, the clinical safety profile of 
nirmatrelvir appears to be acceptable at single doses up to 1500 mg alone and up to 2250 mg 
administered with ritonavir (100 mg at -12h, 0h, 12h), split dosing administration (3 doses of 
750 mg) at short intervals (approximately 2 hours from the previous dose), and at repeated 
daily doses administered orally for 10 days of up to 500 mg nirmatrelvir q12h with 100 mg 
ritonavir q12h. 
More detailed information about the known and expected benefits and risks and reasonably 
expected AEs of nirmatrelvir and ritonavir may be found in the IB2, 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: 
Nirmatrelvir
Dysgeusia
In Study C4671005, dysgeusia 
was recorded as an AE by 6% of 
participants receiving 
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 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 used in this 
study. There is a single dose PK 
study. There will be close 
observation of AEs. 
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 of 100 mg used in this 
study. There will be close 
observation of AEs. 
Rash (most commonly reported 
as erythematous and 
maculopapular, followed by 
pruritic)
Frequently reported adverse 
reaction in patients who are HIV-
positive at 600 mg BID.
Lower dose of 100 mg used in this 
study. There will be close 
observation of AEs and monitoring 
through physical exams. If needed 
therapeutic interventions per SOC 
may be provided.
Fatigue/Asthenia
Frequently reported adverse 
reaction in patients who are HIV-
positive at 600 mg BID.
Lower dose of 100 mg 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 physical 
examinations. 


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Potential Risk of Clinical 
Significance
Summary of Data/Rationale for 
Risk
Mitigation Strategy
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 to
an upper extremity.
There is risk of bleeding, bruising, 
hematoma formation, and 
infection in the upper extremity 
with Tasso device placement.
Only appropriately qualified 
personnel will obtain blood 
utilizing the Tasso device.
3. OBJECTIVES AND ENDPOINTS
Objectives
Endpoints
Primary: 
Primary: 

To estimate the rBA of the nirmatrelvir/ritonavir 
300/100 mg (2 × 150/50 mg) FDC tablets Test
formulation 1 (low disintegrant) compared to the 
nirmatrelvir/ritonavir 300 (2 × 150)/100 mg 
commercial tablets under fasted conditions 
(reference).    

To estimate the rBA of the nirmatrelvir/ritonavir 
300/100 mg (2 × 150/50 mg) FDC tablets Test
formulation 2 (high disintegrant) compared to the 
nirmatrelvir/ritonavir 300 (2 × 150)/100 mg 
commercial tablets under fasted conditions 
(reference).

To estimate the rBA of the nirmatrelvir/ritonavir 
300/100 mg (2 × 150/50 mg) FDC tablets Test 
formulation 3 (high drug load) compared to the 
nirmatrelvir/ritonavir 300 (2 × 150)/100 mg 
commercial tablets under fasted conditions 
(reference).

To estimate the rBA of the nirmatrelvir/ritonavir 
300/100 mg (3 × 100/33.3 mg ) FDC tablets Test
formulation 4 compared to the nirmatrelvir/ritonavir 
300 (2 × 150)/100 mg commercial tablets under 
fasted conditions (reference).

The test/reference ratios for AUCinf (if data 
permits), AUClast, and Cmax of nirmatrelvir 
and ritonavir.
Secondary: 
Secondary: 

To evaluate the safety and tolerability of 
nirmatrelvir/ritonavir in healthy participants.

Assessment of TEAEs, clinical laboratory 
abnormalities, vital signs, PEs, and 12-lead 
ECGs.


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Objectives
Endpoints
 
 
 
 
 
 
 
 
 
 
 
 
 
4. STUDY DESIGN
4.1. Overall Design
This is a Phase 1, open-label, single-dose, randomized, crossover study in healthy adult 
participants to estimate rBA of 4 different nirmatrelvir/ritonavir 300/100 mg FDC tablets 
formulations (Test formulations) compared to the nirmatrelvir/ritonavir 300/100 mg 
commercial tablet formulation (Reference formulation) under fasted conditions. The study 
will also assess the safety and tolerability, of nirmatrelvir/ritonavir FDC and commercial
tablet formulations in healthy adult participants.
 
Approximately 15 healthy male and/or female participants will be enrolled and randomized 
to 1 of 5 possible treatment sequences to ensure at least 12 participants will complete the 
study. Participants who discontinue from the study for non-safety reasons may be replaced at 
the sponsor’s discretion in collaboration with the investigator. The replacement participant 
will receive the same treatment sequences as the participant who discontinued. 
The study will consist of 5 treatments. Each enrolled participant will participate in 4 study 
periods to receive 4 different treatments according to the sequence determined by 
randomization: 

Treatment A: Single oral dose of nirmatrelvir/ritonavir 300 (2 × 150 )/100 mg 
commercial tablets under fasted conditions (Reference) 
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
Treatment B: Single oral dose of nirmatrelvir/ritonavir 300/100 mg (2 × 150/50 mg)
FDC tablets Test formulation 1 (low disintegrant) under fasted conditions (Test 1)

Treatment C: Single oral dose of nirmatrelvir/ritonavir 300/100 mg  (2 × 150/50 mg)
FDC tablets Test formulation 2 (high disintegrant) under fasted conditions (Test 2)

Treatment D: Single oral dose of nirmatrelvir/ritonavir 300/100 mg (2 × 150/50 mg)
FDC tablets Test formulation 3 (high drug loading) under fasted conditions (Test 3)

Treatment E: Single oral dose of nirmatrelvir/ritonavir 300/100 mg (3 × 100/33.3 mg)
FDC tablets Test formulation 4 under fasted conditions (Test 4)
Participants will be randomly assigned to 1 of 5 sequences as shown below in Table 1.
Participants will be discharged on Day 4 of Period 4, following completion of all
assessments. Between each treatment, a minimum of 4 days washout is proposed to minimize 
any residual nirmatrelvir and ritonavir concentrations prior to start of the next treatment. The 
total planned duration of participation from the Screening visit to the last follow-up phone 
call, is approximately 12 weeks.
Table 1.
Randomized Treatment Sequences
Treatment Sequence
Period 1
Period 2
Period 3
Period 4
Sequence 1 (N =3)
Treatment A
Treatment B
Treatment C
Treatment D
Sequence 2 (N =3)
Treatment B
Treatment C
Treatment D
Treatment E
Sequence 3 (N =3)
Treatment C
Treatment D
Treatment E
Treatment A
Sequence 4 (N =3)
Treatment D
Treatment E
Treatment A
Treatment B
Sequence 5 (N =3)
Treatment E
Treatment A
Treatment B
Treatment C
Healthy participants will be screened to determine eligibility within 28 days prior to study 
treatment. Medical history and results of PEs, vital signs, 12-lead ECGs, and clinical 
laboratory evaluations will determine eligibility. Eligible participants will be admitted to the 
PCRU on Day -1 and will be confined in the PCRU until discharge on Day 4 of Period 4.
On Day 1 of each period, participants will receive a single oral dose of study intervention 
nirmatrelvir/ritonavir 300/100 mg as per the randomization schedule. Study treatments will 
be administered with approximately 240 mL of ambient temperature water under fasted
conditions (overnight fast of at least 10 hours and no food until 4 hours after dosing). Serial 
PK samples will be collected up to 72 hours post dose.
 
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. Participants will be discharged from the 
PCRU on Day 4 of Period 4, following completion of all assessments.
If a participant has any clinically significant, study related abnormalities at the conclusion of 
a scheduled inpatient portion of the study, the Pfizer medical monitor (or designated 
representative) should be notified and the participant may be asked to remain in the PCRU
until such abnormalities are deemed not clinically significant, or it is safe for outpatient 
follow-up. A safety follow-up call will be made to participants approximately 28 to 35 days 
from administration of the final dose of study intervention.
4.2. Scientific Rationale for Study Design
Nirmatrelvir/ritonavir FDC tablet is an alternative formulation for current commercial tablets 
to increase the adherence. The 4 different test formulations are designed to evaluate the effect 
of nirmatrelvir drug loading and disintegrant level on the performance of FDC tablets relative 
to the commercial product. The objective of the study is to estimate the rBA of 
nirmatrelvir/ritonavir of 4 different FDC tablets formulations (Test formulations) compared 
to the nirmatrelvir/ritonavir commercial tablets (Reference formulation) under fasted
conditions. The study will also assess the safety and tolerability of nirmatrelvir/ritonavir oral 
FDC and commercial tablet formulations in healthy adult participants.
The study is being designed as a crossover study to account for any period effect. Between 
each treatment, a minimum of 4 days washout is proposed to minimize any residual 
nirmatrelvir and ritonavir concentrations prior to start of the next treatment, as nirmatrelvir
has a half-life of approximately 6 to 13 hours when co-administered with ritonavir.
4.2.1. Choice of Contraception/Barrier Requirements 
Human reproductive safety data are limited for nirmatrelvir, 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 (see Appendix 4).
4.2.2. Collection of Retained Research Samples
Retained Research Samples will be collected and stored for further analyses which may, for 
example, provide greater understanding of the study intervention.
4.3. Justification for Dose
The dose of nirmatrelvir/ritonavir 300/100 mg BID for 5 days is the approved therapeutic 
dose and treatment duration under emergency use authorization. This dose is lower than the 
highest dose evaluated in the Phase 1 C4671001 study and is safe and well-tolerated.
This study is designed to evaluate rBA of nirmatrelvir/ritonavir of 4 different FDC tablets 
formulations compared to nirmatrelvir/ritonavir commercial tablets in healthy adult 
participants at the approved therapeutic dose. Therefore, a single oral dose 
nirmatrelvir/ritonavir 300/100 mg will be used in this relative bioavailability study. 
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4.4. End of Study Definition
The end of the study is defined as the date of the last scheduled procedure shown in the SoA
for the last participant in the trial.
A participant is considered to have completed the study if they have completed all parts of 
the study, including the last scheduled procedure shown in the SoA.
5. STUDY POPULATION
This study can fulfill its objectives only if appropriate participants are enrolled, including 
participants across diverse and representative racial and ethnic backgrounds. Use of a 
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, and race, and ethnicity. The following eligibility 
criteria are designed to select participants for whom participation in the study is considered 
appropriate. All relevant medical and nonmedical conditions should be taken into 
consideration when deciding whether a particular participant is suitable for this protocol.
Prospective approval of protocol deviations to recruitment and enrollment criteria, also 
known as protocol waivers or exemptions, is not permitted.
5.1. Inclusion Criteria
Participants are eligible to be included in the study only if all of the following criteria apply:
Age and Sex:
1. Male and/or female participants must be ≥18 years of age, inclusive, at the time of 
signing the ICD.

Refer to Appendix 4 for reproductive criteria for male (Section 10.4.1) and female
(Section 10.4.2) participants.
Type of Participant and Disease Characteristics:
2. Male and female participants who are overtly healthy as determined by medical 
evaluation including medical history, PE, laboratory tests, vital signs and standard 
12-lead ECGs.
3. Participants who are willing and able to comply with all scheduled visits, treatment 
plan, laboratory tests, lifestyle considerations, and other study procedures.
4. Female participants of childbearing potential must have a negative pregnancy test at 
screening.


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Weight: 
5. BMI of 17.5 to 30.5 kg/m2; and a total body weight >50 kg (110 lb).
Informed Consent: .
6. Capable of giving signed informed consent as described in Appendix 1, which 
includes compliance with the requirements and restrictions listed in the ICD and in 
this protocol.
5.2. Exclusion Criteria
Participants are excluded from the study if any of the following criteria apply:
Medical Conditions:
1. Positive test result for SARS-CoV-2 infection on Day -1.
2. Evidence or history of clinically significant hematological, renal, endocrine, 
pulmonary, gastrointestinal, cardiovascular, hepatic, psychiatric, neurological, or 
allergic disease (including drug allergies, but excluding untreated, asymptomatic, 
seasonal allergies at the time of dosing).
3. Clinically relevant abnormalities requiring treatment (eg, acute myocardial infarction, 
unstable ischemic conditions, evidence of ventricular dysfunction, serious tachy- or 
brady-arrhythmias) or indicating serious underlying heart disease (eg, prolonged PR 
interval, cardiomyopathy, heart failure greater than NYHA 1, underlying structural 
heart disease, Wolff Parkinson-White syndrome). 
4. Any condition possibly affecting drug absorption (eg, gastrectomy, cholecystectomy). 
5. History of HIV infection, hepatitis B, or hepatitis C; positive testing for HIV, HBsAg, 
HBcAb or HCVAb. Hepatitis B vaccination is allowed.
6. Other medical or psychiatric condition including recent (within the past year) or 
active suicidal ideation/behavior or laboratory abnormality or other conditions or 
situations related to COVID-19 pandemic (eg, contact with positive case) that may 
increase the risk of study participation or, in the investigator’s judgment, make the 
participant inappropriate for the study.


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Prior/Concomitant Therapy:
7. Use of prescription or nonprescription drugs and dietary and herbal supplements 
within 7 days or 5 half-lives (whichever is longer) prior to the first dose of study 
intervention. Refer to Section 6.9 Prior and Concomitant Therapy for additional 
details.

Concomitant use of any medications or substances that are strong inducers of
CYP3A4 are prohibited within 28 days prior to first dose of nirmatrelvir/ritonavir
and during study treatment.

Concomitant use of any medications or substances that are inhibitors of CYP3A4 
are prohibited during study treatment and 4 days after the last dose of study 
intervention.
8. Current use of any prohibited concomitant medication(s) or participant
unwilling/unable to use a permitted concomitant medication(s). Refer to Section 6.9
Prior and Concomitant Therapy.
9. Participants who have received a COVID-19 vaccine within 7 days before screening 
or admission, or who are to be vaccinated with a COVID-19 vaccine at any time 
during the study confinement period.
Prior/Concurrent Clinical Study Experience:
10. Previous administration with an investigational product (drug or vaccine) within 
30 days (or as determined by the local requirement) or 5 half-lives preceding the first 
dose of study intervention used in this study (whichever is longer). Participants who 
have participated in previous clinical trials with nirmatrelvir may be eligible to 
participate in this study as long as they meet all other criteria. 
Diagnostic Assessments:
11. A positive urine drug test.
12. Screening supine BP ≥140 mm Hg (systolic) or ≥90 mm Hg (diastolic), following at 
least 5 minutes of supine rest. If BP is ≥140 mm Hg (systolic) or ≥90 mm Hg
(diastolic), the BP should be repeated 2 more times and the average of the 3 BP 
values should be used to determine the participant’s eligibility.
13. Standard 12-lead ECG (single) that demonstrates clinically relevant abnormalities that
may affect participant safety or interpretation of study results (eg, baseline QTcF 
interval >450 msec, complete LBBB, signs of an acute, old or age indeterminate 
myocardial infarction, ST-T interval changes suggestive of myocardial ischemia, 
second- or third-degree AV block, or serious bradyarrhythmias or tachyarrhythmias). 
If the baseline uncorrected QT interval is >450 msec, this interval should be 


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rate-corrected using the Fridericia method and the resulting QTcF should be used for 
decision making and reporting. If QTcF exceeds 450 msec, or QRS exceeds 
120 msec, the ECG should be repeated 2 more times and the average of the 3 QTcF or 
QRS values should be used to determine the participant’s eligibility.
Computer-interpreted ECGs should be overread by a physician experienced in 
reading ECGs before excluding a participant.
14. Participants with ANY of the following abnormalities in clinical laboratory tests at 
Screening, as assessed by the study-specific laboratory and confirmed by a single 
repeat test, if deemed necessary: 

AST or ALT level >1.5 × ULN;

Total bilirubin level ≥1.5 × ULN; participants with a history of Gilbert's 
syndrome may have direct bilirubin measured and would be eligible for this study 
provided the direct bilirubin level is ≤ULN.

eGFR <60 mL/min/1.73 m2 based on the CKD-EPI equation.
Other Exclusion Criteria:
15. History of alcohol abuse or binge drinking and/or any other illicit drug use or 
dependence within 6 months of Screening. Binge drinking is defined as a pattern of 
5 (male) and 4 (female) or more alcoholic drinks in about 2 hours. As a general rule, 
alcohol intake should not exceed 14 units per week (1 unit = 8 ounces (240 mL) beer, 
1 ounce (30 mL) of 40% spirit, 3 ounces (90 mL) of wine).
16. Use of tobacco or nicotine-containing products in excess of the equivalents of 
5 cigarettes per day or 2 chews of tobacco per day.
17. Blood donation (excluding plasma donations) of approximately 1 pint (500 mL) or 
more within 60 days prior to dosing. 
18. History of sensitivity to heparin, heparin-induced thrombocytopenia. 
19. Unwilling or unable to comply with the criteria in the Lifestyle Considerations
section of this protocol.
20. 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. 
21. History of sensitivity reactions to nirmatrelvir, ritonavir, or any of the formulation 
components of nirmatrelvir, or ritonavir.


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22. Pregnant or breastfeeding women.
5.3. Lifestyle Considerations
5.3.1. Contraception
The investigator or their designee, in consultation with the participant, will confirm that the 
participant is utilizing an appropriate method of contraception for the individual participant 
and their partner(s) from the permitted list of contraception methods (see 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 SoA, the investigator or designee will inform the 
participant of the need to use highly effective contraception consistently and correctly and 
document the conversation and the participant’s affirmation in the participant’s chart. 
Participants need to affirm their consistent and correct use of at least 1 of the selected 
methods of contraception, considering that their risk for pregnancy may have changed since 
the last visit. 
In addition, the investigator or designee will instruct the participant to call immediately if the 
selected contraception method is discontinued and document the requirement to use an 
alternate protocol-specified method, including if the participant will no longer use abstinence 
as the selected contraception method, or if pregnancy is known or suspected in the participant 
or partner.
5.3.2. Meals and Dietary Restrictions

Participants must abstain from all food and drink (except water) at least 4 hours prior 
to any safety laboratory evaluations and 10 hours prior to the collection of the predose 
PK sample on Day 1 of each Period.

Water is permitted until 1 hour prior to study intervention administration. Water may 
be consumed without restriction beginning 1 hour after nirmatrelvir/ritonavir dosing.
Noncaffeinated drinks (except red wine, grapefruit or grapefruit-related citrus fruit 
juices—see below) may be consumed with meals and the evening snack.

Lunch will be provided approximately 4 hours after nirmatrelvir/ritonavir dosing.

Dinner will be provided approximately 9 to 10 hours after nirmatrelvir/ritonavir 
dosing.

An evening snack may be permitted.

Participants will refrain from consuming red wine, grapefruit, or grapefruit-related 
citrus fruits (eg, Seville oranges, pomelos, fruit juices) from 7 days prior to the first 
dose of study intervention until collection of the final PK blood sample.


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
While participants are confined, their total daily nutritional composition should be 
approximately 55% carbohydrate, 30% fat, and 15% protein. The daily caloric intake 
per participant should not exceed approximately 3200 kcal.
5.3.3. Caffeine, Alcohol, and Tobacco

Participants will abstain from caffeine-containing products for 24 hours prior to the 
start of dosing until collection of the final PK sample.

Participants will abstain from alcohol for 24 hours prior to admission (or as specified 
above for red wine) to the CRU and continue abstaining from alcohol until collection 
of the final PK sample. Participants may undergo an alcohol breath test or blood 
alcohol test at the discretion of the investigator.

Participants will abstain from the use of tobacco or nicotine-containing products for 
24 hours prior to dosing and during confinement in the CRU.
5.3.4. Activity

Participants will abstain from strenuous exercise (eg, heavy lifting, weight training, 
calisthenics, aerobics) for at least 48 hours prior to each blood collection for clinical 
laboratory tests. Walking at a normal pace will be permitted;

In order to standardize the conditions on PK sampling days, participants will be 
required to refrain from lying down (except when required for BP, PR, and ECG 
measurements), eating, and drinking beverages other than water during the first 
4 hours after nirmatrelvir/ritonavir dosing;

Participants may be confined to the procedure room for the first 4 hours after dosing 
on Day 1, except to use the bathroom. After this, participants may be ambulatory but 
should not engage in strenuous activities.
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. Screen failure data are collected and remain as 
source and are not reported on the CRF.
Individuals who do not meet the criteria for participation in this study (screen failure) may be 
rescreened.
6. STUDY INTERVENTION(S) AND CONCOMITANT THERAPY
Study interventions are all prespecified investigational and noninvestigational medicinal 
products/auxiliary medicinal products, medical devices, and other interventions (eg, surgical 
and behavioral) intended to be administered to the study participants during the study 
conduct.


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For the purposes of this protocol, study intervention refers to nirmatrelvir and ritonavir.
6.1. Study Intervention(s) Administered
For this study, the study interventions are the nirmatrelvir/ritonavir FDC tablets Test 
formulation 1 (Test 1), nirmatrelvir/ritonavir FDC tablets Test formulation 2 (Test 2), 
nirmatrelvir/ritonavir FDC tablets Test formulation 3 (Test 3), nirmatrelvir/ritonavir FDC 
tablets Test formulation 4 (Test 4) and a commercial tablet formulation of nirmatrelvir 
(Reference formulation), and will be supplied by Pfizer. 
Commercially available 100 mg ritonavir tablets will be supplied by the PCRU.
Study Intervention(s)
Intervention Name
Nirmatrelvir
Ritonavir
Nirmatrelvir/ 
ritonavir
Nirmatrelvir/ 
ritonavir
Nirmatrelvir/ 
ritonavir
Nirmatrelvir/ 
ritonavir
Arm Name
(group of 
participants 
receiving a specific 
treatment or no 
treatment)
nirmatrelvir/ 
ritonavir 
commercial 
tablets 
nirmatrelvir/ 
ritonavir 
commercial 
tablets 
nirmatrelvir/ 
ritonavir 
FDC tablets 
Test 
formulation 
1
nirmatrelvir/ 
ritonavir 
FDC tablets 
Test 
formulation 
2
nirmatrelvir/ 
ritonavir 
FDC tablets 
Test 
formulation 3
nirmatrelvir/ 
ritonavir FDC 
tablets Test 
formulation 4
Unit Dose Strength(s)
150 mg
100 mg 
150/50 mg
150/50 mg
150/50 mg
100/33.3 mg 
Route of 
Administration
Oral
Oral
Oral
Oral
Oral
Oral
Use
Reference
Reference 
Test 1
Test 2
Test 3
Test 4
IMP or NIMP/AxMP
IMP
NIMP
IMP
IMP
IMP
IMP
Study Arm(s)
Arm Title
Nirmatrelvir/ 
ritonavir 
commercial tablets
Nirmatrelvir/ 
ritonavir FDC 
tablets Test 
formulation 1
Nirmatrelvir/ 
ritonavir FDC 
tablets Test 
formulation 2
Nirmatrelvir/ 
ritonavir FDC 
tablets Test 
formulation 3
Nirmatrelvir/ 
ritonavir FDC 
tablets Test 
formulation 4
Arm Type
Reference
Experimental
Experimental 
Experimental
Experimental 
Arm 
Description
Single oral dose of 
nirmatrelvir/ 
ritonavir 300 
(2 × 150)/100 mg 
commercial tablets 
under fasted 
conditions 
(Reference)
Single oral dose 
of nirmatrelvir 
/ritonavir 
300/100 mg 
(2 x 150/50 mg) 
FDC tablets Test 
formulation 1 
(low disintegrant)
under fasted 
conditions (Test 
1)
Single oral dose of 
nirmatrelvir/ 
ritonavir 
300/100 mg 
(2 x 150/50 mg) 
FDC tablets Test 
formulation 2 
(high disintegrant) 
under fasted 
conditions (Test 2)
Single oral dose 
of nirmatrelvir/ 
ritonavir 
300/100 mg 
(2 x 150/50 mg) 
FDC tablets Test 
formulation 3 
(high drug 
loading) under 
fasted conditions 
(Test 3)
Single oral dose 
of nirmatrelvir/ 
ritonavir 
300/100 mg 
(3 x 100/33.3 mg) 
FDC tablets Test 
formulation 4
under fasted 
conditions (Test 
4)


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6.1.1. Administration
Study interventions will be administered orally and according to the conditions described in 
the SoA section and Protocol Section 5.3.2 Meals and Dietary Restrictions.
On Day 1 of each treatment period, following an overnight fast of at least 10 hours,
participants will receive nirmatrelvir 300 mg (as 2 × 150 mg tablets) with ritonavir 100 mg 
(as 1 × 100 mg tablet) commercial tablets or nirmatrelvir/ritonavir 300/100 mg as 2 tablets of  
nirmatrelvir/ritonavir 150/50 mg FDC tablets Test formulation 1 (low disintegrant), or 
nirmatrelvir/ritonavir 300/100 mg as 2 tablets of  nirmatrelvir/ritonavir 150 mg/50mg FDC 
tablets Test formulation 2 (high disintegrant), or nirmatrelvir/ritonavir 300 mg/100 mg as 2
tablets of nirmatrelvir/ritonavir 150/50 mg FDC tablets Test formulation 3 (high drug 
loading) or nirmatrelvir/ritonavir 300/100 mg as 3 tablets of nirmatrelvir/ritonavir 
100/33.3 mg FDC tablets Test formulation 4 with approximately 240 mL ambient 
temperature water administered orally starting at approximately 0800 hours (plus or minus 
2 hours). Nirmatrelvir and ritonavir will be dosed simultaneously (within no more than 
5 minutes of each other). Participants will swallow all tablet formulations whole and will not 
manipulate or chew the tablets prior to swallowing. 
In order to standardize the conditions on PK sampling days, all participants will be required 
to refrain from lying down (except when required for BP, PR, and ECG measurements), 
eating, and drinking beverages other than water during the first 4 hours after 
nirmatrelvir/ritonavir dosing.
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 for 
all site storage locations upon return to business.
4. Any excursions from the study intervention label storage conditions should be 
reported to Pfizer upon discovery along with any actions taken. The site should 
actively pursue options for returning the study intervention to the labeled storage 
conditions described in the labeling, as soon as possible. Once an excursion is 
identified, the study intervention must be quarantined and not used until Pfizer 
provides permission to use the study intervention. Specific details regarding the 


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excursion definition and information to report for each excursion will be provided to 
the site in the PCRU site procedures.
5. Any storage conditions stated in the SRSD will be superseded by the storage 
conditions stated on the label.
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.
8. Further guidance and information for the final disposition of unused study 
interventions are provided in the PCRU’s site procedures. 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.
6.2.1. Preparation and Dispensing
Within this protocol, preparation refers to the investigator site activities performed to make 
the study intervention ready for administration or dispensing to the participant by qualified 
staff. Dispensing is defined as the provision of study intervention, concomitant treatments, 
and accompanying information by qualified staff member(s) to a healthcare provider, 
participant in accordance with this protocol. Local health authority regulations or investigator 
site guidelines may use alternative terms for these activities.
Nirmatrelvir 150 mg tablets will be prepared at the PCRU in the individual dosing containers 
by 2 operators, 1 of whom is an appropriately qualified and experienced member of the study 
staff (eg, physician, nurse, physician’s assistant, nurse practitioner, pharmacy 
assistant/technician, or pharmacist). The tablets will be provided in unit dose containers and 
labeled in accordance with Pfizer regulations and the clinical site’s labeling requirements. 
Commercial ritonavir (Norvir® or other local commercialized product) oral tablets will be 
dispensed at the PCRU into individual dosing containers using the package insert as 
guidance. All study intervention should be prepared and dispensed by an appropriately 
qualified and experienced member of the study staff (eg, physician, nurse, physician’s 
assistant, nurse practitioner, pharmacy assistant/technician, or pharmacist) as allowed by 
local, state, and institutional guidance. A second staff member will verify the dispensing.


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Nirmatrelvir/ritonavir FDC tablets will be prepared at the PCRU in the individual dosing 
containers by 2 operators, 1 of whom is an appropriately qualified and experienced member 
of the study staff (eg, physician, nurse, physician’s assistant, nurse practitioner, pharmacy 
assistant/technician, or pharmacist). Prepared doses will be provided in unit dose containers 
and labeled in accordance with Pfizer regulations and the investigator site’s labeling 
requirements.
6.3. Assignment to Study Intervention
The investigator’s knowledge of the treatment should not influence the decision to enroll a 
particular participant or affect the order in which participants are enrolled.
The investigator will assign participant numbers to the participants as they are screened for 
the study. Pfizer will provide a randomization schedule to the investigator and, in accordance 
with the randomization numbers, the participant will receive the study treatment regimen 
assigned to the corresponding randomization number.
6.4. Blinding
This is an open-label study.
6.5. Study Intervention Compliance
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 PCRU will be recorded in the source documents and recorded in the 
CRF. 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 site personnel will examine each participant’s mouth to ensure that 
the study intervention was ingested.
6.6. Dose Modification
No dose modification is anticipated.
6.7. Continued Access to Study Intervention After the End of the Study
No study intervention will be provided to study 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 nirmatrelvir greater than 300 mg or ritonavir 100 mg within a 
24-hour time period [±2 hours] will be considered an overdose.
There is no specific treatment for an overdose.


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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).
6.9. Prior and Concomitant Therapy
Participants will abstain from all concomitant treatments, except for the treatment of adverse
events and hormonal contraceptives that meet the requirements of this study in participants 
who are WOCBP (see Appendix 4).
Use of prescription or nonprescription drugs and dietary and herbal supplements are 
prohibited within 7 days or 5 half-lives (whichever is longer) prior to the first dose of study 
intervention. Limited use of nonprescription medications that are not believed to affect 
participant safety or the overall results of the study may be permitted on a case-by-case basis 
following approval by the sponsor. Acetaminophen/paracetamol may be used at doses 
of ≤1 g/day.
As nirmatrelvir and ritonavir are both primarily metabolized by CYP3A4, concomitant use of 
any medications or substances that are strong inducers of CYP3A4 are prohibited within 28 
days prior to dosing of study intervention. Additionally, ritonavir and nirmatrelvir are 
inhibitors of CYP3A4. Therefore, medications highly dependent on CYP3A4 for clearance 
and for which elevated plasma concentrations may be associated with serious and/or life-
threatening events are not permitted during dosing of nirmatrelvir/ritonavir, through 4 days 
after the last dose of nirmatrelvir/ritonavir.
All concomitant treatments taken during the study must be recorded with indication, daily 
dose, and start and stop dates of administration. All participants will be questioned about 
concomitant treatment at each clinic visit.
Treatments taken within 28 days before the first dose of study intervention will be 
documented as a prior treatment. Treatments taken after the first dose of study intervention 
will be documented as concomitant treatments.


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6.9.1. Rescue Medicine
There is no rescue therapy to reverse the AEs observed with nirmatrelvir or ritonavir; 
standard medical supportive care must be provided to manage the AEs. 
7. DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL
7.1. Discontinuation of Study Intervention
It may be necessary for a participant to permanently discontinue study intervention. Reasons 
for permanent discontinuation of study intervention include the following.

AE requiring discontinuation in investigator’s view;

Pregnancy;

Positive COVID-19 test.
If study intervention is permanently discontinued, the participant will not remain in the study 
for further evaluation. See the SoA for data to be collected at the time of discontinuation of 
study intervention.
7.1.1. ECG Changes
A participant who meets either bulleted criterion based on the average of triplicate ECG 
readings will be withdrawn from the study intervention. 

QTcF >500 msec;

Change from baseline: QTcF >60 msec.
If a clinically significant finding is identified (including, but not limited to, changes from 
baseline in QTcF after enrollment), the investigator or qualified designee will determine if 
the participant can continue in the study and if any change in participant management is 
needed. This review of the ECG printed at the time of collection must be documented. Any 
new clinically relevant finding should be reported as an AE.
7.1.2. Potential Cases of Acute Kidney Injury
Abnormal values in SCr concurrent with presence or absence of increase in BUN that meet 
the criteria below, in the absence of other causes of kidney injury, are considered potential 
cases of acute kidney injury and should be considered important medical events. 
An increase of ≥0.3 mg/dL (or ≥26.5 µmol/L) in SCr level relative to the participant’s own 
baseline measurement should trigger another assessment of SCr as soon as practically 
feasible, preferably within 48 hours from awareness.


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If the second assessment (after the first observations of ≥0.3 mg/dL [or ≥26.5 µmol/L] in SCr
relative to the participant’s own baseline measurement) is ≥0.4 mg/dL (or ≥35.4 µmol/L), the 
participant should be discontinued from the study and adequate, immediate, supportive 
measures taken to correct apparent acute kidney injury.
Participants should return to the investigator site and be evaluated as soon as possible, 
preferably within 48 hours from awareness of the second assessment confirming abnormal 
SCr result. This evaluation should include laboratory tests, detailed history, and physical 
assessment. In addition to repeating SCr, laboratory tests should include serum BUN, serum 
creatine kinase, and serum electrolytes (including at a minimum potassium, sodium, 
phosphate/phosphorus, and calcium), in addition to urinary dipstick, urine microscopic 
examination, and urinary indices. All cases confirmed on repeat testing as meeting the 
laboratory criteria for acute kidney injury, with no other cause(s) of laboratory abnormalities 
identified, should be considered potential cases of drug-induced kidney injury irrespective of 
availability of all the results of the investigations performed to determine etiology of the 
abnormal SCr. If ≥2 healthy participants are noted to have 2 consecutive SCr results of 
≥0.3 mg/dL (or ≥26.5 µmol/L), an assessment of whether the finding may be considered an 
adverse drug reaction should be undertaken.
7.1.3. Stopping Rules
Dosing will be halted at any time if 1 of the following circumstances occurs and it is 
determined by the investigator that the occurrence is at least possibly related to the 
administration of study intervention: 

A SAE (eg, a serious AE considered at least possibly related to study intervention
administration) in 1 participant.

Severe NSAE (eg, severe NSAEs considered at least possibly related to study 
intervention administration) in 2 participants, independent of whether it is within or 
not within the same SOC.
When stopping rules are met, a data review will be conducted by the sponsor and 
investigator. If integrated analysis of available data leads to the conclusion that further dosing 
is justified, an amendment to the protocol may be required if additional safety monitoring is 
warranted.
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;


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
Study terminated by sponsor;

Investigator’s decision;

Pregnancy.
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.
The participant will be permanently discontinued from the study intervention and the study at 
that time.
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.


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The following actions must be taken if a participant fails to attend a required study visit:

The site must attempt to contact the participant and reschedule the missed visit as 
soon as possible. Counsel the participant on the importance of maintaining the 
assigned visit schedule and ascertain whether the participant wishes to and/or should 
continue in the study;

Before a participant is deemed lost to follow-up, the investigator or designee must 
make every effort to regain contact with the participant (where possible, 3 telephone 
calls and, if necessary, a certified letter to the participant’s last known mailing 
address or local equivalent methods). These contact attempts should be documented 
in the participant’s medical record;

Should the participant continue to be unreachable, the participant will be considered 
to have withdrawn from the study. 
8. STUDY ASSESSMENTS AND PROCEDURES
8.1. Administrative 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.
Participants will be screened within 28 days prior to administration of the study intervention
to confirm that they meet the study population criteria for the study. If the time between 
screening and dosing exceeds 28 days as a result of unexpected delays (eg, delayed drug 
shipment), then participants do not require rescreening if the laboratory results obtained prior 
to first dose administration meet eligibility criteria.
Every effort should be made to ensure that protocol-required tests and procedures are 
completed as described. However, it is anticipated that from time to time there may be 
circumstances outside the control of the investigator that may make it unfeasible to perform 


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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.
If an IV catheter is utilized for blood sample collections, ECGs and vital sign assessments 
(PR and BP) should be collected prior to the insertion of the catheter.
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
360 mL. The actual collection times of blood sampling may change. Additional blood 
samples may be taken for safety assessments at times specified by Pfizer, provided the total 
volume taken during the study does not exceed 550 mL during any period of 56 consecutive 
days.
To prepare for study participation, participants will be instructed on the information in the
Lifestyle Considerations and Concomitant Therapy sections of the protocol.
8.2. Efficacy Assessments
Not applicable.
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. Physical Examinations
A complete physical examination will include, at a minimum, head, ears, eyes, nose, mouth, 
skin, heart and lung examinations, lymph nodes, and gastrointestinal, musculoskeletal, and 
neurological systems. 
A brief physical examination will include, at a minimum, assessments of general appearance, 
the respiratory and cardiovascular systems, and participant-reported symptoms.
Physical examinations may be conducted by a physician, trained physician's assistant, or 
nurse practitioner as acceptable according to local regulation. 
Height and weight will also be measured and recorded as per the SoA. For measuring weight, 
a scale with appropriate range and resolution is used and must be placed on a stable, flat 
surface. Participants must remove shoes, bulky layers of clothing, and jackets so that only 


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light clothing remains. They must also remove the contents of their pockets and remain still 
during measurement of weight. 
Physical examination findings collected during the study will be considered source data and 
will not be required to be reported, unless otherwise noted. Any untoward physical 
examination findings that are identified during the active collection period and meet the 
definition of an AE or SAE (Appendix 3) must be reported according to the processes in 
Sections 8.4.1 to 8.4.3.
8.3.2. Vital Signs
8.3.2.1. Blood Pressure and Pulse Rate
Supine BP, PR will be measured with the participant’s arm supported at the level of the heart
and recorded to the nearest mm Hg after approximately 5 minutes of rest. The same arm 
(preferably the dominant arm) will be used throughout the study. Participants should be 
instructed not to speak during measurements.
The same properly sized and calibrated BP cuff will be used to measure BP each time. The 
use of an automated device for measuring BP and pulse rate is acceptable; however, when 
done manually, pulse rate will be measured in the brachial/radial artery for at least 
30 seconds. When the timing of these measurements coincides with a blood collection, BP 
and PR should be obtained prior to the nominal time of the blood collection.
Additional collection times, or changes to collection times, of BP and PR will be permitted, 
as necessary, to ensure appropriate collection of safety data.
Any untoward vital sign findings that are identified during the active collection period and 
meet the definition of an AE or SAE (Appendix 3) must be reported according to the 
processes in Sections 8.4.1 to 8.4.3.
8.3.2.2. Temperature
Temperature will be measured orally. No eating, drinking, or smoking is allowed for 
15 minutes prior to the measurement.
8.3.3. Electrocardiograms
Standard 12-lead ECGs utilizing limb leads (with a 10-second rhythm strip) should be 
collected at times specified in the SoA section of this protocol using an ECG machine that 
automatically calculates the HR and measures PR interval, QT interval, QTcF, and QRS 
complex. Alternative lead placement methodology using torso leads (eg, Mason-Likar) 
should not be used given the potential risk of discrepancies with ECGs acquired using 
standard limb lead placement. All scheduled ECGs should be performed after the participant
has rested quietly for at least 5 minutes in a supine position. 
To ensure safety of the participants, a qualified individual at the investigator site will make 
comparisons to baseline measurements. Additional ECG monitoring will occur if a) a post


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dose QTcF interval is increased by ≥60 msec from the baseline and is >450 msec; or b) an 
absolute QT value is ≥500 msec for any scheduled ECG. If either of these conditions occurs, 
then 2 additional ECGs will be collected approximately 2 to 4 minutes apart to confirm the 
original measurement. If the QTc values from these repeated ECGs remain above the 
threshold value, then a single ECG must be repeated at least hourly until QTc values from 
2 successive ECGs fall below the threshold value that triggered the repeat measurement.
If a) a post dose QTcF interval remains ≥60 msec from the baseline and is >450 msec; or b) 
an absolute QT value is ≥500 msec for any scheduled ECG for greater than 4 hours (or 
sooner, at the discretion of the investigator); or c) QTcF intervals get progressively longer, 
the participant should undergo continuous ECG monitoring. A cardiologist should be 
consulted if QTcF intervals do not return to less than the criteria listed above after 8 hours of 
monitoring (or sooner, at the discretion of the investigator).
In some cases, it may be appropriate to repeat abnormal ECGs to rule out improper lead 
placement as contributing to the ECG abnormality. It is important that leads be placed in the 
same positions each time in order to achieve precise ECG recordings. If a machine-read QTc 
value is prolonged, as defined above, repeat measurements may not be necessary if a 
qualified medical provider’s interpretation determines that the QTcF values are in the 
acceptable range.
ECG values of potential clinical concern are listed in Appendix 8.
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.
The investigator must review the laboratory report, document this review, and record any 
clinically significant changes occurring during the study in the AE section of the CRF.
Clinically significant abnormal laboratory test findings are those that are not associated with 
the underlying disease, unless judged by the investigator to be more severe than expected for 
the participant's condition.
All laboratory tests with values considered clinically significant and abnormal during 
participation in the study or within 48 hours 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.


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See Appendix 7 for instructions for laboratory testing to monitor kidney function and 
reporting laboratory test abnormalities.
Participants may undergo random urine drug testing at the discretion of the investigator.
Drug testing conducted prior to dosing must be negative for participants to receive study 
intervention.
8.3.5. COVID-19 Specific Assessments
Participants will be tested for COVID-19 infection by PCR prior to being admitted to the 
PCRU for confinement and a subsequent COVID-19 test will be performed after 4 days (ie,
upon completion of 4 × 24 hours in house), or if they develop COVID-19-like symptoms. 
Additional testing may be required by local regulations or by the principal investigator.
8.3.6. Pregnancy Testing 
A serum pregnancy test is required at screening. Following screening, pregnancy tests may 
be urine or serum tests, and must have a sensitivity of at least 25 mIU/mL. Pregnancy tests 
will be performed in WOCBP at the times listed in the SoA. Following a negative pregnancy 
test result at screening, appropriate contraception must be commenced and a second negative 
pregnancy test result will be required at the baseline visit prior to the participant’s receiving 
the study intervention. Pregnancy tests will also be done whenever 1 menstrual cycle is 
missed during the active treatment period (or when potential pregnancy is otherwise 
suspected) and at the end of the study. Pregnancy tests may also be repeated if requested by 
IRBs/ECs or if required by local regulations. If a urine test cannot be confirmed as negative 
(eg, an ambiguous result), a serum pregnancy test is required. In such cases, the participant 
must be excluded if the serum pregnancy result is positive.
8.4. Adverse Events, Serious Adverse Events, and Other Safety Reporting
The definitions of an AE and an SAE can be found in Appendix 3.
AEs may arise from symptoms or other complaints reported to the investigator by the 
participant (or, when appropriate, by a caregiver, surrogate, or the participant's legally 
authorized representative), or they may arise from clinical findings of the investigator or 
other healthcare providers (clinical signs, test results, etc.).
The investigator and any qualified designees are responsible for detecting, documenting, and 
recording events that meet the definition of an AE or SAE and remain responsible to pursue 
and obtain adequate information both to determine the outcome and to assess whether the 
event meets the criteria for classification as an SAE or caused the participant to discontinue 
the study intervention (see Section 7.1). 
During the active collection period as described in Section 8.4.1, each participant will be 
questioned about the occurrence of AEs in a nonleading manner.
In addition, the investigator may be requested by Pfizer Safety to obtain specific follow-up 
information in an expedited fashion.


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8.4.1. Time Period and Frequency for Collecting AE and SAE Information
The time period for actively eliciting and collecting AEs and SAEs (“active collection 
period”) for each participant begins from the time the participant provides informed consent, 
which is obtained before the participant’s participation in the study (ie, before undergoing 
any study-related procedure and/or receiving study intervention), through and including a 
minimum of 28 calendar days, except as indicated below, after the last administration of the 
study intervention.
Follow-up by the investigator continues throughout and after the active collection period and 
until the AE or SAE or its sequelae resolve or stabilize at a level acceptable to the 
investigator.
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 CT SAE Report Form.
Investigators are not obligated to actively seek information on AEs or SAEs after the 
participant has concluded study participation. However, if the investigator learns of any SAE, 
including a death, at any time after a participant has completed the study, and they consider 
the event to be reasonably related to the study intervention, the investigator must promptly 
report the SAE to Pfizer using the CT SAE Report Form.
8.4.1.1. 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 on the CT SAE Report Form immediately upon 
awareness and under no circumstance should this exceed 24 hours, as indicated in 
Appendix 3. The investigator will submit any updated SAE data to the sponsor within 
24 hours of 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.


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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.
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.


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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 exposes 
a female partner prior to or around the time of conception.

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, inhalation, or skin 
contact.

A male family member or healthcare provider who has been exposed to the study 
intervention by ingestion, inhalation, or skin contact 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 


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should include the anticipated date of delivery (see below for information related to 
termination of pregnancy). 

If EDP occurs in a participant or a participant’s partner, the investigator must report 
this information to Pfizer Safety on the CT SAE Report Form and an EDP 
Supplemental Form, regardless of whether an SAE has occurred. Details of the 
pregnancy will be collected after the start of study intervention and until 28 days after 
the last dose.

If EDP occurs in the setting of environmental exposure, the investigator must report 
information to Pfizer Safety using the CT SAE Report Form and EDP Supplemental 
Form. Since the exposure information does not pertain to the participant enrolled in 
the study, the information is not recorded on a CRF; however, a copy of the 
completed CT SAE Report Form is maintained in the investigator site file.
Follow-up is conducted to obtain general information on the pregnancy and its outcome for 
all EDP reports with an unknown outcome. The investigator will follow the pregnancy until 
completion (or until pregnancy termination) and notify Pfizer Safety of the outcome as a 
follow-up to the initial EDP Supplemental Form. In the case of a live birth, the structural 
integrity of the neonate can be assessed at the time of birth. In the event of a termination, the 
reason(s) for termination should be specified and, if clinically possible, the structural 
integrity of the terminated fetus should be assessed by gross visual inspection (unless 
preprocedure test findings are conclusive for a congenital anomaly and the findings are 
reported).
Abnormal pregnancy outcomes are considered SAEs. If the outcome of the pregnancy meets 
the criteria for an SAE (ie, ectopic pregnancy, spontaneous abortion, intrauterine fetal 
demise, neonatal death, or congenital anomaly in a live-born baby, a terminated fetus, an 
intrauterine fetal demise, or a neonatal death), the investigator should follow the procedures 
for reporting SAEs. Additional information about pregnancy outcomes that are reported to 
Pfizer Safety as SAEs follows: 

Spontaneous abortion including miscarriage and missed abortion should be reported 
as an SAE;

Neonatal deaths that occur within 1 month of birth should be reported, without regard 
to causality, as SAEs. In addition, infant deaths after 1 month should be reported as 
SAEs when the investigator assesses the infant death as related or possibly related to 
exposure to the study intervention. 
Additional information regarding the EDP may be requested by the sponsor. Further 
follow-up of birth outcomes will be handled on a case-by-case basis (eg, follow-up on 
preterm infants to identify developmental delays). In the case of paternal exposure, the 
investigator will provide the participant with the Pregnant Partner Release of Information 
Form to deliver to his partner. The investigator must document in the source documents that 


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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, inhalation, or skin contact.
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 CT SAE Report Form. 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 CT SAE Report 
Form 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 CT SAE Report Form regardless of whether 
there is an associated SAE. Since the information about the occupational exposure does not 
pertain to a participant enrolled in the study, the information is not recorded on a CRF; 
however, a copy of the completed CT SAE Report Form must be maintained in the 
investigator site file.
8.4.6. 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.


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8.4.8.1. Lack of Efficacy
This section is not applicable because efficacy is not expected in the study population.
8.4.9. Medical Device Deficiencies
Not applicable.
8.4.9.1. Time Period for Detecting Medical Device Deficiencies
Not applicable.
8.4.9.2. Follow-Up of Medical Device Deficiencies
Not applicable.
8.4.9.3. Prompt Reporting of Device Deficiencies to the Sponsor
Not applicable.
8.4.9.4. Regulatory Reporting Requirements for 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 on the CT SAE 
Report Form 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.
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.


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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 on a CT SAE Report 
Form only when associated with an SAE.
8.5. Pharmacokinetics 
8.5.1. Plasma for Analysis of Nirmatrelvir and Ritonavir
Blood samples of approximately 4 mL, to provide approximately 1.5 mL plasma, will be 
collected for measurement of plasma concentrations of nirmatrelvir and ritonavir as specified 
in the SoA. Instructions for the collection and handling of biological samples will be 
provided in the laboratory manual or by the sponsor. The actual date and time (24-hour clock 
time) of each sample will be recorded.
The actual times may change, but the number of samples will remain the same. All efforts 
will be made to obtain the samples at the exact nominal time relative to dosing. Collection of 
samples up to and including 10 hours after dose administration that are obtained within 
10% of the nominal time relative to dosing (eg, within 6 minutes of a 60-minute sample) will 
not be captured as a protocol deviation, as long as the exact time of the collection is noted on 
the source document and the CRF. Collection of samples more than 10 hours after dose
administration that are obtained ≤1 hour away from the nominal time relative to dosing will 
not be captured as a protocol deviation, as long as the exact time of the collection is noted on 
the source document and the CRF. 
 
 
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.
The PK samples must be processed and shipped as indicated in the instructions provided to 
the investigator site to maintain sample integrity. Any deviations from the PK sample 
handling procedure (eg, sample collection and processing steps, interim storage or shipping 
conditions), including any actions taken, must be documented and reported to the sponsor.
CCI
CCI


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On a case-by-case basis, the sponsor may make a determination as to whether sample 
integrity has been compromised.
Any changes in the timing or addition of time points for any planned study assessments must 
be documented and approved by the relevant study team member and then archived in the 
sponsor and site study files, but will not constitute a protocol amendment. The IRB/EC will 
be informed of any safety issues that require alteration of the safety monitoring scheme or 
amendment of the ICD.
 
 
 
 
 
 
 
 
 
 
 
CCI
CCI


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8.6. Genetics
8.6.1. Specified Genetics
Specified genetic analyses are not evaluated in this study.
8.6.2. Retained Research Samples for Genetics
A 4-mL blood sample optimized for DNA isolation Prep D1 will be collected according to 
the SoA, as local regulations and IRBs/ECs allow.
Retained Research Samples may be used for research related to the study intervention(s). 
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 and 
supporting documentation.
8.7. Biomarkers
Biomarkers are not evaluated in this study.
8.7.1. Specified Gene Expression (RNA) Research 
Specified gene expression (RNA) research is not included in this study.
8.7.2. Specified Protein Research 
Specified protein research is not included in this study.
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8.7.3. Specified Metabolomic Research 
Specified metabolomic research is not included in this study.
8.7.4. Retained Research Samples for Biomarkers
These Retained Research Samples will be collected in this study:

10 mL whole blood (Prep B2 optimized for serum).
Retained Research Samples will be collected as local regulations and IRB/ECs allow 
according to the SoA.
Retained Research Samples may be used for research related to the study intervention(s).
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 and 
supporting documentation. 
8.8. Immunogenicity Assessments
Immunogenicity assessments are not included in this study.
8.9. Health Economics
Health economics/medical resource utilization and health economics parameters are not 
evaluated in this study.
 
 
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.
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9.1. Statistical Hypotheses
There are no statistical hypotheses for this study.
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 
randomization. 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.
Safety analysis set
All participants who take at least 1 dose of study intervention.
Participants will be analyzed according to the product they 
actually received.
PK concentration set
All participants who take at least 1 dose of study intervention 
and in whom at least 1 plasma concentration value is reported.
PK parameter set
All participants who take at least 1 dose of study intervention 
and in whom at least 1 of the plasma PK parameters of primary
interest are reported.
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. Pharmacokinetic Analyses
9.3.1.1. Derivation of Pharmacokinetic Parameters
Plasma PK parameters of nirmatrelvir and ritonavir will be derived (as data permits) from the 
concentration-time data using standard noncompartmental methods as outlined in Table 2.
Actual PK sampling times will be used in the derivation of PK parameters. In the case that 
actual PK sampling times are not available, nominal PK sampling time will be used in the 
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Table 2.
Plasma Nirmatrelvir and Ritonavir PK Parameters Definitions
Parameter
Definition
Method of Determination
AUCinf*
Area under the concentration-time curve from 
time 0 extrapolated to infinity
AUClast + (Clast*/kel),
where Clast* is the predicted plasma 
concentration at the last quantifiable 
time point from the log-linear 
regression analysis
AUClast
Area under the plasma concentration-time curve 
from time 0 to the time of the last measurable
concentration (Clast).
Linear/Log trapezoidal method.
AUC12
Area under the concentration-time curve from 
time 0 to 12 hours
Linear/Log trapezoidal method.
Cmax
Maximum observed concentration
Observed directly from data
Tmax
Time for Cmax
Observed directly from data as time of 
first occurrence
t½*
Terminal half-life
Loge(2)/kel, where kel is the terminal 
phase rate constant calculated by a 
linear regression of the loglinear 
concentration-time curve. Only those 
data points judged to describe the 
terminal loglinear decline will be used 
in the regression.
CL/F*
Apparent clearance of drug from eg, plasma
Dose/AUCinf
Vz/F*
Apparent volume of distribution
Dose/(AUCinf • kel)
*If data permits.
Additionally, saliva concentration by nominal collection time and by treatment will be 
provided, if collected and analyzed. The ratio of saliva/plasma concentrations will be listed 
for each time point saliva is collected.
9.3.2. Statistical Methods for PK Data
For the primary objective, natural log transformed AUCinf (if data permits), AUClast and Cmax
for nirmatrelvir and ritonavir will be analyzed using a mixed effect model with sequence, 
period and treatment as fixed effects and participant within sequence as a random effect.
Estimates of the adjusted mean differences (Test-Reference) and corresponding 
90% confidence intervals will be obtained from the model. The adjusted mean differences 
and 90% confidence intervals for the differences will be exponentiated to provide estimates 
of the ratio of adjusted geometric means (Test/Reference) and 90% confidence intervals for 
the ratios. Treatment A will be the Reference treatment while Treatments B, C, D and E will 
be the Test treatments.
PK parameters, including plasma AUCinf (if data permits), AUClast, Cmax, and
(if data 
permits) of nirmatrelvir and ritonavir will be summarized descriptively by treatment. For 
AUCinf (if data permits), AUClast, and Cmax, a listing of the individual participant ratios 
(Test/Reference) will be provided. Box and whisker plots for AUCinf (if data permits), 
AUClast, and Cmax, will be plotted by treatment.
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The plasma concentrations of nirmatrelvir and ritonavir will be listed and descriptively 
summarized by nominal PK sampling time and treatment. Individual participant, as well as 
mean and median profiles of the plasma concentration time data will be plotted by treatment 
using actual (for individual) and nominal (for mean and median) times respectively. Mean 
and median profiles will be presented on both linear and semi-log scales. 
Additional specifications about the tables, listings, and figures will be outlined in the SAP.
9.3.3. Other Safety Analyses
All safety analyses will be performed on the safety population.
AEs, ECGs, 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, 
ECG, 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 PE and neurological examination information, as applicable, 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, ECGs, 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.
9.3.4. Other Analyse(s)
9.3.4.1. Biomarker Assessment
Biomarker data from Retained Research Samples may be collected as per SoA, during or 
after the trial and retained for future analyses; the results of such analyses are not planned to 
be included in the CSR.
9.4. Interim Analyses
No formal interim analysis will be conducted for this study. As this is an open-label
study, the sponsor may conduct unblinded reviews of the data during the course of the study 
for the purpose of safety assessment, facilitating PK/PD modeling, and/or supporting clinical 
development.
9.5. Sample Size Determination
A sample size of 15 evaluable participants will provide 90% CIs for the difference between 
treatments of ± 0.1175 and ± 0.0924 on the natural log scale for AUCinf and Cmax for 
nirmatrelvir, respectively, with 80% coverage probability.


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Parameter
Estimated Effect 
(100*Test/Reference)
90% CI
CI Width
AUCinf
85%
90%
95%
100%
105%
110%
115%
0.7558, 0.9560
0.8002, 1.0122
0.8447, 1.0684
0.8892, 1.1246
0.9336, 1.1809
0.9781, 1.2371
1.0225, 1.2933
0.2002
0.2119
0.2237
0.2355
0.2473
0.2590
0.2708
Cmax
85%
90%
95%
100%
105%
110%
115%
0.7750, 0.9323
0.8206, 0.9871
0.8662, 1.0420
0.9117, 1.0968
0.9573, 1.1516
1.0029, 1.2065
1.0485, 1.2613
0.1573
0.1665
0.1758
0.1851
0.1943
0.2036
0.2128
These estimates are based on the assumption that within-participant standard deviations 
are 0.1752 and 0.1378 for lnAUCinf  and lnCmax, respectively, as obtained from clinical 
Studies C4671008 and C4671014 in healthy participants.
In addition, a sample size of 15 evaluable participants will provide 90% CIs for the 
difference between treatments of ±0.1625 and ±0.2201 on the natural log scale for AUCinf
and Cmax for ritonavir, respectively, with 80% coverage probability.
Parameter
Estimated Effect 
(100*Test/Reference)
90% CI
CI Width
AUCinf
85%
90%
95%
100%
105%
110%
115%
0.7225, 1.0000
0.7650, 1.0588
0.8075, 1.1177
0.8500, 1.1765
0.8925, 1.2353
0.9350, 1.2941
0.9775, 1.3530
0.2775
0.2938
0.3102
0.3265
0.3428
0.3591
0.3755
Cmax
85%
90%
95%
100%
105%
110%
115%
0.6821, 1.0592
0.7222, 1.1215
0.7623, 1.1838
0.8025, 1.2461
0.8426, 1.3085
0.8827, 1.3708
0.9228, 1.4331
0.3771
0.3993
0.4215
0.4437
0.4659
0.4880
0.5102
These estimates are based on the assumption that within-participant standard deviations 
are 0.2424 and 0.3282 for lnAUCinf  and lnCmax, respectively, as obtained from clinical 
studies C4671008 and C4671014 in healthy participants that used nirmatrelvir/ritonavir 
commercial tablets.
Participants who withdraw from the study or discontinue treatment, or whose PK samples are 
considered to be nonevaluable with respect to the primary PK objective may be replaced at 
the discretion of the investigator upon consultation with the sponsor.


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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
Not applicable.
10.1.3. Informed Consent Process
The investigator or the investigator’s representative will explain the nature of the study, 
including the risks and benefits, to the participant and answer all questions regarding the 
study. The participant 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 will be 
required to sign a statement of informed consent that meets the requirements of 21 CFR 50, 
local regulations, ICH guidelines, privacy and data protection requirements, where 
applicable, and the IRB/EC or study center.
The investigator must ensure that each study participant 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 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.
The participant 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 is fully informed about their
right to access and correct their personal data and to withdraw consent for the processing of 
their personal data.
The medical record must include a statement that written informed consent was obtained 
before the participant was enrolled in the study and the date on which the written consent was 
obtained. The authorized person obtaining the informed consent must also sign the ICD.
Participants 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.


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A participant who is rescreened is not required to sign another ICD if the rescreening occurs 
within 10 days from the previous ICD signature date.
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 or secured in a locked room 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 not use an E-DMC.
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.


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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.
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.


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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 or secured in a locked room to 
prevent access by unauthorized third parties.
QTLs are predefined parameters that are monitored during the study. Important deviations 
from the QTLs and any remedial actions taken will be summarized in the CSR.
The investigator must permit study-related monitoring, audits, IRB/EC review, and 
regulatory agency inspections and provide direct access to source 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 [IQMP] 
maintained and utilized by the sponsor or designee.
The sponsor or designee is responsible for the data management of this study, including 
quality checking of the data.
Records and documents, including signed ICDs, pertaining to the conduct of this study must 
be retained by the investigator for 15 years after study completion unless local regulations or 
institutional policies require a longer retention period. No records may be destroyed during 
the retention period without the written approval of the sponsor. No records may be 
transferred to another location or party without written notification to the sponsor. The 
investigator must ensure that the records continue to be stored securely for as long as they are 
maintained.
When participant data are to be deleted, the investigator will ensure that all copies of such 
data are promptly and irrevocably deleted from all systems.
The investigator(s) will notify the sponsor or its agents immediately of any regulatory 
inspection notification in relation to the study. Furthermore, the investigator will cooperate 
with the sponsor or its agents to prepare the investigator site for the inspection and will allow 


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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’s designee (Pfizer CRU).
Description of the use of the computerized system is documented in the Data Management 
Plan, which is maintained by the sponsor’s designee (Pfizer Clinical Research Unit).
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.
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.


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The investigator may initiate study-site closure at any time upon notification to the sponsor if 
requested to do so by the responsible IRB/EC or if such termination is required to protect the 
health of study participants.
Reasons for the early closure of a study site by the sponsor may include but are not limited 
to:

Failure of the investigator to comply with the protocol, the requirements of the 
IRB/EC or local health authorities, the sponsor's procedures, or the ICH GCP 
guidelines;

Inadequate recruitment of participants by the investigator;

Discontinuation of further study intervention development.
If the study is prematurely terminated or suspended, the sponsor shall promptly inform the 
investigators, the ECs/IRBs, the regulatory authorities, and any CRO(s) used in the study of 
the reason for termination or suspension, as specified by the applicable regulatory 
requirements. The investigator shall promptly inform the participant and should assure 
appropriate participant therapy and/or follow-up.
Study termination is also provided for in the clinical study agreement. If there is any conflict 
between the contract and this protocol, the contract will control as to termination rights.
10.1.10. Publication Policy
For multicenter trials, the primary publication will be a joint publication developed by the 
investigator and Pfizer reporting the primary endpoint(s) of the study covering all study sites. 
The investigator agrees to refer to the primary publication in any subsequent publications. 
Pfizer will not provide any financial compensation for the investigator’s participation in the 
preparation of the primary congress abstract, poster, presentation, or primary manuscript for 
the study.
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  


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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 CTMS.
To facilitate access to their investigator and the sponsor’s MQI for study-related medical 
questions or problems from nonstudy 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.
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. 


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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
Urinalysis
Other
Hemoglobin
Hematocrit
RBC count
MCV
MCH
MCHC
Platelet count
WBC count
Total neutrophils (Abs)
Eosinophils (Abs)
Monocytes (Abs)
Basophils (Abs)
Lymphocytes (Abs)
BUN and creatinine
Glucose (fasted)
Calcium
Sodium
Potassium
Chloride
Total CO2 (bicarbonate)
AST, ALT
Total bilirubin
Alkaline phosphatase
Uric acid
Albumin
Total protein
Local Dipstick:
pH
Glucose (qual)
Protein (qual)
Blood (qual)
Ketones
Nitrites
Leukocyte esterase
Laboratory:
Microscopy and 
Culturea

SARS-CoV-2 RT-PCR

Urine drug screeningb

Pregnancy test (β-hCG)c

eGFR [CKD-EPI]

aPTT

PT-INR

Fibrinogen
At Screening only:

FSHd

HBsAbe

HBsAg

HBcAb

HCVAb

HIV
a.
Only if urine dipstick is positive for blood, protein, nitrites, or leukocyte esterase and culture only if bacteriuria.
b.
The minimum requirement for drug screening includes cocaine, THC, opiates/opioids, benzodiazepines, and 
amphetamines (others are site and study specific).
c.
Serum or urine β-hCG for female participants of childbearing potential.
d.
For confirmation of postmenopausal status only.
e.
HBsAb will be tested if HBsAg and/or HBcAb are positive.
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.
Any remaining serum/plasma from samples collected for clinical safety laboratory 
measurements at baseline and at all times after dose administration may be retained and 
stored for the duration of the study.
 
 
CCI


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10.3. Appendix 3: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-Up, and Reporting
10.3.1. Definition of AE
AE Definition

An AE is any untoward medical occurrence in a patient or clinical study 
participant, temporally associated with the use of study intervention, whether or 
not considered related to the study intervention.

Note: An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease (new or exacerbated) 
temporally associated with the use of study intervention.
Events Meeting the AE Definition

Any abnormal laboratory test results (hematology, clinical chemistry, or 
urinalysis) or other safety assessments (eg, ECG, radiological scans, vital sign 
measurements), including those that worsen from baseline, considered clinically 
significant in the medical and scientific judgment of the investigator. Any 
abnormal laboratory test results that meet any of the conditions below must be 
recorded as an AE:

Is associated with accompanying symptoms;

Requires additional diagnostic testing or medical/surgical intervention;

Leads to a change in study dosing (outside of any protocol-specified dose 
adjustments) or discontinuation from the study, significant additional 
concomitant drug treatment, or other therapy.

Exacerbation of a chronic or intermittent preexisting condition, including either 
an increase in 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 non-pathogenic
The event may be suspected from clinical symptoms or laboratory findings 
indicating an infection in a participant exposed to a Pfizer product. The terms 
“suspected transmission” and “transmission” are considered synonymous. These 
cases are considered unexpected and handled as serious expedited cases by 
pharmacovigilance personnel. Such cases are also considered for reporting as 
product defects, if appropriate.
g. Other situations:

Medical or scientific judgment should be exercised by the investigator in 
deciding whether SAE reporting is appropriate in other situations, such as 
significant medical events that may jeopardize the participant or may require 
medical or surgical intervention to prevent one of the other outcomes listed in the 
above definition. These events should usually be considered serious.

Examples of such events include invasive or malignant cancers, intensive 
treatment in an emergency room or at home for allergic bronchospasm, blood 
dyscrasias or convulsions that do not result in hospitalization, or development of 
drug dependency or drug abuse.
10.3.3. Recording/Reporting and Follow-Up of AEs and/or SAEs During the Active 
Collection Period
AE and SAE Recording/Reporting
The table below summarizes the requirements for recording AEs on the CRF and for 
reporting SAEs on the CT SAE Report Form to Pfizer Safety throughout the active 
collection period. These requirements are delineated for 3 types of events: (1) SAEs; (2) 
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 CT SAE Report Form for reporting of SAE information is not 
the same as the AE page of the CRF. When the same data are collected, the forms must 
be completed in a consistent manner. AEs should be recorded using concise medical 
terminology and the same AE term should be used on both the CRF and the CT SAE 
Report Form for reporting of SAE information.
Safety Event
Recorded on the CRF
Reported on the CT SAE 
Report Form to Pfizer 
Safety Within 24 Hours 
of Awareness
SAE
All
All
Nonserious AE
All
None
Exposure to the study 
intervention under study 
during pregnancy or 
breastfeeding
All AEs/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 non-
participant (not 
involving EDP or EDB).
None. Exposure to a study 
non-participant is not 
collected on the CRF.
The exposure (whether or 
not there is an associated 
AE or SAE) must be 
reported.***
*
EDP (with or without an associated AE or SAE): any pregnancy information is reported to 
Pfizer Safety using the CT SAE Report Form and EDP Supplemental Form; if the EDP is 
associated with an SAE, then the SAE is reported to Pfizer Safety using the CT SAE 
Report Form. 
** EDB is reported to Pfizer Safety using the CT SAE Report Form, which would also 
include details of any SAE that might be associated with the EDB. 
*** Environmental or occupational exposure: AEs or SAEs associated with occupational 
exposure are reported to Pfizer Safety using the CT SAE Report Form. 

When an AE or SAE occurs, it is the responsibility of the investigator to review 
all documentation (eg, hospital progress notes, laboratory reports, and diagnostic 
reports) related to the event.

The investigator will then record all relevant AE or SAE information in the CRF.


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
It is not acceptable for the investigator to send photocopies of the participant’s 
medical records to Pfizer Safety in lieu of completion of the CT SAE Report 
Form/AE or SAE CRF page.

There may be instances when copies of medical records for certain cases are 
requested by Pfizer Safety. In this case, all participant identifiers, with the 
exception of the participant number, will be redacted on the copies of the medical 
records before submission to Pfizer Safety.

The investigator will attempt to establish a diagnosis of the event based on signs,
symptoms, and/or other clinical information. Whenever possible, the diagnosis 
(not the individual signs/symptoms) will be documented as the AE or SAE.
Assessment of Intensity
The investigator will make an assessment of intensity for each AE and SAE reported 
during the study and assign it to 1 of the following categories: 

Mild: A type of AE that is usually transient and may require only minimal 
treatment or therapeutic intervention.  The event does not generally interfere with 
usual ADL.

Moderate: A type of AE that is usually alleviated with additional specific 
therapeutic intervention. The event interferes with usual ADL, causing 
discomfort, but poses no significant or permanent risk of harm to the research 
participant.

Severe: A type of AE that interrupts usual ADL, or significantly affects clinical 
status, or may require intensive therapeutic intervention.
An event is defined as “serious” when it meets at least 1 of the predefined outcomes as 
described in the definition of an SAE, NOT when it is rated as severe.
Assessment of Causality

The investigator is obligated to assess the relationship between study intervention 
and each occurrence of each AE or SAE. The investigator will use clinical judgment 
to determine the relationship.

A “reasonable possibility” of a relationship conveys that there are facts, evidence, 
and/or arguments to suggest a causal relationship, rather than a relationship cannot 
be ruled out.


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


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
New or updated information will be recorded in the originally submitted 
documents.

The investigator will submit any updated SAE data to the sponsor within 
24 hours of receipt of the information.
10.3.4. Reporting of SAEs
SAE Reporting to Pfizer Safety via an Electronic 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 data collection tool 
will be taken off-line to prevent the entry of new data or changes to existing data.

If a site receives a report of a new SAE from a study participant or receives 
updated data on a previously reported SAE after the electronic 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 definitions below in Section 10.4.3).
OR

Is a WOCBP and agrees to use a highly effective contraceptive method (failure rate of 
<1% per year) during the intervention period and for at least 28 days after the last 
dose of study intervention, which corresponds to the time needed to eliminate any 
reproductive safety risk of the study intervention(s). If a highly effective, 
user-dependent method is chosen, she agrees to concurrently use an effective barrier 
method of contraception. The investigator should evaluate the effectiveness of the 
contraceptive method in relationship to the first dose of study intervention.
The investigator is responsible for review of medical history, menstrual history, and recent 
sexual activity to decrease the risk for inclusion of a woman with an early undetected 
pregnancy. 
10.4.3. Woman of Childbearing Potential
A woman is considered fertile following menarche and until becoming postmenopausal 
unless permanently sterile (see below).
If fertility is unclear (eg, amenorrhea in adolescents or athletes) and a menstrual cycle cannot 
be confirmed before the first dose of study intervention, additional evaluation should be 
considered.
Women in the following categories are not considered WOCBP:
1. Premenopausal female with 1 of the following:

Documented hysterectomy;


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
Documented bilateral salpingectomy;

Documented bilateral oophorectomy.
For individuals with permanent infertility due to an alternate medical cause other than the 
above, (eg, mullerian agenesis, androgen insensitivity), investigator discretion should be 
applied to determining study entry.
Note: Documentation for any of the above categories can come from the site personnel’s 
review of the participant’s medical records, medical examination, or medical history 
interview. The method of documentation should be recorded in the participant’s medical 
record for the study.
2. Postmenopausal female.

A postmenopausal state is defined as no menses for 12 months without an 
alternative medical cause. In addition:

A high FSH level in the postmenopausal range must be used to confirm a 
postmenopausal state in women under 60 years old and not using hormonal 
contraception or HRT. 

A female on HRT and whose menopausal status is in doubt will be required to 
use one of the highly effective nonestrogen hormonal highly effective 
contraception methods if she wishes to continue her HRT during the study.
Otherwise, she must discontinue HRT to allow confirmation of 
postmenopausal status before study enrollment.
10.4.4. 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.
3. Intrauterine hormone-releasing system.
4. Bilateral tubal occlusion.


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


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10.5. Appendix 5: Genetics
Use/Analysis of DNA

Genetic variation may impact a participant’s response to study intervention, 
susceptibility to, and severity and progression of disease. Therefore, where local 
regulations and IRBs/ECs allow, a blood sample will be collected for DNA analysis.

The scope of the genetic research may be narrow (eg, 1 or more candidate genes) or
broad (eg, the entire genome), as appropriate to the scientific question under 
investigation.

The samples may be analyzed as part of a multistudy assessment of genetic factors 
involved in the response to study intervention or study interventions of this class to 
understand treatments for the disease(s) under study or the disease(s) themselves.

The results of genetic analyses may be reported in 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
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 may 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 estimate glomerular filtration rate [Scr-based eGFR] or 
creatinine clearance [eCrCl]). Baseline and postbaseline serum 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
10.7.2.1. Adults (18 Years and Above)—2021 CKD-EPI Equations3
2021 CKD-
EPI          
Scr Only
Scr
(mg/dL)
Scys
(mg/L)
Recommended eGFR Equation
Female
if ≤ 0.7
NA
eGFR = 143 × (Scr/0.7)-0.241  ×  (0.9938)Age
Female
if > 0.7
NA
eGFR = 143 × (Scr/0.7)-1.200  ×  (0.9938)Age
Male
if ≤ 0.9
NA
eGFR = 142 × (Scr/0.9)-0.302  ×  (0.9938)Age
Male
if > 0.9
NA
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
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: ECG Findings of Potential Clinical Concern
ECG Findings That May Qualify as AEs

Marked sinus bradycardia (rate <40 bpm) lasting minutes.

New PR interval prolongation >280 msec.

New prolongation of QTcF to >480 msec (absolute) or by ≥60 msec from 
baseline.

New-onset atrial flutter or fibrillation, with controlled ventricular response rate: ie, 
rate <120 bpm.

New-onset type I second-degree (Wenckebach) AV block of >30 seconds’
duration.

Frequent PVCs, triplets, or short intervals (<30 seconds) of consecutive 
ventricular complexes.
ECG Findings That May Qualify as SAEs

QTcF prolongation >500 msec.

New ST-T changes suggestive of myocardial ischemia.

New-onset LBBB block (QRS complex>120 msec).

New-onset right bundle branch block (QRS complex>120 msec).

Symptomatic bradycardia.

Asystole:

In awake, symptom-free participants in sinus rhythm, with documented 
periods of asystole ≥3.0 seconds or any escape rate <40 bpm, or with an 
escape rhythm that is below the AV node. 

In awake, symptom-free participants with atrial fibrillation and bradycardia 
with 1 or more pauses of at least 5 seconds or longer. 

Atrial flutter or fibrillation, with rapid ventricular response rate: rapid = rate 
>120 bpm.

Sustained supraventricular tachycardia (rate >120 bpm) (“sustained” = short 
duration with relevant symptoms or lasting >1 minute).


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


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Example: How to provide a mark () on the color bar.
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10.10. Appendix 10: Abbreviations
The following is a list of abbreviations that may be used in the protocol.
Abbreviation
Term
Abs
absolute
ADL
activities of daily living
AE
adverse event
AKI
acute kidney injury
ALT
alanine aminotransferase
aPTT
activated partial thromboplastin time
AST
aspartate aminotransferase
AUC
area under the concentration-time curve
 
AUCinf
area under the concentration-time curve from time zero 0 extrapolated to 
infinity
AUClast
area under the plasma concentration-time curve from time 0 to the time of 
the last measurable concentration
AV
atrioventricular
AxMP
auxiliary medicinal product
BBS
Biospecimen Banking System
-hCG
‑human chorionic gonadotropin
BID
twice a day
BMI
body mass index
BP
blood pressure
bpm
beats per minute
BUN
blood urea nitrogen
CFR
Code of Federal Regulations
CI
confidence interval
CIOMS
Council for International Organizations of Medical Sciences
CK
creatine kinase
CKD-EPI
Chronic Kidney Disease Epidemiology Collaboration
Clast
last quantifiable concentration
3CLpro
3C-like protein
Cmax
maximum observed concentration
CO2
carbon dioxide (bicarbonate)
COVID-19
coronavirus disease 2019
CRF
case report form
CRO
contract research organization
CRU
clinical research unit
CSR
Clinical Study Report
CT
clinical trial
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Abbreviation
Term
CTIS
Clinical Trial Information System
CTMS
Clinical Trial Management System
CYP
cytochrome P450 
CYP3A
cytochrome P450, family 3, subfamily A
CYP3A4
cytochrome P450 3A4 
CYP3A5
cytochrome P450 3A5 
DCT
data collection tool
DILI
drug‑induced liver injury
DNA
deoxyribonucleic acid
DMC
Data Monitoring Committee
EC
ethics committee
ECC
emergency contact card
ECG
electrocardiogram
eCrCl
estimated creatinine clearance
eCRF
electronic case report form
EDB
exposure during breastfeeding
E-DMC
External Data Monitoring Committee
EDP
exposure during pregnancy
eGFR
estimated glomerular filtration rate
eSAE
electronic serious adverse event
EU
European Union
EudraCT
European Union Drug Regulating Authorities Clinical Trials (European
Clinical Trials Database)
FDC
fixed dose combination
FIH
first in human
fm
fraction metabolized
19F-NMR
19F nuclear magnetic resonance
FSH
follicle‑stimulating hormone
GCP
Good Clinical Practice
GGT
gamma‑glutamyl transferase
GLP
Good Laboratory Practice
HBcAb
hepatitis B core antibody
HBsAb
hepatitis B surface antibody
HBsAg 
hepatitis B surface antigen
HCVAb
hepatitis C antibody
HIV
human immunodeficiency virus
HR
heart rate
HRT
hormone replacement therapy
IB
Investigator’s Brochure
ICD
informed consent document
ICH
International Council for Harmonisation for Technical Requirements for 
Pharmaceuticals for Human Use


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Abbreviation
Term
ID
identification
IMP
investigational medicinal product
IND
Investigational New Drug 
IPAL
Investigational Product Accountability Log
IQMP
Integrated Quality Management Plan
IRB
Institutional Review Board
IV
Intravenous(ly)
KDIGO
Kidney Disease Improving Global Outcomes
kel
elimination rate constant
Ki
inhibition constant
LBBB
left bundle branch block
LFT
liver function test
lnAUCinf
log-transformed AUCinf
lnCmax
log-transformed Cmax
Loge
natural logarithm
MAD
multiple ascending dose
MCH
mean corpuscular hemoglobin
MCHC
mean corpuscular hemoglobin concentration
MCV
mean corpuscular volume
Mpro
main protease
MQI
medically qualified individual
msec
millisecond
NA
Not Applicable
NHP
nonhuman primate
NIMP
non-investigational medicinal product
NOAEL
No observed adverse effect level
NSAE
non-serious adverse event
NYHA
New York Heart Association
PCR
polymerase chain reaction
PCRU
Pfizer Clinical Research Unit
PD
pharmacodynamic(s)
PE
physical examination 
pH
potential of Hydrogen
PK
pharmacokinetic(s)
PR
pulse rate
PSSA
Pfizer's Serious Adverse Event Submission Assistant
PT-INR
prothrombin time-international normalized ratio
PVC
premature ventricular contraction/complex
q12h
every 12 hours
QT
measure between Q wave and T wave in the heart's electrical cycle
QTc
corrected QT interval
QTcF
QT corrected using Fridericia’s formula


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Abbreviation
Term
QTL
Quality Tolerance Limit
qual
qualitative
rBA
relative bioavailability
RBC
red blood cell
RNA
ribonucleic acid
RT-PCR
reverse-transcriptase polymerase chain reaction
SAD
single ascending dose
SAE
serious adverse event
SAP
Statistical Analysis Plan
SARS-CoV-2
severe acute respiratory syndrome coronavirus 2
SCr
serum creatinine
Scys
serum cystatin C
SE
supratherapeutic exposure
SoA
schedule of activities
SOC
System Organ Class
SOP
standard operating procedure
SRSD
single reference safety document
SUSAR
Suspected Unexpected Serious Adverse Reaction
T bili
total bilirubin
TEAE
treatment-emergent adverse event
THC
tetrahydrocannabinol
ULN
upper limit of normal
US
United States
WBC
white blood cell
WHO
World Health Organization
WOCBP
woman/women of childbearing potential
C
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11. REFERENCES
1
World Health Organization. WHO Situation Report –51 Coronavirus disease 2019 
(COVID-19). 11 March 2020. Available from: 
https://www.who.int/emergencies/diseases/novel-coronavirus-2019/situation-reports. 
Accessed: 29 March 2020.
2
Investigator’s Brochure, PF-07321332. January 2022.
3
Inker LA, Eneanya ND, Coresh J, et al. New Creatinine- and Cystatin C-Based 
Equations to Estimate GFR without Race. N Engl J Med. 2021;385(19):1737-49.

SAP_001.pdf: 
Protocol C4671023 (PF-07321332) Statistical Analysis Plan
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Protocol C4671023
A PHASE 1, OPEN-LABEL, RANDOMIZED, SINGLE DOSE, 
CROSSOVER STUDY TO ESTIMATE THE RELATIVE 
BIOAVAILABILITY OF NIRMATRELVIR AND RITONAVIR 
FOLLOWING ORAL ADMINISTRATION OF 4 DIFFERENT FIXED 
DOSE COMBINATION TABLET FORMULATIONS RELATIVE TO THE 
COMMERCIAL TABLET FORMULATION IN HEALTHY ADULT 
PARTICIPANTS UNDER FASTED CONDITIONS
Statistical Analysis Plan 
(SAP)
Version:
1.0
SAP Author: 
                       (
 
Pune)
Date:
28-SEP-2022
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Revision History
Version
Date
Author(s)
Summary of Changes/Comments
1.0
September 28, 2022
Not Applicable
NOTE: Italicized text within this document has been taken verbatim from the Protocol.
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TABLE OF CONTENTS 
LIST OF TABLES.....................................................................................................................4
LIST OF FIGURES ...................................................................................................................4
APPENDICES ...........................................................................................................................4
1. AMENDMENTS FROM PREVIOUS VERSION(S) ...........................................................5
2. INTRODUCTION .................................................................................................................5
2.1. Study Design .............................................................................................................5
2.2. Study Objectives .......................................................................................................7
2.2.1. Primary Objectives .......................................................................................7
2.2.2. Secondary Objectives ...................................................................................7
3. INTERIM ANALYSES, FINAL ANALYSES AND UNBLINDING..................................8
4. HYPOTHESES AND DECISION RULES...........................................................................8
4.1. Statistical Hypotheses ...............................................................................................8
4.2. Statistical Decision Rules..........................................................................................8
5. ANALYSIS SETS .................................................................................................................8
5.1. Pharmacokinetic (PK) Analysis Set ..........................................................................8
5.1.1. Concentration Analysis Set...........................................................................8
5.1.2. Parameter Analysis Set.................................................................................8
5.2. Pharmacodynamic Analysis Set................................................................................8
5.3. Safety Analysis Set....................................................................................................8
5.4. Enrolled .....................................................................................................................8
5.5. Other Analysis Sets ...................................................................................................9
5.6. Treatment Misallocations..........................................................................................9
5.7. Protocol Deviations...................................................................................................9
5.7.1. Deviations Assessed Prior to Randomization...............................................9
5.7.2. Deviations Assessed Post-Randomization....................................................9
6. ENDPOINTS AND COVARIATES .....................................................................................9
6.1. Efficacy Endpoint(s) .................................................................................................9
6.2. Safety Endpoints .......................................................................................................9
6.3. Other Endpoints.......................................................................................................10
6.3.1. PK Endpoints..............................................................................................10
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6.3.2. PD Endpoints..............................................................................................11
6.4. Covariates................................................................................................................11
7. HANDLING OF MISSING VALUES ................................................................................11
7.1. Concentrations Below the Limit of Quantification.................................................11
7.2. Deviations, Missing Concentrations and Anomalous Values .................................11
7.3. Pharmacokinetic Parameters ...................................................................................11
8. STATISTICAL METHODOLOGY AND STATISTICAL ANALYSES ..........................12
8.1. Statistical Methods ..................................................................................................12
8.2. Statistical Analyses .................................................................................................12
8.3. Safety Analysis........................................................................................................13
8.3.1. Treatment and Disposition of Participants .................................................14
8.3.2. Demographic and Clinical Examination Data............................................14
8.3.3. Discontinuation(s).......................................................................................14
8.3.4. Adverse Events...........................................................................................14
8.3.5. Laboratory Data..........................................................................................14
8.3.6. Vital Signs Data..........................................................................................14
8.3.7. ECG Data....................................................................................................14
8.3.8. Other Safety Data .......................................................................................14
8.3.9. Concomitant Treatments.............................................................................15
8.3.10. Screening and Other Special Purpose Data ..............................................15
8.3.11. Banked Bio specimens..............................................................................15
9. REFERENCES ....................................................................................................................16
10. APPENDICES ...................................................................................................................17
LIST OF TABLES
Table 1.
Noncompartmental PK Parameters...........................................................10
Table 2.
PK Parameters to be Summarized Descriptively by Analyte and 
Treatment..................................................................................................12
LIST OF FIGURES
None.
APPENDICES
Appendix 1. SAS CODE FOR ANALYSES...........................................................................17


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1. AMENDMENTS FROM PREVIOUS VERSION(S) 
None.
2. INTRODUCTION
Nirmatrelvir is a potent and selective inhibitor of the SARS-CoV-2 Mpro that is currently 
being developed as an oral treatment of COVID-19. Ritonavir is a strong CYP3A4 inhibitor 
being used to inhibit the metabolism of nirmatrelvir in order to increase plasma 
concentrations of nirmatrelvir to values that are efficacious.
The purpose of this study is to estimate the rBA of nirmatrelvir/ritonavir of 4 different FDC 
tablet formulations relative to the commercial tablet formulation under fasted conditions in 
healthy adult participants.
 
 
2.1. Study Design
This is a Phase 1, open label, single dose, randomized, crossover study in healthy adult 
participants to estimate rBA of nirmatrelvir/ritonavir 300/100 mg of 4 different FDC Test 
formulations compared to the nirmatrelvir/ritonavir 300/100 mg commercial tablets 
(Reference formulation) under fasted conditions. The study will also assess the safety and 
tolerability of nirmatrelvir/ritonavir FDC and commercial tablet formulations in healthy 
adult participants.
 
Approximately 15 healthy male and/or female participants will be enrolled and randomized 
to the study. Participants who discontinue from the study for non-safety reasons may be 
replaced at the sponsor’s discretion in collaboration with the investigator. 
Healthy participants will be screened to determine eligibility within 28 days prior to study 
treatment. Medical history and results of PEs, vital signs, 12-lead ECGs, and clinical 
laboratory evaluations will determine eligibility. Eligible participants will be admitted to the 
PCRU on Day -1 and will be confined in the PCRU until discharge on Day 4 of Period 4. 
On Day 1 of each period, participants will receive a single oral dose of study intervention 
nirmatrelvir/ritonavir 300/100 mg as per the randomization schedule. Study treatments will 
be administered with approximately 240 mL of ambient temperature water under fasted 
conditions (overnight fast and no food until 4 hours after dosing). Serial PK samples will be 
collected up to 72 hours post dose. Participants will be discharged from the PCRU on Day 4 
of Period 4, following completion of all assessments.
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If a participant has any clinically significant, study-related abnormalities at the conclusion 
of a scheduled inpatient portion of the study, the Pfizer medical monitor (or designated 
representative) should be notified and the participant may be asked to remain in the PCRU 
until such abnormalities are deemed not clinically significant, or it is safe for outpatient 
follow up.
A safety follow-up call will be made to participants approximately 28 to 35 days from 
administration of the final dose of study intervention.
Number of Participants
Approximately 15 healthy male and/or female participants will be enrolled and randomized 
to 1 of 5 possible treatment sequences to ensure at least 12 participants will complete the 
study. 
Intervention Groups and Duration
The study will consist of 5 treatments. Each enrolled participant will participate in 4 study 
periods to receive 4 different treatments according to the sequence determined by 
randomization: 

Treatment A: Single oral dose of nirmatrelvir/ritonavir 300 (2 × 150)/100 mg 
commercial tablets under fasted conditions (Reference).

Treatment B: Single oral dose of nirmatrelvir/ritonavir 300/100 mg (2 × 150/50 mg) 
FDC tablets Test formulation 1 (low disintegrant) under fasted conditions (Test 1).

Treatment C: Single oral dose of nirmatrelvir/ritonavir 300/100 mg (2 × 150/50 mg) 
FDC tablets Test formulation 2 (high disintegrant) under fasted conditions (Test 2).

Treatment D: Single oral dose of nirmatrelvir/ritonavir 300/100 mg (2 × 150/50 mg) 
FDC tablets Test formulation 3 (high drug loading) under fasted conditions (Test 3).

Treatment E: Single oral dose of nirmatrelvir/ritonavir 300/100 mg (3 × 100/33.3 
mg) FDC tablets Test formulation 4 under fasted conditions (Test 4).
Participants will be randomly assigned to 1 of 5 sequences as below:
Treatment Sequence
Period 1
Period 2
Period 3
Period 4
Sequence 1 (N =3)
Treatment A
Treatment B
Treatment C
Treatment D
Sequence 2 (N =3)
Treatment B
Treatment C
Treatment D
Treatment E
Sequence 3 (N =3)
Treatment C
Treatment D
Treatment E
Treatment A
Sequence 4 (N =3)
Treatment D
Treatment E
Treatment A
Treatment B
Sequence 5 (N =3)
Treatment E
Treatment A
Treatment B
Treatment C


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Between each treatment, a minimum of 4 days washout is proposed to minimize any residual 
nirmatrelvir and ritonavir concentrations prior to start of the next treatment. Participants 
will be discharged on Day 4 of Period 4, following completion of all assessments. 
The total planned duration of participation from the Screening visit to the last follow-up 
phone call, is approximately 12 weeks.
2.2. Study Objectives
2.2.1. Primary Objectives

To estimate the rBA of the nirmatrelvir/ritonavir 300/100 mg (2 × 150/50 mg) FDC 
tablets Test formulation 1 (low disintegrant) compared to the nirmatrelvir/ritonavir 
300 (2 × 150)/100 mg commercial tablets under fasted conditions (reference). 

To estimate the rBA of the nirmatrelvir/ritonavir 300/100 mg (2 × 150/50 mg) FDC 
tablets Test formulation 2 (high disintegrant) compared to the nirmatrelvir/ritonavir 
300 (2 × 150)/100 mg commercial tablets under fasted conditions (reference).

To estimate the rBA of the nirmatrelvir/ritonavir 300/100 mg (2 × 150/50 mg) FDC 
tablets Test formulation 3 (high drug load) compared to the nirmatrelvir/ritonavir
300 (2 × 150)/100 mg commercial tablets under fasted conditions (reference).

To estimate the rBA of the nirmatrelvir/ritonavir 300/100 mg (3 × 100/33.3 mg) FDC 
tablets Test formulation 4 compared to the nirmatrelvir/ritonavir 300 (2 × 150)/100 
mg commercial tablets under fasted conditions (reference).  
2.2.2. Secondary Objectives

To evaluate the safety and tolerability of nirmatrelvir/ritonavir in healthy 
participants.
 
 
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3. INTERIM ANALYSES, FINAL ANALYSES AND UNBLINDING
No formal interim analysis will be conducted for this study. As this is an open label study, the 
sponsor may conduct unblinded reviews of the data during the course of the study for the 
purpose of safety assessment, facilitating PK/PD modeling, and/or supporting clinical 
development.
Final analysis will follow the official database release. As this will be an open-label study, 
there is no formal unblinding of the randomization code.
4. HYPOTHESES AND DECISION RULES
4.1. Statistical Hypotheses
There are no statistical hypotheses for this study.
4.2. Statistical Decision Rules
There are no statistical decision rules.
5. ANALYSIS SETS
5.1. Pharmacokinetic (PK) Analysis Set
5.1.1. Concentration Analysis Set
The PK concentration analysis set is defined as all participants who take at least 1 dose of 
study intervention and in whom at least 1 concentration value is reported.
5.1.2. Parameter Analysis Set
The PK parameter analysis set is defined as all participants who take at least 1 dose of study 
intervention and in whom at least 1 of the PK parameters of primary interest are reported.
5.2. Pharmacodynamic Analysis Set
None.
5.3. Safety Analysis Set
All participants who take at least 1 dose of study intervention. Participants will be analyzed 
according to the product they actually received.
5.4. 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 
randomization. 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.


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5.5. Other Analysis Sets
None.
5.6. Treatment Misallocations 
All analyses will be performed on an “as-treated” basis and will not include data from 
participants who are randomized but not treated.
If a participant takes a treatment that is not consistent with the treatment they are randomized 
to, for example takes a treatment out of sequence or takes the same treatment twice, then they 
will be reported under the treatment that they actually receive for all safety, and PK analyses, 
where applicable.
5.7. Protocol Deviations
Participants who experience events that may affect their PK profile (eg, lack of compliance 
with dosing) may be excluded from the PK analysis. At the discretion of the 
pharmacokineticist a concentration value may also be excluded if the deviation in sampling 
time is of sufficient concern or if the concentration is anomalous for any other reason.
A full list of protocol deviations will be compiled and reviewed to identify major and minor 
deviations prior to database closure.
5.7.1. Deviations Assessed Prior to Randomization
At Screening, the investigator will assess participants against the inclusion and exclusion 
criteria as set out in Sections 4.1 and 4.2 of the protocol.
5.7.2. Deviations Assessed Post-Randomization
A full list of protocol deviations for the study report will be compiled prior to database 
closure. Any significant deviation from the protocol will be reviewed prior to database 
closure and a decision taken regarding evaluation for each analysis population.
6. ENDPOINTS AND COVARIATES
6.1. Efficacy Endpoint(s)
None.
6.2. Safety Endpoints
AEs may arise from symptoms or other complaints reported to the investigator by the 
participant (or, when appropriate, by a caregiver, surrogate, or the participant's legally 
authorized representative), or they may arise from clinical findings of the Investigator or 
other healthcare providers (clinical signs, test results, etc.).


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An adverse event will be considered a Treatment-Emergent Adverse Event (TEAE) if the 
event started during the effective duration of treatment. All events that start on or after the 
first dosing day and time/ start time, if collected, but before the last dose plus the lag time 
(28 days) will be flagged as TEAEs. The algorithm will not consider any events that started 
prior to the first dose date. 
Events that occur in a non-treatment period (for example, Washout or Follow-up) will be 
counted as treatment emergent and attributed to the previous treatment taken.
The following data are considered in standard safety assessments (see protocol for collection 
days and list of parameters):

adverse events,

laboratory data,

vital signs data,

ECG results,

Pregnancy Testing.
6.3. Other Endpoints
6.3.1. PK Endpoints
Blood samples for PK analysis of nirmatrelvir and ritonavir will be taken according to the 
Schedule of Activities given in the protocol.
Plasma PK parameters of nirmatrelvir and ritonavir will be derived (as data permits) from the 
concentration-time data using standard noncompartmental methods as outlined in Table 1. 
Actual PK sampling times will be used in the derivation of PK parameters. In the case that 
actual PK sampling times are not available, nominal PK sampling time will be used in the 
derivation of PK parameters.
Table 1.
Noncompartmental PK Parameters
PK Parameter
Analysis Scale
nirmatrelvir and ritonavir
AUClast
ln
A, D
AUCinf*
ln
A, D
AUC12
ln
D
Cmax
ln
A, D
Tmax
R
D
t1/2*
R
D
CL/F*
ln
D
Vz/F*
ln
D


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Key:
A=analyzed using statistical model, D=displayed with descriptive statistics,
ln=natural-log transformed, R=raw (untransformed), *=if data permits.
6.3.2. PD Endpoints
None.
6.4. Covariates
None.
7. HANDLING OF MISSING VALUES
For the analysis of safety endpoints, the sponsor data standard rules for imputation will be 
applied.
7.1. Concentrations Below the Limit of Quantification
In all data presentations (except listings), concentrations below the limit of quantification 
(BLQ) will be set to zero.  (In listings BLQ values will be reported as “<LLQ”, where LLQ 
will be replaced with the value for the lower limit of quantification.)
7.2. Deviations, Missing Concentrations and Anomalous Values
In summary tables and plots of median profiles, statistics will be calculated having set 
concentrations to missing if 1 of the following cases is true:
1. A concentration has been collected as ND (ie, not done) or NS (ie, no sample).
2. A deviation in sampling time is of sufficient concern or a concentration has been 
flagged anomalous by the pharmacokineticist.
Note that summary statistics will not be presented at a particular time point if more than 
50% of the data are missing.
7.3. Pharmacokinetic Parameters
Actual PK sampling times will be used in the derivation of PK parameters.
If a PK parameter cannot be derived from a participant’s concentration data, the parameter 
will be coded as NC (ie, not calculated). (Note that NC values will not be generated beyond 
the day that a participant discontinues.)
In summary tables, statistics will be calculated by setting NC values to missing; and statistics 
will be presented for a particular treatment with ≥3 evaluable measurements. For statistical 
analyses (ie, analysis of variance), PK parameters coded as NC will also be set to missing; 
and analyses will not be performed for a particular parameter if more than 50% of the data 
are NC.


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If an individual participant has a known biased estimate of a PK parameter (due for example 
to an unexpected event such as vomiting before all the compound is adequately absorbed in 
the body), this will be footnoted in summary tables and will not be included in the calculation 
of summary statistics or statistical analyses.
8. STATISTICAL METHODOLOGY AND STATISTICAL ANALYSES
8.1. Statistical Methods
8.2. Statistical Analyses
For the primary objective, natural log transformed AUCinf (if data permits), AUClast and Cmax
for nirmatrelvir and ritonavir will be analyzed using a mixed effect model with sequence, 
period and treatment as fixed effects and participant within sequence as a random effect. 
Estimates of the adjusted mean differences (Test-Reference) and corresponding 90% 
confidence intervals will be obtained from the model. The adjusted mean differences and 
90% confidence intervals for the differences will be exponentiated to provide estimates of the 
ratio of adjusted geometric means (Test/Reference) and 90% confidence intervals for the 
ratios. Treatment A will be the Reference treatment while Treatments B, C, D and E will be 
the Test treatments.
PK parameters, including plasma AUCinf (if data permits), AUClast, Cmax, 
(if data 
permits) of nirmatrelvir and ritonavir will be summarized descriptively by analyte and 
treatment. Box and whisker plots for AUCinf (if data permits), AUClast, and Cmax, will be 
plotted by treatment.
Residuals from the model will be examined for normality and the presence of outliers via 
visual inspection of plots of residuals vs predicted values and normal probability plots of 
residuals but these will not be included in the clinical study report. If there are major 
deviations from normality or outliers then the effect of these on the conclusions will be 
investigated through alternative transformations and/or analyses excluding outliers.  
Justification for any alternative to the planned analysis will be given in the report of the 
study.
Table 2.
PK Parameters to be Summarized Descriptively by Analyte and 
Treatment
Parameter
Summary Statistics
AUCinf, AUClast, 
AUC12, Cmax, 
N, arithmetic mean, median, cv%, standard deviation, minimum, 
maximum, geometric mean and geometric cv%.
 
For AUCinf (if data permits), AUClast, and Cmax, a listing of the individual participant ratios 
(Test/Reference) will be provided. 
CCI
CCI
C
CI


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Supporting data from the estimation of
 AUCinf or AUClast will be listed by analyte and 
treatment: terminal phase rate constant (kel); goodness of fit statistic from the log-linear 
regression (r2); the percent of AUCinf based on extrapolation (AUCextrap%); and the first, last, 
and number of time points used in the estimation of kel. This data may be included in the 
clinical study report.
Presentations for nirmatrelvir and ritonavir concentrations separately will include:

A listing of all concentrations sorted by participant ID, period and nominal time 
postdose. The concentration listing will also include the actual times. Deviations from 
the nominal time will be given in a separate listing.

A summary of concentrations by treatment and nominal time postdose, where the set 
of statistics will include n, mean, median, standard deviation, coefficient of variation 
(cv), minimum, maximum and the number of concentrations above the lower limit of 
quantification.

Median concentrations time plots (on both linear and semi-log scales) against 
nominal time postdose by treatment (all treatments on the same plot per scale, based 
on the summary of concentrations by treatment and time postdose).

Mean concentrations time plots (on both linear and semi-log scales) against nominal 
time postdose by treatment (all treatments on the same plot per scale, based on the 
summary of concentrations by treatment and time postdose).

Individual concentration time plots by treatment (on both linear and semi-log scales) 
against actual time postdose (there will be separate spaghetti plots for each treatment
per scale).

Individual concentration time plots by participant (on both linear and semi-log scales) 
against actual time postdose [there will be separate plots for each participant
(containing all treatments) per scale].
For summary statistics, median and mean plots 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.
 
8.3. Safety Analysis
A set of summary tables split by treatment will be produced to evaluate any potential risk 
associated with the safety and toleration of administering study treatments.
CC
I
CCI


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8.3.1. Treatment and Disposition of Participants
Participant evaluation groups will show end of study participant disposition and will show 
which participants were analyzed for pharmacokinetics, as well as for safety (adverse events 
and laboratory data). Frequency counts will be supplied for participant discontinuation(s) by 
treatment.
Data will be reported in accordance with the sponsor reporting standards.
8.3.2. Demographic and Clinical Examination Data
A breakdown of demographic data will be provided for age, race, weight, body mass index, 
and height. Each will be summarized by sex at birth and ‘All Participants’ in accordance with 
the sponsor reporting standards.
8.3.3. Discontinuation(s)
Participant discontinuations, temporary discontinuations or dose reductions due to adverse 
events will be detailed and summarized by treatment.
Data will be reported in accordance with the sponsor reporting standards.
8.3.4. Adverse Events
Adverse events will be reported in accordance with the sponsor reporting standards by 
treatment.
8.3.5. Laboratory Data
The baseline is defined as measurement taken on Day -1 of Period 1.
Laboratory data will be listed in accordance with the sponsor reporting standards.
8.3.6. Vital Signs Data
The baseline is defined as pre-dose measurement taken on Day 1 of each period.
Supine blood pressure, pulse rate and temperature will be measured at the protocol specified 
timepoints.
These data will be listed in accordance with the sponsor reporting standards.
8.3.7. ECG Data
The baseline is defined as pre-dose measurement taken on Day 1 of Period 1.
ECG data will be listed in accordance with the sponsor reporting standards.
8.3.8. Other Safety Data
None.


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8.3.9. Concomitant Treatments
All concomitant medication(s) as well as non-drug treatment(s) will be provided in the 
listings.
8.3.10. Screening and Other Special Purpose Data
The screening data will not be brought in-house, and therefore will not be listed.
8.3.11. Banked Bio specimens
Banked bio specimens will be collected for the purpose of conducting research in future. This 
data will not be reported in the Clinical study report.


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9. REFERENCES
None.


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10. APPENDICES
Appendix 1. SAS CODE FOR ANALYSES

An example of the PROC MIXED code is provided below:
proc mixed data=tab.pk;
class seq period trt subject;
model l&var= seq period trt / ddfm=KR;
            random subject(seq) / subject = subject(seq);
lsmeans trt;
estimate ' B vs A' trt  -1  1  0  0  0;
estimate ' C vs A' trt  -1  0  1  0  0;
estimate ' D vs A' trt  -1  0  0  1  0;
estimate ' E vs A' trt  -1  0  0  0  1;
ods 'Estimates' out=est&var;
ods 'lsmeans' out=ls&var;
            ods 'covparms' out = cov&var;
ods 'tests3'       out = tst&var;
run;
/* Letter assignments for treatments (trt) within the estimate statement above are as 
follows;
A= Single oral dose of nirmatrelvir/ritonavir 300 (2 × 150)/100 mg commercial 
tablets under fasted conditions (Reference)
B = Single oral dose of nirmatrelvir/ritonavir 300/100 mg (2 × 150/50 mg) FDC 
tablets Test formulation 1 (low disintegrant) under fasted conditions (Test 1)
C = Single oral dose of nirmatrelvir/ritonavir 300/100 mg (2 × 150/50 mg) FDC 
tablets Test formulation 2 (high disintegrant) under fasted conditions (Test 2)
D = Single oral dose of nirmatrelvir/ritonavir 300/100 mg (2 × 150/50 mg) FDC 
tablets Test formulation 3 (high drug loading) under fasted conditions (Test 3)
E = Single oral dose of nirmatrelvir/ritonavir 300/100 mg (3 × 100/33.3 mg) FDC 
tablets Test formulation 4 under fasted conditions (Test 4) */;