Clinical trial NCT05544786
Conditions: Biological Availability
Keywords: Coronavirus disease 2019 (COVID-19) Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Nirmatrelvir Paxlovid
Sponsor: Pfizer
Start date: 2022-09-28; Completion date: 2022-11-29
Enrollment: 12 participants; Allocation: RANDOMIZED; Intervention model: CROSSOVER

Brief summary:
The purpose of this study is to estimate the relative bioavailability (rBA) of nirmatrelvir/ritonavir oral powder in 3 different food vehicles relative to the Paxlovid® tablets under fasted condition in healthy adult participants, and to estimate the effect of food on the rBA of the nirmatrelvir/ritonavir oral powder formulation. The study will also assess the safety, tolerability, and palatability of nirmatrelvir/ritonavir oral powder in healthy adult participants.

Detailed description:

Arms: arm 1: Nirmatrelvir and ritonavir tablets arm 2: Nirmatrelvir/ritonavir with water arm 3: Nirmatrelvir/ ritonavir with infant formula arm 4: Nirmatrelvir/ ritonavir with vanilla pudding arm 5: Nirmatrelvir/ ritonavir with food and vanilla pudding
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 mixed in water under fasted condition intervention 3: Single oral dose of nirmatrelvir/ritonavir mixed in infant formula under fasted condition intervention 4: Single oral dose of nirmatrelvir/ritonavir mixed in vanilla pudding under fasted condition intervention 5: Single oral dose of nirmatrelvir/ritonavir mixed in vanilla pudding under fed condition

Protocol documents:
Prot_000.pdf: 
Nirmatrelvir
Protocol C4671036
Final Protocol 19 July 2022
PFIZER CONFIDENTIAL
Page 1
Title Page
A PHASE 1, OPEN-LABEL, RANDOMIZED, SINGLE DOSE, CROSSOVER STUDY 
TO ESTIMATE THE RELATIVE BIOAVAILABILITY OF NIRMATRELVIR
(PF-07321332) /RITONAVIR ORAL POWDER IN 3 DIFFERENT FOOD DELIVERY 
VEHICLES RELATIVE TO THE NIRMATRELVIR (PF-07321332) /RITONAVIR
COMMERCIAL TABLETS UNDER FASTED CONDITIONS, AND THE EFFECT 
OF FOOD ON RELATIVE BIOAVAILABILITY OF NIRMATRELVIR
(PF-07321332) /RITONAVIR ORAL POWDER IN HEALTHY ADULT 
PARTICIPANTS 
Study Intervention Number:
Nirmatrelvir (PF-07321332)
Study Intervention Name:
NA
US IND Number:
153517
EudraCT Number:
2022-002497-86
ClinicalTrials.gov ID:
NA
Pediatric Investigational Plan Number:
NA
Protocol Number:
C4671036
Phase:
1
Brief Title: A Phase 1 Relative Bioavailability Study of Nirmatrelvir/Ritonavir Oral 
Powder Relative to the Nirmatrelvir/Ritonavir Commercial Tablets, and Estimation of 
the Effect of Food on Bioavailability of the Nirmatrelvir/Ritonavir Oral Powder 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
Protocol C4671036
Final Protocol 19 July 2022
PFIZER CONFIDENTIAL
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Document History
Document
Version Date
Original protocol
19 July 2022


Nirmatrelvir
Protocol C4671036
Final Protocol 19 July 2022
PFIZER CONFIDENTIAL
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TABLE OF CONTENTS
LIST OF TABLES.....................................................................................................................8
1. PROTOCOL SUMMARY.....................................................................................................9
1.1. Synopsis ....................................................................................................................9
1.2. Schema ....................................................................................................................15
1.3. Schedule of Activities .............................................................................................16
2. INTRODUCTION ...............................................................................................................21
2.1. Study Rationale .......................................................................................................21
2.2. Background .............................................................................................................21
2.2.1. Nonclinical Pharmacology..........................................................................21
2.2.2. Nonclinical Pharmacokinetics and Metabolism .........................................21
2.2.3. Nonclinical Safety ......................................................................................22
2.2.4. Clinical Overview.......................................................................................22
2.2.4.1. Safety Overview........................................................................23
2.2.4.2. Summary of Nirmatrelvir Pharmacokinetics in Human............24
2.3. Benefit/Risk Assessment.........................................................................................26
2.3.1. Risk Assessment.........................................................................................27
3. OBJECTIVES AND ENDPOINTS.....................................................................................29
4. STUDY DESIGN.................................................................................................................30
4.1. Overall Design.........................................................................................................30
4.2. Scientific Rationale for Study Design.....................................................................32
4.2.1. Choice of Contraception/Barrier Requirements .........................................32
4.2.2. Collection of Retained Research Samples..................................................32
4.3. Justification for Dose ..............................................................................................33
4.4. End of Study Definition ..........................................................................................33
5. STUDY POPULATION......................................................................................................33
5.1. Inclusion Criteria.....................................................................................................33
5.2. Exclusion Criteria....................................................................................................34
5.3. Lifestyle Considerations..........................................................................................37
5.3.1. Contraception..............................................................................................37
5.3.2. Meals and Dietary Restrictions...................................................................37
5.3.3. Caffeine, Alcohol, and Tobacco .................................................................38


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5.3.4. Activity .......................................................................................................38
5.4. Screen Failures ........................................................................................................38
6. STUDY INTERVENTION(S) AND CONCOMITANT THERAPY.................................39
6.1. Study Intervention(s) Administered........................................................................39
6.1.1. Administration............................................................................................40
6.2. Preparation, Handling, Storage, and Accountability...............................................41
6.2.1. Preparation and Dispensing........................................................................42
6.3. Assignment to Study Intervention...........................................................................43
6.4. Blinding...................................................................................................................43
6.5. Study Intervention Compliance...............................................................................43
6.6. Dose Modification...................................................................................................43
6.7. Continued Access to Study Intervention After the End of the Study......................43
6.8. Treatment of Overdose............................................................................................43
6.9. Prior and Concomitant Therapy..............................................................................44
6.9.1. Rescue Medicine.........................................................................................44
7. DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL...........................................................................45
7.1. Discontinuation of Study Intervention ....................................................................45
7.1.1. ECG Changes..............................................................................................45
7.1.2. Potential Cases of Acute Kidney Injury .....................................................45
7.1.3. Stopping Rules............................................................................................46
7.2. Participant Discontinuation/Withdrawal From the Study.......................................46
7.2.1. Withdrawal of Consent...............................................................................47
7.3. Lost to Follow-up....................................................................................................47
8. STUDY ASSESSMENTS AND PROCEDURES...............................................................48
8.1. Administrative Procedures ......................................................................................48
8.2. Efficacy Assessments..............................................................................................49
8.3. Safety Assessments .................................................................................................49
8.3.1. Physical Examinations................................................................................49
8.3.2. Vital Signs ..................................................................................................50
8.3.2.1. Blood Pressure and Pulse Rate..................................................50
8.3.3. Electrocardiograms.....................................................................................50


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8.3.4. Clinical Safety Laboratory Assessments ....................................................51
8.3.5. COVID-19 Specific Assessments...............................................................51
8.3.6. Pregnancy Testing ......................................................................................52
8.4. Adverse Events, Serious Adverse Events, and Other Safety Reporting .................52
8.4.1. Time Period and Frequency for Collecting AE and SAE Information.......52
8.4.1.1. Reporting SAEs to Pfizer Safety...............................................53
8.4.1.2. Recording Nonserious AEs and SAEs on the CRF...................53
8.4.2. Method of Detecting AEs and SAEs ..........................................................54
8.4.3. Follow-Up of AEs and SAEs......................................................................54
8.4.4. Regulatory Reporting Requirements for SAEs...........................................54
8.4.5. Environmental Exposure, Exposure During Pregnancy or 
Breastfeeding, and Occupational Exposure.....................................................54
8.4.5.1. Exposure During Pregnancy......................................................55
8.4.5.2. Exposure During Breastfeeding ................................................56
8.4.5.3. Occupational Exposure .............................................................57
8.4.6. Cardiovascular and Death Events...............................................................57
8.4.7. Disease-Related Events and/or Disease-Related Outcomes Not 
Qualifying as AEs or SAEs..............................................................................57
8.4.8. Adverse Events of Special Interest.............................................................57
8.4.8.1. Lack of Efficacy........................................................................57
8.4.9. Medical Device Deficiencies......................................................................57
8.4.9.1. Time Period for Detecting Medical Device Deficiencies .........57
8.4.9.2. Follow-Up of Medical Device Deficiencies..............................57
8.4.9.3. Prompt Reporting of Device Deficiencies to the Sponsor ........58
8.4.9.4. Regulatory Reporting Requirements for Device 
Deficiencies .......................................................................................58
8.4.10. Medication Errors.....................................................................................58
8.5. Pharmacokinetics ....................................................................................................59
8.5.1. Plasma for Analysis of Nirmatrelvir and Ritonavir....................................59
8.6. Genetics...................................................................................................................60
8.6.1. Specified Genetics ......................................................................................60
8.6.2. Retained Research Samples for Genetics ...................................................60
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8.7.1. Specified Gene Expression (RNA) Research .............................................60
8.7.2. Specified Protein Research.........................................................................60
8.7.3. Specified Metabolomic Research ...............................................................60
8.8. Immunogenicity Assessments.................................................................................61
8.9. Health Economics ...................................................................................................61
8.10. Taste Assessment of Nirmatrelvir Oral Powder....................................................61
9. STATISTICAL CONSIDERATIONS ................................................................................61
9.1. Statistical Hypotheses .............................................................................................61
9.2. Analysis Sets ...........................................................................................................61
9.3. Statistical Analyses .................................................................................................62
9.3.1. Pharmacokinetic Analyses..........................................................................62
9.3.1.1. Derivation of Pharmacokinetic Parameters...............................62
9.3.2. Statistical Methods for PK Data .................................................................63
9.3.3. Other Safety Analyses ................................................................................63
9.3.4. Other Analyse(s).........................................................................................64
9.3.4.1. Taste Assessment ......................................................................64
9.3.4.2. Biomarker Assessment..............................................................64
9.4. Interim Analyses .....................................................................................................64
9.5. Sample Size Determination.....................................................................................64
10. SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS..........................................................................................................66
10.1. Appendix 1: Regulatory, Ethical, and Study Oversight Considerations...............66
10.1.1. Regulatory and Ethical Considerations ....................................................66
10.1.1.1. Reporting of Safety Issues and Serious Breaches of the 
Protocol or ICH GCP.........................................................................66
10.1.2. Financial Disclosure .................................................................................67
10.1.3. Informed Consent Process ........................................................................67
10.1.4. Data Protection .........................................................................................68
10.1.5. Committees Structure ...............................................................................68
10.1.5.1. Data Monitoring Committee ...................................................68
10.1.6. Dissemination of Clinical Study Data ......................................................68
10.1.7. Data Quality Assurance ............................................................................69
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10.1.8. Source Documents....................................................................................71
10.1.9. Study and Site Start and Closure ..............................................................71
10.1.10. Publication Policy...................................................................................72
10.1.11. Sponsor’s Medically Qualified Individual..............................................73
10.2. Appendix 2: Clinical Laboratory Tests .................................................................74
10.3. Appendix 3: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-Up, and Reporting .....................................................................75
10.3.1. Definition of AE .......................................................................................75
10.3.2. Definition of an SAE ................................................................................76
10.3.3. Recording/Reporting and Follow-Up of AEs and/or SAEs During 
the Active Collection Period............................................................................77
10.3.4. Reporting of SAEs....................................................................................81
10.4. Appendix 4: Contraceptive and Barrier Guidance ................................................82
10.4.1. Male Participant Reproductive Inclusion Criteria....................................82
10.4.2. Female Participant Reproductive Inclusion Criteria.................................82
10.4.3. Woman of Childbearing Potential ............................................................82
10.4.4. Contraception Methods.............................................................................83
10.5. Appendix 5: Genetics............................................................................................85
10.6. Appendix 6: Liver Safety: Suggested Actions and Follow-Up Assessments .......86
10.7. Appendix 7: Kidney Safety: Monitoring Guidelines ............................................88
10.7.1. Laboratory Assessment of Change in Kidney Function and 
Detection of Kidney Injury..............................................................................88
10.7.2. Age-Specific Kidney Function Calculation Recommendations...............88
10.7.2.1. Adults (18 Years and Above)—2021 CKD-EPI 
Equations ...........................................................................................88
10.7.2.2. Adolescents (12 Years to <18 Years)—Cockcroft-Gault 
Formula..............................................................................................89
10.7.2.3. Children (2 Years to <12 Years)—Modified Schwartz 
Equation.............................................................................................89
10.7.2.4. Infants (1 Month to <2 Years) and Neonates (<1 
Month)—Bedside Schwartz Equation...............................................89
10.7.3. Adverse Event Grading for Kidney Safety Laboratory 
Abnormalities...................................................................................................89
10.8. Appendix 8: ECG Findings of Potential Clinical Concern ...................................90


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10.9. Appendix 9: Palatability Questionnaire ................................................................92
10.10. Appendix 10: Abbreviations .............................................................................100
11. REFERENCES ................................................................................................................104
LIST OF TABLES
Table 1.
Study Schedule of Assessment.................................................................16
Table 2.
Pharmacokinetic Sampling Schema .........................................................20
Table 3.
Randomized Treatment Sequences...........................................................31
Table 4.
Plasma Nirmatrelvir and Ritonavir PK Parameters Definitions...............62
Table 5.
Protocol-Required Safety Laboratory Assessments .................................74


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Final Protocol 19 July 2022
PFIZER CONFIDENTIAL
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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 (PF-07321332)/Ritonavir Oral Powder 
in 3 Different Food Delivery Vehicles Relative to the Nirmatrelvir/Ritonavir Commercial 
Tablets Under Fasted Conditions and the Effect of Food on Relative Bioavailability of 
Nirmatrelvir (PF-07321332) /Ritonavir Oral Powder in Healthy Adult Participants
Brief Title: A Phase 1 Relative Bioavailability Study of Nirmatrelvir/Ritonavir Oral Powder 
Relative to the Nirmatrelvir/Ritonavir Commercial Tablets, and Estimation of the Effect of 
Food on Bioavailability of the Nirmatrelvir/Ritonavir Oral Powder in Healthy Participants.
Regulatory Agency Identification Number(s):
US IND Number:
153517
EudraCT Number:
2022-002497-86
ClinicalTrials.gov ID:
NA
Pediatric Investigational Plan Number:
NA
Protocol Number:
C4671036
Phase:
1
Rationale:
Nirmatrelvir, a potent and selective inhibitor of the SARS-CoV-2 Mpro is being developed as 
an oral treatment for COVID-19. Ritonavir is a strong CYP3A4 inhibitor being used to 
inhibit the metabolism of nirmatrelvir in order to increase plasma concentrations of 
nirmatrelvir sufficient to suppress viral replication through the entire dosing interval. 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 impaired participants (C4671010) and 
2 Phase 2/3 pivotal studies in COVID-19 patients (C4671005 and C4671006).
The purpose of this study is to estimate the rBA of nirmatrelvir/ritonavir oral powder in 
3 different food vehicles relative to the Paxlovid® tablets under fasted condition in healthy 
adult participants, and to estimate the effect of food on the rBA of the nirmatrelvir/ritonavir 
oral powder formulation. The study will also assess the safety, tolerability, and palatability of 
nirmatrelvir/ritonavir oral powder in healthy adult participants.


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Final Protocol 19 July 2022
PFIZER CONFIDENTIAL
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Objectives and Endpoints:
Objectives
Endpoints
Primary: 
Primary:
•
To estimate the rBA of the nirmatrelvir/ritonavir 
 oral powder mixed with water compared 
to the nirmatrelvir/ritonavir 
 
commercial tablets under fasted conditions.
•
To estimate the rBA of the nirmatrelvir/ritonavir 
 oral powder mixed with infant formula 
compared to the nirmatrelvir/ritonavir 
 commercial tablets under 
fasted conditions.
•
To estimate the rBA of the nirmatrelvir/ritonavir 
 oral powder mixed with vanilla pudding 
compared to the nirmatrelvir/ritonavir 
 commercial tablets under 
fasted conditions.
•
To estimate the rBA of the nirmatrelvir/ritonavir 
 oral powder mixed with vanilla pudding 
under fed conditions compared to the 
nirmatrelvir/ritonavir 
 
commercial tablets under fasted conditions.
•
The test/reference ratios for AUCinf (if data 
permits), AUClast, and Cmax of nirmatrelvir 
and ritonavir.
Secondary: 
Secondary:
•
To estimate the effect of food on the rBA of the 
nirmatrelvir/ritonavir 
 oral powder mixed 
with vanilla pudding.
•
To evaluate the safety and tolerability of 
nirmatrelvir/ritonavir in healthy participants.
•
To assess the palatability of nirmatrelvir/ritonavir oral 
powder mixed with water/ infant formula/ vanilla 
pudding.
•
The test/reference ratios for AUCinf (if data 
permits), AUClast, and Cmax of nirmatrelvir 
and ritonavir.
•
Assessment of TEAEs, clinical laboratory 
abnormalities, vital signs, PEs, and 12 lead 
ECGs.
•
Assessment of palatability via questionnaire: 
mouth feel, bitterness, tongue/mouth burn, 
throat burn and overall liking.
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Objectives
Endpoints
 
 
 
 
 
Overall Design:
This is a Phase 1, open-label, single dose, randomized, crossover study in healthy adult 
participants to estimate rBA of nirmatrelvir/ritonavir 
 oral powder mixed with 
3 different delivery vehicles (Test formulations) compared to the nirmatrelvir/ritonavir 
 commercial tablets (Reference formulation) under fasted
conditions, and to estimate the effect of food on the rBA of nirmatrelvir/ritonavir 
 oral powder mixed with vanilla pudding. The study will also assess the 
safety, tolerability, and palatability of nirmatrelvir/ritonavir oral powder in healthy adult 
participants.
The study will consist of 5 treatments: 
•
A single oral dose of nirmatrelvir/ritonavir 
tablets under 
fasted condition (Treatment A)
•
A single oral dose of nirmatrelvir/ritonavir 
 oral powder mixed in 
water under fasted condition (Treatment B)
•
A single oral dose of nirmatrelvir/ritonavir 
 oral powder mixed in 
infant formula under fasted condition (Treatment C)
•
A single oral dose of nirmatrelvir/ritonavir 
 oral powder mixed in 
vanilla pudding under fasted condition (Treatment D)
•
A single oral dose of nirmatrelvir/ritonavir 
 oral powder mixed in 
vanilla pudding under fed condition (Treatment E)
Between each treatment, a minimum of 4 days washout is required to minimize any residual 
nirmatrelvir and ritonavir concentrations prior to start of the next treatment.
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Approximately 12 healthy adult male and/or female participants will be 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 PE, vital signs, 12-lead ECG, and clinical laboratory 
evaluations will determine eligibility. Eligible participants will be admitted to the CRU on
Period 1 Day -1 and will be confined in the CRU until discharge which is Day 4 of Period 5.
On Day 1 of each period, participants will receive a single oral dose of study interventions 
nirmatrelvir/ritonavir 
as per the randomization schedule.
Study treatments A, and D will be administered with approximately 240 mL of ambient 
temperature water and study treatments B and C will be administered with approximately 
210 mL of ambient temperature water under fasted conditions (10 hours overnight fast and 
no food until 4 hours after dosing). Study treatments E will be administered with 
approximately 240 mL of ambient temperature water approximately 30 minutes after the start 
of a standard high-fat, high-calorie breakfast. Serial PK samples will be collected up to 
72 hours post dose. Participants will be discharged from the CRU on Period 5, Day 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 CRU
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 12 participants will be randomly assigned to study intervention such that 
approximately 2 participants will be enrolled into 1 of 6 sequences.
Note: "Enrolled" means a participant's agreement to participate in a clinical study following 
completion of the informed consent process and screening. A participant will be considered 
enrolled if the informed consent is not withdrawn prior to participating in any study activity
after screening. Potential participants who are screened for the purpose of determining 
eligibility for the study, but do not participate in the study, are not considered enrolled, unless 
otherwise specified by the protocol.
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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 ECG.
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:
Each enrolled participant will participate in 5 study periods to receive 5 different treatments 
according to the sequence determined by randomization: 
•
Treatment A: Single oral dose of nirmatrelvir/ritonavir 
tablets under fasted condition 
•
Treatment B: Single oral dose of nirmatrelvir/ritonavir 
 oral powder 
mixed in water under fasted condition
•
Treatment C: Single oral dose of nirmatrelvir/ritonavir 
 oral powder 
mixed in infant formula under fasted condition
•
Treatment D: Single oral dose of nirmatrelvir/ritonavir 
 oral powder 
mixed in vanilla pudding under fasted condition 
•
Treatment E: Single oral dose of nirmatrelvir/ritonavir 
 oral powder 
mixed in vanilla pudding under fed condition
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Participants will be randomly assigned to 1 of 6 sequences as below: 
Treatment 
Sequence
Period 1
Period 2
Period 3
Period 4
Period 5
Sequence 1 (N = 2)
Treatment A
Treatment B
Treatment C
Treatment D
Treatment E
Sequence 2 (N = 2)
Treatment B
Treatment C
Treatment A
Treatment D
Treatment E
Sequence 3 (N = 2)
Treatment C
Treatment A
Treatment B
Treatment D
Treatment E
Sequence 4 (N = 2)
Treatment A
Treatment C
Treatment B
Treatment E
Treatment D
Sequence 5 (N = 2)
Treatment B
Treatment A
Treatment C
Treatment E
Treatment D
Sequence 6 (N = 2)
Treatment C
Treatment B
Treatment A
Treatment E
Treatment D
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 5, 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.
Study Intervention(s)
Intervention Name
Nirmatrelvir Tablets
Ritonavir Tablets
Nirmatrelvir Oral 
Powder
Ritonavir Oral 
Powder
Arm Name
(group of participants 
receiving a specific 
treatment or no 
treatment)
nirmatrelvir/ritonavir 
commercial tablets 
nirmatrelvir/ritonavir 
commercial tablets 
nirmatrelvir/ritonavir
oral powder
nirmatrelvir/ritonavir
oral powder
Unit Dose Strength(s)
 
 
Route of 
Administration
Oral
Oral
Oral
Oral
IMP or NIMP/AxMP
IMP
NIMP
IMP
IMP
Former name
PF-07321332
PF-07321332
Study Arm(s)
Arm Title
Nirmatrelvir/ 
ritonavir
commercial tablets
Nirmatrelvir/ 
ritonavir oral 
powder mixed 
with water
Nirmatrelvir/ 
ritonavir oral 
powder mixed 
with infant 
formula
Nirmatrelvir/ 
ritonavir oral powder 
mixed with vanilla 
pudding (fasted)
Nirmatrelvir/ 
ritonavir oral 
powder mixed 
with vanilla 
pudding (fed)
Arm Type
Reference
Experimental
Experimental
Experimental
Experimental
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Study Arm(s)
Arm 
Description
Single oral dose of 
nirmatrelvir/ 
ritonavir 
ommercial 
tablets under fasted 
conditions 
Single oral dose 
of nirmatrelvir/ 
ritonavir 
 
 oral 
powder mixed 
with water under 
fasted 
conditions 
Single oral dose 
of nirmatrelvir/ 
ritonavir 
 
 oral 
powder mixed 
with infant 
formula under 
fasted conditions 
Single oral dose of 
nirmatrelvir/ ritonavir 
 oral 
powder mixed with 
vanilla pudding under 
fasted conditions 
Single oral dose 
of nirmatrelvir/ 
ritonavir 
 
oral 
powder mixed 
with vanilla 
pudding under 
fed conditions 
Statistical Methods:
Natural log transformed AUCinf (if data permits), AUClast and Cmax 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.
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 of 
nirmatrelvir.
Based on data from Study C4671001, C4671019, C4671024, C4671005 and C4671006, 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. 
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.
Table 1.
Study Schedule of Assessment
Visit Identifier
Abbreviations 
used in this table 
may be found in 
Appendix 10
Screening
Period 1 
Period 2, 3 and 4
Period 5
F/U
E/T
Notes
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 
Days

Screening will be performed within 28 days prior to the 
first dose of nirmatrelvir/ritonavir. 

Follow-up contact may occur via telephone contact and 
must occur 28 to 35 days from administration of the 
final dose of study intervention.
Informed consent
X

Informed consent should be obtained prior to 
undergoing any study-specific procedures
CRU 
Confinement
X











X
X

Participants will be admitted to the CRU on Period 1 
Day -1. Participants will be discharged on Period 5
Day 4 following the final assessments.
Inclusion/
exclusion criteria
X
X

See Sections 5.1 and 5.2 for additional information.
Medical/
medication 
history (update)
X
X

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.
Demography
X

Demographics will include participant race, ethnicity, 
age, and gender during the Screening visit. 


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Table 1.
Study Schedule of Assessment
Visit Identifier
Abbreviations 
used in this table 
may be found in 
Appendix 10
Screening
Period 1 
Period 2, 3 and 4
Period 5
F/U
E/T
Notes
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 
Days

Screening will be performed within 28 days prior to the 
first dose of nirmatrelvir/ritonavir. 

Follow-up contact may occur via telephone contact and 
must occur 28 to 35 days from administration of the 
final dose of study intervention.
Physical Exam
X
X

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. 
Safety laboratory
X
X
X
X

Safety laboratory assessments including urinalysis, 
hematology, and chemistry will be performed at 
Screening, Period 1 Day -1, Period 5 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.
FSH
(postmenopausal 
women only)
X

For confirmation of postmenopausal (amenorrheic for at 
least 12 consecutive months) female participants.
Urine drug 
testing
X
X

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.
Serology: 
HBsAg, HBsAb, 
HBcAb, HCVAb, 
and HIV
X

HBsAb will be tested if HBsAg and/or HBcAb are 
positive. 
Pregnancy test 
(WOCBP only)
X
X
X
X


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Table 1.
Study Schedule of Assessment
Visit Identifier
Abbreviations 
used in this table 
may be found in 
Appendix 10
Screening
Period 1 
Period 2, 3 and 4
Period 5
F/U
E/T
Notes
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 
Days

Screening will be performed within 28 days prior to the 
first dose of nirmatrelvir/ritonavir. 

Follow-up contact may occur via telephone contact and 
must occur 28 to 35 days from administration of the 
final dose of study intervention.
Contraception 
check
X
X
X
X
X

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 (Appendix 4).
12-lead ECG 
(single)
X
X
X
X

Single 12-lead ECG readings 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.

The reading on Period 1 Day 1 will be done predose of 
Period 1 Day 1.
Vital signs 
(BP/PR)
X
X
X
X
X
X

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 predose, 2 hours and 6 hours post dose on Day 1 
of each treatment period and also on Day 4 of Period 5. 
COVID-19 
questionnaire
X

Check COVID-19 related signs and symptoms as per 
local procedures. 
COVID-19 
testing
X
X

The testing for COVID-19 pathogen by RT-PCR will be 
performed as per local procedures.
Nirmatrelvir/
ritonavir dosing
X
X
X

Nirmatrelvir/ritonavir will be administered orally after 
overnight fasting of 10 hours on Day 1 for treatments A, 
B, C and D and after high fat breakfast for treatment E. 
There will be at least a 4 day washout between each 
dose.


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Table 1.
Study Schedule of Assessment
Visit Identifier
Abbreviations 
used in this table 
may be found in 
Appendix 10
Screening
Period 1 
Period 2, 3 and 4
Period 5
F/U
E/T
Notes
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 
Days
•
Screening will be performed within 28 days prior to the 
first dose of nirmatrelvir/ritonavir. 
•
Follow-up contact may occur via telephone contact and 
must occur 28 to 35 days from administration of the 
final dose of study intervention.
Palatability
questionnaire 
Review
X
X
•
Review palatability questionnaire and instructions with 
participants prior to the first taste assessment to 
Treatment B, C and D on Day 1 of period 1 or 2.
Palatability 
Questionnaire
X
X
X
•
Each participant will record the sensory attributes at 
timed intervals of 1 (immediately after dosing), 5, 10 
and 20 minutes after swallowing the suspension, using a 
Taste Assessment Questionnaire (see Appendix 9).
•
PK assessments will take priority if the PK and 
palatability assessment conflict
PK Blood 
Sampling for 
nirmatrelvir/ 
ritonavir
X
X
X
X
X
X
X
X
X
X
X
X
X
•
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 2.
 
 
 
 
 
 
 
 
 
 
 
 
Serious and 
nonserious AE 
monitoring
X
→
→
→
→
→
→
→
→
→
→
→
→
→
X
X
•
See Section 8.4.3 for follow-up AE and SAE 
assessments.
Concomitant 
treatments
X
X
X
→
→
→
→
→
→
→
→
→
→
X
X
X
•
See Section 6.9 for additional information.
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Table 1.
Study Schedule of Assessment
Visit Identifier
Abbreviations 
used in this table 
may be found in 
Appendix 10
Screening
Period 1 
Period 2, 3 and 4
Period 5
F/U
E/T
Notes
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 
Days

Screening will be performed within 28 days prior to the 
first dose of nirmatrelvir/ritonavir. 

Follow-up contact may occur via telephone contact and 
must occur 28 to 35 days from administration of the 
final dose of study intervention.
CRU discharge
X

Participants will be discharged from clinic on Day 4 of 
period 5 after collection of last PK sample.
Table 2.
Pharmacokinetic Sampling Schema
Visit Identifier
Treatment Period 1 to 5
Study Day
Day 1
Day 2
Day 3
Day 4
Planned Hours Post Dose on That Day
0
0.5
1
1.5
2
2.5
3
4
6
8
12
16
24
48
72
PK blood sampling for 
nirmatrelvir/ritonavir
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X


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2. INTRODUCTION
Nirmatrelvir a potent and selective inhibitor of the SARS-CoV-2 Mpro is 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 sufficient to suppress viral replication through the entire dosing interval. 
2.1. Study Rationale 
The purpose of this study is to estimate the rBA of nirmatrelvir/ritonavir oral powder in 
3 different food vehicles relative to the Paxlovid® tablets under fasted condition, and to 
estimate the effect of food on the rBA of the nirmatrelvir/ritonavir oral powder formulation
in healthy adult participants. The study will also assess the safety, tolerability, and 
palatability of nirmatrelvir/ritonavir oral powder 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 sufficient to 
suppress viral replication through the entire dosing interval. 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: 
eight Phase 1 studies in healthy participants (C4671001, C4671008, C4671019, C4671024, 
C4671012, C4671013, C4671014 and C4671015), one Phase 1 study in renal impairment 
participants (C4671011), one Phase 1 study in hepatic impairment participants (C4671010) 
and two Phase 2/3 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 
(rat, monkey, and human), and in vivo in rat and monkey after repeat oral dosing.
 
 
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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 were explored in Phase 1 studies in healthy adult 
participants (C4671001, C4671008, C4671012, C4671013, C4671014, C4671015, C4671019 
and C4671024), 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 volunteers. Efficacy and 
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safety of nirmatrelvir was evaluated in two interventional Phase 2/3 Studies (C4671005 and
C4671006).
Included in this Clinical Overview are summaries of the results of Study C4671001, 
C4671019, C4671024, and C4671005.
Study C4671001 was a 5-part study consisting of SAD (PART-1), MAD (PART-2), relative 
bioavailability/food effect (PART-3), metabolism and excretion study (PART-4) and 
supratherapeutic exposure cohort (PART-5). PART-1 and -2 are randomized, double-blind, 
sponsor-open, and placebo-controlled to evaluate safety, tolerability, and PK of single and 
multiple escalating oral doses of nirmatrelvir, respectively. PART-3 was randomized and 
open-label to evaluate relative bioavailability and food effect of an oral tablet formulation. 
PART-4 was an open-label, nonrandomized, single-period to evaluate the metabolism and 
excretion of nirmatrelvir. PART-5 was a double-blind, sponsor-open, randomized, crossover 
study to evaluate safety and tolerability at supratherapeutic exposures.
C4671019 was a Phase 1, open-label, single dose, randomized, 2-treatment, 2-sequence, 
2-period crossover study to evaluate the effect of a high-fat meal on the relative 
bioavailability of nirmatrelvir boosted with ritonavir following a single dose oral 
administration of nirmatrelvir in combination with ritonavir using 
 tablets of 
nirmatrelvir in healthy adult participants. 
C4671024 was a Phase 1, open-label, single dose, randomized, crossover study in healthy 
adult participants to estimate rBA of nirmatrelvir/ritonavir 
 oral powder 
mixed with 3 different delivery vehicles (Test formulations) compared to the nirmatrelvir 
/ritonavir commercial tablets (Reference formulation) under fasted conditions. 
C4671005 was a Phase 2/3 randomized, placebo-controlled trial in nonhospitalized adult 
participants with a laboratory-confirmed diagnosis of SARS-CoV-2 infection.
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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2.2.4.2. Summary of Nirmatrelvir Pharmacokinetics in Human
Study 1001- FIH
 
 
 
 
 
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Study 1019-Food Effects
 
 
 
 
 
 
 
 
 
Study 1024-Relative Bioavailability for oral powder formulation
 
 
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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, C4671024 and C4671005 and C4671006,
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. This 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. 


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Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
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. 
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. 


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3. OBJECTIVES AND ENDPOINTS
Objectives
Endpoints
Primary: 
Primary:
•
To estimate the rBA of the nirmatrelvir/ritonavir 
 oral powder mixed with water 
compared to the nirmatrelvir/ritonavir 
 commercial tablets under 
fasted conditions.
•
To estimate the rBA of the nirmatrelvir/ritonavir 
 oral powder mixed with infant formula 
compared to the nirmatrelvir/ritonavir 
 commercial tablets under 
fasted conditions.
•
To estimate the rBA of the nirmatrelvir/ritonavir 
 oral powder mixed with vanilla 
pudding compared to the nirmatrelvir/ritonavir 
 commercial tablets under 
fasted conditions.
•
To estimate the rBA of the nirmatrelvir/ritonavir 
 oral powder mixed with vanilla 
pudding under fed conditions compared to the 
nirmatrelvir/ritonavir 
 
commercial tablets under fasted conditions. 
•
The test/reference ratios for AUCinf (if data 
permits), AUClast, and Cmax of nirmatrelvir 
and ritonavir.
Secondary: 
Secondary:
•
To estimate the effect of food on the rBA of the 
nirmatrelvir/ritonavir 
 oral powder 
mixed with vanilla pudding.
•
To evaluate the safety and tolerability of 
nirmatrelvir/ritonavir in healthy participants.
•
To assess the palatability of nirmatrelvir/ritonavir oral 
powder mixed with water/infant formula/vanilla 
pudding.
•
The test/reference ratios for AUCinf (if data 
permits), AUClast, and Cmax of nirmatrelvir 
and ritonavir.
•
Assessment of TEAEs, clinical laboratory 
abnormalities, vital signs, PEs, and 12 lead 
ECGs.
•
Assessment of palatability via 
questionnaire: mouth feel, bitterness, 
tongue/mouth burn, throat burn and overall 
liking.
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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 nirmatrelvir/ritonavir 
 oral powder mixed with 
3 different food vehicles (Test formulations) compared to the nirmatrelvir/ritonavir 
 commercial tablets (Reference formulation) under fasted
conditions, and to estimate the effect of food on the rBA of the nirmatrelvir/ritonavir oral 
powder formulation mixed with vanilla pudding. The study will also assess the safety, 
tolerability, and palatability of nirmatrelvir/ritonavir in healthy adult participants.
Approximately 12 adult healthy male and/or female participants will be enrolled and 
randomized to 1 of 6 possible treatment sequences. 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. 
Each enrolled participant will participate in 5 study periods to receive 5 different treatments 
according to the sequence determined by randomization: 
•
Treatment A: Single oral dose of nirmatrelvir/ritonavir 
tablets under fasted condition 
•
Treatment B: Single oral dose of nirmatrelvir/ritonavir 
 oral powder 
mixed in water under fasted condition
•
Treatment C: Single oral dose of nirmatrelvir/ritonavir 
 oral powder 
mixed in infant formula under fasted condition
•
Treatment D: Single oral dose of nirmatrelvir/ritonavir 
 oral powder 
mixed in vanilla pudding under fasted condition 
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•
Treatment E: Single oral dose of nirmatrelvir/ritonavir 
 oral powder 
mixed in vanilla pudding under fed condition
Participants will be randomly assigned to 1 of 6 sequences as shown below in Table 3.
Participants will be discharged on Day 4 of Period 5, following completion of all 
assessments. Between each treatment, a minimum of 4 days washout is proposed to minimize 
any residual nirmatrelvir 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 3.
Randomized Treatment Sequences
Treatment 
Sequence
Period 1
Period 2
Period 3
Period 4
Period 5
Sequence 1 (N = 2)
Treatment A
Treatment B
Treatment C
Treatment D
Treatment E
Sequence 2 (N = 2)
Treatment B
Treatment C
Treatment A
Treatment D
Treatment E
Sequence 3 (N = 2)
Treatment C
Treatment A
Treatment B
Treatment D
Treatment E
Sequence 4 (N = 2)
Treatment A
Treatment C
Treatment B
Treatment E
Treatment D
Sequence 5 (N = 2)
Treatment B
Treatment A
Treatment C
Treatment E
Treatment D
Sequence 6 (N = 2)
Treatment C
Treatment B
Treatment A
Treatment E
Treatment D
Healthy participants will be screened to determine eligibility within 28 days prior to study 
treatment. Medical history and results of PE, vital signs, 12-lead ECG, and clinical laboratory 
evaluations will determine eligibility. Eligible participants will be admitted to the CRU on
Period 1 Day -1 and will be confined in the CRU until discharge which is Day 4 of Period 5.
On Day 1 of each period, participants will receive a single oral dose of study interventions
nirmatrelvir/ritonavir 
 as per the randomization schedule. Study treatments A 
and D will be administered with approximately 240 mL of ambient temperature water and 
treatments B and C will be administered with approximately 210 mL of ambient temperature 
water under fasted conditions (10 hours overnight fast and no food until 4 hours after 
dosing). Study treatment E will be administered with approximately 240 mL of ambient 
temperature water approximately 30 minutes after the start of a standard high-fat, 
high-calorie breakfast. Serial PK samples will be collected up to 72 hours post dose. 
Participants will be discharged from the CRU on Period 5, Day 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 CRU
until such abnormalities are deemed not clinically significant, or it is safe for outpatient 
follow-up. 
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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 oral powder is an alternative formulation for adult and pediatric 
patients who are not able to swallow nirmatrelvir/ritonavir commercial tablets. C4671024 
study results showed nirmatrelvir exposure is higher for oral powder mixed with apple sauce 
and vanilla pudding compared to commercial tablets (data on file). Specifically nirmatrelvir 
Cmax was 61% (90% CI 46%, 79%) higher and AUCinf was 25% (90% CI 16%, 35%) higher 
for nirmatrelvir/ritonavir oral powder mixed with vanilla pudding compared to 
nirmatrelvir/ritonavir commercial tablets. 
The objective of the study is to estimate the rBA of nirmatrelvir/ritonavir oral powder mixed 
with 3 different delivery vehicles (Test treatments) compared to nirmatrelvir/ritonavir 
commercial tablets (Reference treatment), and to estimate the effect of food on the rBA of 
the nirmatrelvir/ritonavir oral powder mixed with vanilla pudding. The study will also assess 
the safety, tolerability and palatability of nirmatrelvir/ritonavir oral powder in healthy adult 
participants.
Specifically for the food effect period of the study, the formulation to be tested should be 
administered on an empty stomach during one period and the high-fat meal during the 
alternate period. The FDA guidance for evaluation of a food effect on bioavailability 
recommends using meal conditions that are expected to provide the greatest effects on 
gastrointestinal physiology so that systemic drug availability is maximally affected. 
Therefore, a high-fat (approximately 50% of total caloric content of the meal), high-calorie 
(approximately 800 to 1000 calories) meal will be used for the evaluation of food effect in 
this study. 
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.


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4.3. Justification for Dose
The dose of nirmatrelvir/ritonavir 
 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 oral powder mixed with
3 different delivery vehicles compared to nirmatrelvir/ritonavir commercial tablet 
formulation in healthy adult participants at the approved therapeutic dose. The same dose 
was evaluated in C4671024 rBA study for oral powder. Therefore, a single oral dose
nirmatrelvir/ritonavir 
 will be used in this rBA study. 
4.4. End of Study Definition
The end of the study is defined as the date of 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 periods 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.
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Type of Participant and Disease Characteristics:
2. Male and female participants who are overtly healthy as determined by medical 
evaluation including medical history, physical exam, laboratory tests, vital signs and 
standard 12-lead ECG.
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.
Weight: 
5. BMI of 17.5 to 30.5 kg/m2; and a total body weight >50 kg (110 lb). 
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).

Any condition possibly affecting drug absorption (eg, gastrectomy, 
cholecystectomy). 

History of HIV infection, hepatitis B, or hepatitis C; positive testing for HIV, 
HBsAg, HBcAb or HCVAb. Hepatitis B vaccination is allowed.
3. 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 (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:
4. 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.
5. 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:
6. Previous administration with an investigational drug 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:
7. A positive urine drug test.
8. 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.
9. Baseline 12-lead ECG 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 brady arrhythmias or tachyarrhythmias). If the 
baseline uncorrected QT interval is >450 msec, this interval should be 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 


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should be overread by a physician experienced in reading ECGs before excluding a 
participant. 
10. 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;

T bili 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:
11. 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 or 3 ounces (90 mL) of wine).
12. Use of tobacco or nicotine containing products in excess of the equivalents of 
5 cigarettes per day or 2 chews of tobacco per day.
13. Blood donation (excluding plasma donations) of approximately 1 pint (500 mL) or 
more within 60 days prior to dosing. 
14. History of sensitivity to heparin or heparin-induced thrombocytopenia, nirmatrelvir, 
ritonavir, or any of the formulation components of nirmatrelvir, or ritonavir.
15. Unwilling or unable to comply with the criteria in the Lifestyle Considerations
section of this protocol.
16. 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. 
17. Pregnant or breastfeeding women.


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5.3. Lifestyle Considerations
The following guidelines are provided:
5.3.1. Contraception 
The investigator or his or her designee, in consultation with the participant, will confirm that 
the participant has selected an appropriate method of contraception for the individual 
participant and his or her partner(s) from the permitted list of contraception methods (see 
Appendix 4, Section 10.4.4) and will confirm that the participant has been instructed in its 
consistent and correct use. At time points indicated in 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.

For the fed periods (Treatment E) only, on Day 1, following an overnight fast of at 
least 10 hours, participants should begin breakfast approximately 30 minutes prior to 
nirmatrelvir/ritonavir administration. The breakfast will be consumed over 
approximately a 20-minute interval with nirmatrelvir/ritonavir administered within 
approximately 10 minutes of completion of the meal. Participants should finish the 
entire breakfast. 

For the fasted periods (Treatment A;B;C;D) only,on Day 1, following an overnight 
fast of at least 10 hours, participants should take the medications. 

Water is permitted until 1 hour prior to study intervention administration. Water may 
be consumed without restriction beginning 1 hour after dosing. Noncaffeinated drinks 
(except 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.


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
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.

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 of each study period. 

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 of each study period. 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 will be confined to the procedure room for the first 1 hour after dosing on 
Day 1 of each period, 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. 


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6. STUDY INTERVENTION(S) AND CONCOMITANT THERAPY
Study interventions are all prespecified  investigational and noninvestigational medicinal 
products/auxiliary medicinal products, medical devices, and other interventions (eg, surgical 
and behavioral) intended to be administered to the study participants during the study 
conduct. 
For the purposes of this protocol, study intervention refers to nirmatrelvir and ritonavir.
6.1. Study Intervention(s) Administered
Study Intervention(s)
Intervention Name
Nirmatrelvir 
Tablets
Ritonavir Tablets
Nirmatrelvir Oral 
Powder
Ritonavir Oral 
Powder
Arm Name
(group of participants 
receiving a specific treatment 
or no treatment)
nirmatrelvir/ 
ritonavir 
commercial 
tablets 
nirmatrelvir/ 
ritonavir 
commercial 
tablets 
nirmatrelvir/ 
ritonavir oral powder
nirmatrelvir/ 
ritonavir oral 
powder
Type
Drug
Drug
Drug
Drug
Dose Formulation
Tablet
Tablet
Powder
Powder
Unit Dose Strength(s)
 
 
Dosage Level(s)
Single dose
Single dose
Single dose
Single dose
Route of Administration
Oral
Oral
Oral
Oral
IMP or NIMP/AxMP
IMP
NIMP
IMP
IMP
Sourcing
Provided 
centrally by the 
sponsor
Provided locally 
by the trial site
Provided centrally by 
the sponsor
Provided centrally 
by the sponsor
Packaging and Labeling
Study 
intervention will 
be provided in a 
bulk container for 
dispensing into 
individual 
participant
containers by the 
trial site
N/A
Study intervention 
will be provided in a 
bulk container for 
dispensing into 
individual participant 
containers by the 
trial site
Study intervention 
will be provided in 
a bulk container
for dispensing into 
individual 
participant 
containers by the 
trial site
Former name
PF-07321332
PF-07321332
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Study Arm(s)
Arm Title
Nirmatrelvir/ 
ritonavir 
commercial tablets
Nirmatrelvir/ 
ritonavir oral 
powder mixed 
with water
Nirmatrelvir/ 
ritonavir oral 
powder mixed 
with infant 
formula
Nirmatrelvir/ 
ritonavir oral powder 
mixed with vanilla 
pudding (fasted)
Nirmatrelvir/ 
ritonavir oral 
powder mixed 
with vanilla 
pudding (fed)
Arm Type
Reference
Experimental
Experimental
Experimental
Experimental
Arm 
Description
Single oral dose of 
nirmatrelvir/ 
ritonavir 
commercial 
tablets under fasted 
conditions 
Single oral dose 
of nirmatrelvir/ 
ritonavir 
 oral 
powder mixed 
with water under 
fasted conditions 
Single oral dose 
of nirmatrelvir/ 
ritonavir 
 oral 
powder mixed 
with infant 
formula under 
fasted conditions 
Single oral dose of 
nirmatrelvir/ritonavir 
 oral 
powder mixed with 
vanilla pudding under 
fasted conditions 
Single oral dose 
of nirmatrelvir/ 
ritonavir
ral 
powder mixed 
with vanilla 
pudding under 
fed conditions 
Nirmatrelvir 
 tablets and nirmatrelvir oral powder will be supplied to CRU in bulk 
along with individual dosing containers for unit dosing. 
Ritonavir oral powder will be supplied to CRU in bulk along with individual dosing 
containers for unit dosing
Commercially available ritonavir 
 tablets will be sourced by the CRU.
Vehicles (infant formula and vanilla pudding) for nirmatrelvir and ritonavir oral powder 
administration will be sourced by the CRU.
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.
Doses taken under fasted condition: On Day 1 of each treatment period, following an 
overnight fast of at least 10 hours, participants will receive nirmatrelvir 
 (as 
 tablets) with ritonavir 
 (as 
 tablet) with approximately 240 mL 
ambient temperature water or nirmatrelvir/ritonavir 
 oral powder mixed with 
either water or infant formula with approximately 210 mL ambient temperature water or 
nirmatrelvir/ritonavir 
 oral powder mixed with vanilla pudding with 
approximately 240 mL ambient temperature water administered orally starting at 
approximately 0800 hours (plus or minus 2 hours). The use of food vehicles for delivery of 
oral powder are not considered a fed condition. Nirmatrelvir and ritonavir tablets 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. Water will be withheld for 1 hour predose (with the exception of the water
consumed as part of the breakfast) and 1 hour after the study treatment administration.
Doses taken under fed condition: On Day 1, following an overnight fast of at least 10 hours, 
participants will be administered the standard high-fat, high-calorie breakfast approximately 
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30 minutes prior to the administration of nirmatrelvir/ritonavir oral powder mixed with 
vanilla pudding. The entire breakfast will be consumed within approximately 20 minutes. 
The nirmatrelvir/ritonavir 
 oral powder mixed with vanilla pudding will be 
administered 30 minutes after the start of breakfast (allowable window approximately 
30 minutes) with 240 mL ambient temperature water. Participants who do not finish the 
entire meal within approximately 20 minutes or who vomit after consuming the meal will not 
be dosed resulting in early termination from the study. No additional food will be allowed for 
at least 4 hours post-dose. Water will be withheld for 1 hour predose (with the exception of 
the liquid consumed as part of the breakfast) and 1 hour after the study treatment 
administration.
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 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 
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, as soon as possible. Once an excursion is identified, the study intervention
must be quarantined and not used until Pfizer provides permission to use the study 
intervention. Specific details regarding the excursion definition and information to
report for each excursion will be provided to the site in the CRU 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.
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7. The investigator, institution, or the 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 CRU’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
tablets will be dispensed at the CRU into 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 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 CRU into individual dosing containers using the package insert as guidance 
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 labeled in accordance with Pfizer 
regulations and the clinical site’s labeling requirements
Nirmatrelvir/ritonavir oral powder will be prepared at the CRU 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). Details of dose preparations, volume/amount of food 
vehicle, will be given in the EDR. Prepared doses will be labeled in accordance with Pfizer 
regulations and the investigator site’s labeling requirements.
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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
As 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 CRU 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. 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 participants at the end of their study participation.
6.8. Treatment of Overdose
For this study, any dose of nirmatrelvir greater than 
 or ritonavir 
 within a 
24-hour time period [±2 hours] will be considered an overdose.
There is no specific treatment for an overdose.
In the event of an overdose, the investigator should:
1. Contact the medical monitor within 24 hours.
2. Closely monitor the participant for any AEs/SAEs and laboratory abnormalities 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.
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5. Obtain a blood sample for PK analysis within 1 day from the date of the last dose of 
study intervention if requested by the medical monitor (determined on a case-by-case 
basis).
Decisions regarding dose interruptions or modifications will be made by the investigator in 
consultation with the medical monitor as needed based on the clinical evaluation of the 
participant.
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 site 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.
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. 


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7. DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL
7.1. Discontinuation of Study Intervention
It may be necessary for a participant to permanently discontinue study intervention. Reasons 
for permanent discontinuation of study intervention include the following.

AE 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.
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 
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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 drug: 

A SAE (eg, a serious AE considered at least possibly related to study drug 
administration) in 1 participant.

Severe NSAE (eg, severe NSAEs considered at least possibly related to study drug 
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 his/her own request. Reasons for 
discontinuation from the study include the following:

Refused further study procedures;

Lost to follow-up;

Death;

Study terminated by sponsor;

Investigator’s decision;

Pregnancy.


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At the time of discontinuing from the study, if possible, an early discontinuation visit should 
be conducted. See the SoA for assessments to be collected at the time of study 
discontinuation and follow-up and for any further evaluations that need to be completed. 
The early discontinuation visit applies only to participants who are enrolled/randomized and 
then are prematurely withdrawn from the study. Participants should be questioned regarding 
their reason for withdrawal. 
The participant will be permanently discontinued from the study intervention and the study at 
that time.
If a participant withdraws from the study, he/she may request destruction of any remaining 
samples taken and not tested, and the investigator must document any such requests in the 
site study records and notify the sponsor accordingly.
If the participant withdraws from the study and also withdraws consent (see Section 7.2.1) 
for disclosure of future information, no further evaluations should be performed and no 
additional data should be collected. The sponsor may retain and continue to use any data 
collected before such withdrawal of consent.
7.2.1. Withdrawal of Consent 
Participants who request to discontinue receipt of study intervention will remain in the study 
and must continue to be followed for protocol-specified follow-up procedures. The only 
exception to this is when a participant specifically withdraws consent for any further contact 
with 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 he or she repeatedly fails to return for 
scheduled visits and is unable to be contacted by the study site.
The following actions must be taken if a participant fails to 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 


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calls and, if necessary, a certified letter to the participant’s last known mailing 
address or local equivalent methods). These contact attempts should be documented 
in the participant’s medical record;

Should the participant continue to be unreachable, he/she will be considered to have 
withdrawn from the study. 
8. STUDY ASSESSMENTS AND PROCEDURES
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 
the test. In these cases, the investigator must take all steps necessary to ensure the safety and 
well-being of the participant. When a protocol-required test cannot be performed, the 
investigator will document the reason for the missed test and any corrective and preventive 
actions that he or she has taken to ensure that required processes are adhered to as soon as 
possible. The study team must be informed of these incidents in a timely manner.
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.


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For samples being collected and shipped, detailed collection, processing, storage, and 
shipment instructions and contact information will be provided to the investigator site prior 
to initiation of the study.
The total blood sampling volume for individual participants in this study is approximately
350 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 Prior 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 
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.


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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 PR is preferable; however, when done 
manually, PR 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.
8.3.3. 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 heart rate and measures PR, QT, and QTc intervals and QRS 
complex. Alternative lead placement methodology using torso leads (eg, Mason-Likar) 
should not be used given the potential risk of discrepancies with ECGs acquired using 
standard limb lead placement. All scheduled ECGs should be performed after the participant
has rested quietly for at least 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
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). 


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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.
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 RT-PCR prior to being admitted to the 
clinic 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 as 
per local procedures. Additional testing may be required by local regulations or by the PI.


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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 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.
8.4.1. Time Period and Frequency for Collecting AE and SAE Information
The time period for actively eliciting and collecting AEs and SAEs (“active collection 
period”) for each participant begins from the time the participant provides informed consent, 
which is obtained before undergoing any study-related procedure and/or receiving study 
intervention), through and including a minimum of 28 calendar days, except as indicated 
below, after the last administration of the study intervention.
Follow-up by the investigator continues throughout the active collection period and until the 
AE or SAE or its sequelae resolve or stabilize at a level acceptable to the investigator.


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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.
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.


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


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exposure include healthcare providers, family members, and others who may be exposed. An 
environmental exposure may include EDP, EDB, and occupational exposure.
Any such exposures to the study intervention under study are reportable to Pfizer Safety 
within 24 hours of investigator awareness.
8.4.5.1. Exposure During Pregnancy
An EDP occurs if: 

A female participant is found to be pregnant while receiving or after discontinuing 
study intervention.

A male participant who is receiving or has discontinued study intervention 
inseminates a female partner.

A female nonparticipant is found to be pregnant while being exposed or having been 
exposed to study intervention because of environmental exposure. Below are 
examples of environmental EDP: 

A female family member or healthcare provider reports that she is pregnant after 
having been exposed to the study intervention by ingestion, 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 
should include the anticipated date of delivery (see below for information related to 
termination of pregnancy). 

If EDP occurs in a participant/participant’s partner, the investigator must report this 
information to Pfizer Safety 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 


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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 
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. 


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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 accord 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.
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.


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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.
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.


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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 Table 2. 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.
Samples will be used to evaluate the PK of nirmatrelvir and ritonavir.
 
 
Genetic analyses will not be performed on these plasma samples unless consent for this was 
included in the informed consent. Participant confidentiality will be maintained.
 
The PK samples must be processed and shipped as indicated in the instructions provided to 
the investigator site to maintain sample integrity. Any deviations from the PK sample 
handling procedure (eg, sample collection and processing steps, interim storage or shipping 
conditions), including any actions taken, must be documented and reported to the sponsor. 
On a case-by-case basis, the sponsor may make a determination as to whether sample 
integrity has been compromised.
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.
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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 
 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.
8.7.3. Specified Metabolomic Research 
Specified metabolomic research is not included in this study.
 
 
 
 
 
 
 
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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.
8.10. Taste Assessment of Nirmatrelvir Oral Powder
The sensory attributes of nirmatrelvir/ritonavir oral powder will be evaluated by the 
participant using a Palatability Questionnaire (Appendix 9) in the period when suspension 
may be administered. Participants will review the palatability questionnaire and instructions 
prior to the first taste assessment to Treatment B, C, and Don of Day 1 Period 1 or Period 2. 
Each participant will complete the palatability Survey immediately following dosing 
(within 1 min) and at 5, 10, and 20 minutes post oral administration of nirmatrelvir/ritonavir 
oral powder.
9. STATISTICAL CONSIDERATIONS
Detailed methodology for summary and statistical analyses of the data collected in this study 
is outlined here and further detailed in the SAP, which will be maintained by the sponsor. 
The SAP may modify what is outlined in the protocol where appropriate; however, any major 
modifications of the primary endpoint definitions or their analyses will also be reflected in a 
protocol amendment.
9.1. Statistical 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/Randomly 
assigned to study 
intervention 
“Enrolled” means a participant's agreement to participate in a 
clinical study following completion of the informed consent 
process and 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. A participant will be 
considered enrolled if the informed consent is not withdrawn 
prior to participating in any study activity after screening.
Safety Analysis Set
All participants who take at least 1 dose of study intervention. 
Participants will be analyzed according to the product they 
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Participant Analysis 
Set
Description
PK Concentration Set
All participants who take at least 1 dose of study intervention 
and in whom at least 1 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 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.
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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9.3.2. Statistical Methods for PK Data
For the primary objective, natural log transformed AUCinf (if data permits), AUClast and Cmax
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. 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. For primary objective, 
Treatment A will be the Reference treatment while Treatments B, C, D and E will be the Test 
treatments. For food effect estimation (periods 4 and 5 only) Treatment D will be the 
Reference treatment while Treatments E will be the Test treatment.
PK parameters, including plasma AUCinf (if data permits), AUClast, Cmax,
 
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.
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 
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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. Taste Assessment
The data collected for taste assessment using the sponsor-provided taste questionnaire will be 
numerically derived by measuring length (using a scale with gradations of at least 0.1 cm) of 
the “x” marked by the participant relative to the “good trait”. The taste attributes (bitterness, 
and tongue/mouth burn sensation) from the taste questionnaires (Appendix 9) will be listed 
and descriptively summarized and appropriate plots may be generated.
9.3.4.2. Biomarker Assessment
Pharmacogenomic or biomarker data from Retained Research Samples may be collected 
during or after the trial and retained for future analyses; the results of such analyses are not 
planned to be included in the CSR.
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 12 participants will provide adequate precision to estimate the relative 
bioavailability and intrasubject variability nirmatrelvir. The following table presents the 
width of 90% CI for different estimated effects, with 80% coverage probability.
Parameter
Estimated Effect
(100*Test/Reference)
90% CI
CI Width
AUC
85%
78.68
91.83
13.16
90%
83.30
97.23
13.93
95%
87.93
102.64
14.71
100%
92.56
108.04
15.48
105%
97.19
113.44
16.25
110%
101.82
118.84
17.03
115%
106.44
124.24
17.80
Cmax
85%
76.51
94.43
17.91
90%
81.02
99.98
18.97
95%
85.52
105.54
20.02
100%
90.02
111.09
21.07
105%
94.52
116.64
22.13
110%
99.02
122.20
23.18
115%
103.52
127.75
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These estimates are based on the assumption that within-participant standard deviations 
are 0.102 and 0.139 for lnCmax and lnAUCinf, respectively, as obtained from clinical Study 
C4671024 in healthy participants.
In addition, a sample size of 12 participants will provide adequate precision to estimate the 
relative bioavailability and intrasubject variability ritonavir. The following table presents the 
width of 90% CI for different estimated effects, with 80% coverage probability.
Parameter
Estimated Effect
(100*Test/Reference)
90% CI
CI Width
AUC
85%
72.71
99.37
26.66
90%
76.98
105.22
28.23
95%
81.26
111.06
29.80
100%
85.54
116.91
31.37
105%
89.81
122.75
32.94
110%
94.09
128.60
34.51
115%
98.37
134.44
36.07
Cmax
85%
69.29
104.27
34.98
90%
73.37
110.40
37.04
95%
77.44
116.54
39.09
100%
81.52
122.67
41.15
105%
85.60
128.80
43.21
110%
89.67
134.94
45.27
115%
93.75
141.07
47.32
These estimates are based on the assumption that within-participant standard deviations 
are 0.206 and 0.269 for lnAUCinf and lnCmax, respectively, as obtained from clinical Study
C4671024 in healthy participants.
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 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.
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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 a 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 
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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 
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.
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 


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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.
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 
the sponsor or its agent, whenever feasible, to be present during the inspection. The 
investigator site and investigator will promptly resolve any discrepancies that are identified 
between the study data and the participant’s medical records. The investigator will promptly 
provide copies of the inspection findings to the sponsor or its agent. Before response 
submission to the regulatory authorities, the investigator will provide the sponsor or its 
agents with an opportunity to review and comment on responses to any such findings.


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10.1.8. Source Documents
Source documents provide evidence for the existence of the participant and substantiate the 
integrity of the data collected. Source documents are filed at the investigator site.
Data reported on the CRF or entered in the eCRF that are from source documents must be 
consistent with the source documents or the discrepancies must be explained. The 
investigator may need to request previous medical records or transfer records, depending on 
the study. Also, current medical records must be available.
Definition of what constitutes source data and its origin can be found in the 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 Source Document 
Locator, which is maintained by the sponsor’s designee (Pfizer CRU).
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.
The investigator may initiate study-site closure at any time upon notification to the sponsor
designee if requested to do so by the responsible IRB/EC or if such termination is required to 
protect the health of study participants.


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


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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 5.
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
Renal Function
Cystatin C (Scys)
Local Dipstick:
pHe
Glucose (qual)
Protein (qual)
Blood (qual)
Ketones
Nitrites
Leukocyte esterase
Laboratory:
Microscopy a
•
SARS-CoV-2 RT-PCR
•
Urine drug screeningb
•
Pregnancy test (β-hCG)c
•
eGFR [CKD-EPI]
At Screening only:
•
FSHd
•
HBsAg
•
HbsAbf
•
HBcAb
•
HCVAb
•
HIV
a.
Microscopy only if urine dipstick is positive for blood, protein, nitrites, or leukocyte esterase.
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.
Can be performed as per local procedures.
f.
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 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 CT SAE Report Form and EDP Supplemental Form; if the EDP is 
associated with an SAE, then the SAE is reported to Pfizer Safety using the CT SAE 
Report Form. 
** EDB is reported to Pfizer Safety using the CT SAE Report Form which would also include 
details of any SAE that might be associated with the EDB. 
*** Environmental or Occupational exposure: AEs or SAEs associated with occupational 
exposure are reported to Pfizer Safety using the CT SAE Report Form. 

When an AE or SAE occurs, it is the responsibility of the investigator to review 
all documentation (eg, hospital progress notes, laboratory reports, and diagnostic 
reports) related to the event.

The investigator will then record all relevant AE or SAE information in the CRF.

It is not acceptable for the investigator to send photocopies of the participant’s 
medical records to Pfizer Safety in lieu of completion of the CT SAE Report 
Form/AE or SAE CRF page.


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
There may be instances when copies of medical records for certain cases are 
requested by Pfizer Safety. In this case, all participant identifiers, with the 
exception of the participant number, will be redacted on the copies of the medical 
records before submission to Pfizer Safety.

The investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information. Whenever possible, the diagnosis 
(not the individual signs/symptoms) will be documented as the AE or SAE.
Assessment of Intensity
The investigator will make an assessment of intensity for each AE and SAE reported 
during the study and assign it to 1 of the following categories: 

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 ADLcausing 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.
Assessment of Causality

The investigator is obligated to assess the relationship between study intervention 
and each occurrence of each AE or SAE. The investigator will use clinical judgment 
to determine the relationship.

A “reasonable possibility” of a relationship conveys that there are facts, evidence, 
and/or arguments to suggest a causal relationship, rather than a relationship cannot 
be ruled out.

Alternative causes, such as underlying disease(s), concomitant therapy, and other 
risk factors, as well as the temporal relationship of the event to study intervention 
administration, will be considered and investigated.

The investigator will also consult the IB and/or product information, for marketed 
products, in their assessment.

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.


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
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.

New or updated information will be recorded in the originally submitted 
documents.

The investigator will submit any updated SAE data to the sponsor within 
24 hours of receipt of the information.


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10.3.4. Reporting of SAEs
SAE Reporting to Pfizer Safety via an Electronic DCT

The primary mechanism for reporting an SAE to Pfizer Safety will be the 
electronic DCT.

If the electronic system is unavailable, then the site will use the paper SAE DCT
(see next section) to report the event within 24 hours.

The site will enter the SAE data into the electronic DCT (eg, eSAE or PSSA) or 
paper form (as applicable) as soon as the data become available.

After the study is completed at a given site, the electronic DCT will be taken 
offline 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 offline, 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.
Because ritonavir may reduce the effect of estradiol-containing contraceptives when agents 
are co-administered, a barrier method or other nonhormonal method of contraception must 
also be used if the participant is using estradiol-containing contraceptives during the study 
treatment and until one menstrual cycle after stopping study intervention.
The investigator is responsible for review of medical history, menstrual history, and recent 
sexual activity to decrease the risk for inclusion of a woman with an early undetected 
pregnancy. 
10.4.3. Woman of Childbearing Potential
A woman is considered fertile following menarche and until becoming postmenopausal 
unless permanently sterile (see below).
If fertility is unclear (eg, amenorrhea in adolescents or athletes) and a menstrual cycle cannot 
be confirmed before the first dose of study intervention, additional evaluation should be 
considered.


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Women in the following categories are not considered WOCBP:
1. Premenopausal female with 1 of the following: 

Documented hysterectomy;

Documented bilateral salpingectomy;

Documented bilateral oophorectomy.
For individuals with permanent infertility due to a medical cause other than the 
above, (eg, mullerian agenesis, androgen insensitivity), investigator discretion should 
be applied to determining study entry.
Note: Documentation for any of the above categories can come from the site 
personnel’s review of the participant’s medical records, medical examination, or 
medical history interview. The method of documentation should be recorded in the 
participant’s medical record for the study.
2. Postmenopausal female.

A postmenopausal state is defined as no menses for 12 months without an 
alternative medical cause. In addition:

A 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 contraception methods 
if she wishes to continue their 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.


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3. Intrauterine hormone releasing system.
4. Bilateral tubal occlusion .
5. Vasectomized partner:

Vasectomized partner is a highly effective contraceptive method provided that the 
partner is the sole sexual partner of the WOCBP and the absence of sperm has 
been confirmed. If not, an additional highly effective method of contraception 
should be used. The spermatogenesis cycle is approximately 90 days.
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 coadministered, a barrier method or other nonhormonal method of contraception must
also be used if the participant is using estradiol-containing contraceptives. 


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10.5. Appendix 5: Genetics
Use/Analysis of DNA

Genetic variation may impact a participant’s response to study intervention, 
susceptibility to, and severity and progression of disease. Therefore, where local 
regulations and IRBs/ECs allow, a blood sample will be collected for DNA analysis.

The scope of the genetic research may be narrow (eg, 1 or more candidate genes) or 
broad (eg, the entire genome), as appropriate to the scientific question under 
investigation.

The samples may be analyzed as part of a multistudy assessment of genetic factors 
involved in the response to study intervention or study interventions of this class to 
understand treatments for the disease(s) under study or the disease(s) themselves.

The results of genetic analyses may be reported in 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 
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 some of DILI cases, elevations in AST and/or ALT may precede T bili elevations 
(>2 × ULN). Any substantial elevation in ALT, AST or bilirubin above baseline may be a 
potential DILI. The treating physician should report any elevations of concern—in some
cases, elevation in ALT, AST 2 × ULN or T bili value 1.5 × ULN or less prompts treating 
physicians to consider hepatic injury. Hepatic injury may be from the study drug, a 
co-administered study drug or the disease under study.
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. The following criteria are of particularly concern:

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 (Hy’s law criteria).

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).
Increases in AST/ALT and T bili should be assessed individually based on clinical judgment
by the treating physician and their health care team; 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 for causality 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.


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In addition to repeating measurements of AST and ALT and T bili for suspected Hy’s law 
cases, additional laboratory tests should include albumin, CPK, 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 at time and dose of last 
dose of study intervention. 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 cases if no other reason 
for the LT abnormalities has yet been found. The treating physician is encouraged to consult 
with any other specialty that may assist in interpretation of the lab result or patient care 
management (eg, gastroenterologist, clinical pathologist, pharmacy, etc). Such potential 
DILI cases are to be reported as SAEs, irrespective of availability of all the results of 
the investigations performed to determine etiology of the LT abnormalities.
A potential DILI 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
N/A
eGFR = 143 × (Scr/0.7)-0.241  ×  (0.9938)Age
Female
if > 0.7
N/A
eGFR = 143 × (Scr/0.7)-1.200  ×  (0.9938)Age
Male
if ≤ 0.9
N/A
eGFR = 142 × (Scr/0.9)-0.302  ×  (0.9938)Age
Male
if > 0.9
N/A
eGFR = 142 × (Scr/0.9)-1.200  ×  (0.9938)Age
2021 CKD-
EPI          
Scr-Scys 
Combined
Scr
(mg/dL)
Scys
(mg/L)
Recommended eGFR Equation
Female
if ≤ 0.7
if ≤ 0.8
eGFR = 130 × (Scr/0.7)-0.219  × (Scys/0.8)-0.323  × 
(0.9961)Age
Female
if ≤ 0.7
if > 0.8
eGFR = 130 × (Scr/0.7)-0.219  × (Scys/0.8)-0.778  × 
(0.9961)Age
Female
if > 0.7
if ≤ 0.8
eGFR = 130 × (Scr/0.7)-0.544  × (Scys/0.8)-0.323  × 
(0.9961)Age
Female
if > 0.7
if > 0.8
eGFR = 130 × (Scr/0.7)-0.544  × (Scys/0.8)-0.778  × 
(0.9961)Age
Male
if ≤ 0.9
if ≤ 0.8
eGFR = 135 × (Scr/0.9)-0.144  × (Scys/0.8)-0.323  × 
(0.9961)Age
Male
if ≤ 0.9
if > 0.8
eGFR = 135 × (Scr/0.9)-0.144  × (Scys/0.8)-0.778  × 
(0.9961)Age
Male
if > 0.9
if ≤ 0.8
eGFR = 135 × (Scr/0.9)-0.544  ×  (Scys/0.8)-0.323  × 
(0.9961)Age
Male
if > 0.9
if > 0.8
eGFR = 135 × (Scr/0.9)-0.544  ×  (Scys/0.8)-0.778  × 
(0.9961)Age


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10.7.2.2. Adolescents (12 Years to <18 Years)—Cockcroft-Gault Formula
CrCl (mL/min) 
Males: Cr/Cl = [(140 - age) × body weight (in kg)] / [Scr (in mg/dL) × 72]
Females: Cr/Cl = 0.85 × [(140 - age) × body weight (in kg)] / [Scr (in mg/dL) × 72]
10.7.2.3. Children (2 Years to <12 Years)—Modified Schwartz Equation
CrCl normalized to BSA (mL/min/1.73 m2) = (K × Ht) / Scr
Height (Ht) in centimeters; serum creatinine (Scr) in mg/dL.
K (proportionality constant): Female child < 12 years: K = 0.55. Male child <12 years: 
K = 0.70.
10.7.2.4. Infants (1 Month to <2 Years) and Neonates (<1 Month)—Bedside Schwartz 
Equation
eGFR (mL/min/1.73 m2) = 0.413 × (Ht/Scr)
Height (Ht) in centimeters; serum creatinine (Scr) in mg/dL.
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 ms.

New prolongation of QTcF to >480 ms (absolute) or by ≥60 ms 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 (QRS complex >120 ms).

New-onset right bundle branch block (QRS complex >120 ms).

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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10.9. Appendix 9: Palatability Questionnaire
Nirmatrelvir/Ritonavir Oral Powder Palatability Questionnaire
1. Questionnaire should be filled out by adult participants, preferably with the assistance 
from clinician or a nurse.
2. Use colored copy of the Palatability Questionnaire.
3. Do not alter (reduce or enlarge) the original size of the Palatability
Questionnaire.
4. Please collect the following background information:
Background Information
Study #/Study Site
Period and Day
Participant ID (Rand ID)
Treatment
Collect Date
Questionnaire Fully Completed (circle one)
Yes/No


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Please answer the following questions and provide a mark () on the color bar at 
1 (immediately), 5, 10 and 20 minutes after dosing. Please ensure participant has access 
to these descriptions when completing the questionnaire. 
Q1: Mouth feel – Please tell us about the mouth feel (such as grittiness, stickiness, 
waxiness) of the product you tasted.
Q2: Bitterness – Please tell us about the degree of bitterness of the product you tasted.
Q3: Tongue/mouth burn – Please tell us about the degree of tongue/mouth burn of the 
product you tasted.
Q4: Throat burn – Please tell us about the degree of throat burn of the product you 
tasted.
Q5: Overall liking – Please indicate how much you like or dislike the product you 
tasted.


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Example: How to provide a mark () on the color bar.

Good (score = 0)
Bad (score = 100)


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Within 1 minute (immediately) after dosing
Provide a mark ( ) on the color bar.
Mouth Feel
Bitterness
Tongue/Mouth 
Burn
Throat Burn
Overall Liking
Good
Bad


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5 minutes after dosing
Provide a mark ( ) on the color bar.
Mouth Feel
Bitterness
Tongue/Mouth 
Burn
Throat Burn
Overall Liking
Bad
Good


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Final Protocol 19 July 2022
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10 minutes after dosing
Provide a mark ( ) on the color bar.
Mouth Feel
Bitterness
Tongue/Mouth 
Burn
Throat Burn
Overall Liking
Good
Bad


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Final Protocol 19 July 2022
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20 minutes after dosing
Provide a mark ( ) on the color bar.
Mouth Feel
Bitterness
Tongue/Mouth 
Burn
Throat Burn
Overall Liking
Good
Bad


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Additional Feedback – After completing the “20 minute after dosing” palatability questions,
please provide any additional descriptive feedback in the box below regarding the taste or 
odor of the product.


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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
ongoing/continuous event
19F-NMR
19F nuclear magnetic resonance
3CLpro
3C-like protein
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 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 Medical Products
BBS
Biospecimen Banking System
β-hCG
β‑human chorionic gonadotropin
BID
twice a day
BMI
body mass index
BP
blood pressure
bpm
beats per minute
BSA
body surface area
BUN
blood urea nitrogen
CFR
Code of Federal Regulations
CI
confidence interval
CIOMS
Council for International Organizations of Medical Sciences
CKD-EPI
Chronic Kidney Disease Epidemiology Collaboration
Clast
last quantifiable concentration
Cmax
maximum observed concentration
CO2
carbon dioxide (bicarbonate)
COVID-19
coronavirus disease 2019
CPK
creatine phosphokinase
CrCl
creatinine clearance
CRF
case report form
CRO
contract research organization
CRU
clinical research unit
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Abbreviation
Term
CSR
Clinical Study Report
CT
clinical trial
CTIS
Clinical Trial Information System
CTMS
Clinical Trial Management System
CYP
cytochrome P450 
CYP2D6
cytochrome P450 2D6
CYP3A
cytochrome P450, family 3, subfamily A
CYP3A4
cytochrome P450 3A4 
CYP3A5
cytochrome P450 3A5 
DCT
data collection tool
DILI
drug‑induced liver injury
DMC
Data Monitoring Committee
E-DMC
External Data Monitoring Committee
E/T
early discontinuation
EC
ethics committee
ECC
emergency contact card
ECG
electrocardiogram
eCrCl
estimated creatinine clearance
eCRF
electronic case report form
EDB
exposure during breastfeeding
EDP
exposure during pregnancy
EDR
extemporaneous dispensing record
eGFR
estimated glomerular filtration rate
EMA
European Medicines Agency
eSAE
electronic serious adverse event
EU
European Union
EudraCT
European Union Drug Regulating Authorities Clinical Trials (European 
Clinical Trials Database)
F/U
follow-up
FDA
Food and Drug Administration
FIH
first in human
fm
fraction metabolized
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


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Abbreviation
Term
Ht
height
IB
Investigator’s Brochure
ICD
informed consent document
ICH
International Council for Harmonisation for Technical Requirements for 
Pharmaceuticals for Human Use
ID
identification
IMP
investigational medicinal product
lnAUCinf
log-transformed AUCinf
lnCmax
log-transformed Cmax
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
first order elimination rate constant
ki
inhibition constant
LBBB
left bundle branch block
LT
liver test
lnAUCinf
log-transformed AUCinf
lnCmax
log-transformed Cmax
Loge
natural logarithm
LFT
liver function test
M–2
metabolite 2
MAD
multiple ascending dose
MCH
mean corpuscular hemoglobin
MCHC
mean corpuscular hemoglobin concentration
MCV
mean corpuscular volume
Mpro
main protease
MQI
medically qualified individual
ms
millisecond
NA, N/A
not applicable
NHP
nonhuman primate
NIMP
noninvestigational medicinal product
NOAEL
No observed adverse effect level
NSAE
non-serious adverse event
NYHA
New York Heart Association
PSSA
Pfizer’s Serious Adverse Event Submission Assistant
PD
pharmacodynamic(s)
PE
physical examination 
PI
principal investigator
PK
pharmacokinetic(s)
PR
pulse rate


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Abbreviation
Term
PT/INR
prothrombin time-international normalized ratio
PVC
premature ventricular contraction/complex
q12h
every 12 hours
QTc
corrected QT interval
QTcF
QT corrected using Fridericia’s formula
qual
qualitative
rBA
relative bioavailability
RBC
red blood cell
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
SD
standard deviation
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
CCI
CCI
CCI


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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, nirmatrelvir. (Version 5.0)
3
Inker LA et al. N Engl J Med. 2021;385:1737-49.
                                                

SAP_001.pdf: 
Protocol C4671036 (PF-07321332) Statistical Analysis Plan
PFIZER CONFIDENTIAL
Page 1 of 18
Protocol C4671036
A Phase 1, Open-Label, Randomized, Single Dose, Crossover Study to Estimate the 
Relative Bioavailability of Nirmatrelvir (PF-07321332)/Ritonavir Oral Powder in 3 
Different Food Delivery Vehicles Relative to the Nirmatrelvir/Ritonavir Commercial
Tablets Under Fasted Conditions and the Effect of Food on Relative Bioavailability of
Nirmatrelvir (PF-07321332) /Ritonavir Oral Powder in Healthy Adult Participants
Statistical Analysis Plan 
(SAP)
Version:
1
Date:
08 Sep 2022


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TABLE OF CONTENTS
LIST OF TABLES.....................................................................................................................3
APPENDICES ...........................................................................................................................3
1. VERSION HISTORY............................................................................................................4
2. INTRODUCTION .................................................................................................................4
2.1. Modifications to the Analysis Plan Described in the Protocol..................................4
2.2. Study Objectives and Endpoints ...............................................................................4
2.3. Study Design .............................................................................................................6
3. ENDPOINTS AND BASELINE VARIABLES: DEFINITIONS AND 
CONVENTIONS ..................................................................................................................7
3.1. Primary Endpoints.....................................................................................................7
3.2. Secondary Endpoints.................................................................................................7
3.4. Baseline Variables.....................................................................................................8
3.5. Safety Endpoints .......................................................................................................8
3.5.1. Adverse Events.............................................................................................9
3.5.2. Laboratory Data............................................................................................9
3.5.3. Vital Signs ....................................................................................................9
3.5.4. Electrocardiograms.......................................................................................9
4. ANALYSIS SETS (POPULATIONS FOR ANALYSIS).....................................................9
5. GENERAL METHODOLOGY AND CONVENTIONS....................................................10
5.1. Hypotheses and Decision Rules ..............................................................................10
5.2. General Methods .....................................................................................................10
5.2.1. Analyses for Binary/Categorical Endpoints ...............................................10
5.2.2. Analyses for Continuous Endpoints ...........................................................10
5.3. Methods to Manage Missing Data ..........................................................................11
5.3.1. Pharmacokinetic Data.................................................................................11
5.3.2. Safety Data..................................................................................................12
6. ANALYSES AND SUMMARIES ......................................................................................12
6.1. Primary Endpoints...................................................................................................12
6.2. Secondary Endpoints...............................................................................................12
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6.4. Subset Analyses.......................................................................................................14
6.5. Baseline and Other Summaries and Analyses.........................................................14
6.5.1. Demographic Summaries............................................................................14
6.5.2. Study Conduct and Participant Disposition................................................14
6.5.3. Study Treatment Exposure .........................................................................14
6.5.4. Concomitant Medications and Nondrug Treatments..................................14
6.6. Safety Summaries and Analyses .............................................................................14
6.6.1. Adverse Events...........................................................................................15
6.6.2. Laboratory Data..........................................................................................15
6.6.3. Vital Signs ..................................................................................................15
6.6.4. Electrocardiograms.....................................................................................15
7. INTERIM ANALYSES.......................................................................................................15
APPENDICES .........................................................................................................................16
LIST OF TABLES
Table 1.
Summary of Changes..................................................................................4
Table 2.
Randomized Treatment Sequences .............................................................7
Table 3.
Plasma Pharmacokinetic Parameters Definitions......................................8
Table 4.
PK Parameters to be Summarized Descriptively by Treatment ...............14
APPENDICES
Appendix 1. SAS Code for Analyses.......................................................................................16
Appendix 2. List of Abbreviations...........................................................................................18
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NOTE: Italicized text within this document has been taken verbatim from the Protocol.
1. VERSION HISTORY
Table 1.
Summary of Changes
Version/
Date
Associated 
Protocol 
Amendment
Rationale
Specific Changes
1 /
08 Sep 2022
Original 
19 Jul 2022
N/A
N/A
2. INTRODUCTION
Nirmatrelvir a potent and selective inhibitor of the SARS-CoV-2 Mpro is 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 sufficient to suppress viral replication through the entire dosing interval.
The purpose of this study is to estimate the rBA of nirmatrelvir/ritonavir oral powder in 3 
different food vehicles relative to the Paxlovid® tablets under fasted condition, and to
estimate the effect of food on the rBA of the nirmatrelvir/ritonavir oral powder formulation in 
healthy adult participants. The study will also assess the safety, tolerability, and palatability 
of nirmatrelvir/ritonavir oral powder in healthy adult participants.
This SAP provides the detailed methodology for summary and statistical analyses of the data 
collected in Study C4671036.  
2.1. Modifications to the Analysis Plan Described in the Protocol
None.
2.2. Study Objectives and Endpoints
Objectives
Endpoints
Primary: 
Primary: 
To estimate the rBA of the 
nirmatrelvir/ritonavir 
 
oral powder mixed with water compared 
to the nirmatrelvir/ritonavir 
 
 commercial tablets 
under fasted conditions.
The test/reference ratios for AUCinf (if 
data permits), AUClast, and Cmax of 
nirmatrelvir and ritonavir.
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Objectives
Endpoints
To estimate the rBA of the 
nirmatrelvir/ritonavir 
 
oral powder mixed with infant formula 
compared to the nirmatrelvir/ritonavir 
 commercial 
tablets under fasted conditions.
To estimate the rBA of the 
nirmatrelvir/ritonavir 
 
oral powder mixed with vanilla pudding 
compared to the nirmatrelvir/ritonavir 
 commercial 
tablets under fasted conditions.
To estimate the rBA of the 
nirmatrelvir/ritonavir 
 
oral powder mixed with vanilla pudding 
under fed conditions compared to the 
nirmatrelvir/ritonavir 
 
 commercial tablets under 
fasted conditions.
Secondary: 
Secondary: 
To estimate the effect of food on the rBA 
of the nirmatrelvir/ritonavir 
 
 oral powder mixed with vanilla 
pudding.
To evaluate the safety and tolerability of 
nirmatrelvir/ritonavir in healthy 
participants.
To assess the palatability of 
nirmatrelvir/ritonavir oral powder 
mixed with water/ infant formula/ vanilla 
pudding.
The test/reference ratios for AUCinf (if 
data permits), AUClast, and Cmax of 
nirmatrelvir and ritonavir.
Assessment of TEAEs, clinical laboratory 
abnormalities, vital signs, PEs, and 12 
lead ECGs.
Assessment of palatability via 
questionnaire: mouth feel, bitterness, 
tongue/mouth burn, throat burn and 
overall liking.
 
 
 
 
 
 
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Objectives
Endpoints
 
 
 
 
2.3. Study Design
This is a Phase 1, open-label, single dose, randomized, crossover study in healthy adult
participants to estimate rBA of nirmatrelvir/ritonavir 
 oral powder mixed 
with 3 different food vehicles (Test formulations) compared to the nirmatrelvir/ritonavir
 
 commercial tablets (Reference formulation) under fasted conditions, 
and to estimate the effect of food on the rBA of the nirmatrelvir/ritonavir oral powder 
formulation mixed with vanilla pudding. The study will also assess the safety, tolerability, 
and palatability of nirmatrelvir/ritonavir in healthy adult participants.
Approximately 12 adult healthy male and/or female participants will be enrolled and
randomized to 1 of 6 possible treatment sequences. 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 sequence 
as the participant who discontinued.
Each enrolled participant will participate in 5 study periods to receive 5 different treatments
according to the sequence determined by randomization:

Treatment A: Single oral dose of nirmatrelvir/ritonavir 
tablets under fasted condition

Treatment B: Single oral dose of nirmatrelvir/ritonavir 
 oral powder
mixed in water under fasted condition

Treatment C: Single oral dose of nirmatrelvir/ritonavir 
 oral powder
mixed in infant formula under fasted condition

Treatment D: Single oral dose of nirmatrelvir/ritonavir 
 oral powder
mixed in vanilla pudding under fasted condition

Treatment E: Single oral dose of nirmatrelvir/ritonavir 
 oral powder
mixed in vanilla pudding under fed condition
Participants will be randomly assigned to 1 of 6 sequences as shown below in Table 2.
Participants will be discharged on Day 4 of Period 5, following completion of all
assessments. Between each treatment, a minimum of 4 days washout is proposed to minimize
any residual nirmatrelvir concentrations prior to start of the next treatment. The total
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planned duration of participation from the Screening visit to the last follow-up phone call, is
approximately 12 weeks.
Table 2.
Randomized Treatment Sequences
Treatment 
Sequence
Period 1
Period 2
Period 3
Period 4
Period 5
Sequence 1 (n=2)
Treatment A
Tretment B
Treatment C
Treatment D
Treatment E
Sequence 2 (n=2)
Treatment B
Tretment C
Treatment A
Treatment D
Treatment E
Sequence 3 (n=2)
Treatment C
Tretment A
Treatment B
Treatment D
Treatment E
Sequence 4 (n=2)
Treatment A
Tretment C
Treatment B
Treatment E
Treatment D
Sequence 5 (n=2)
Treatment B
Tretment A
Treatment C
Treatment E
Treatment D
Sequence 6 (n=2)
Treatment C
Tretment B
Treatment A
Treatment E
Treatment D
3. ENDPOINTS AND BASELINE VARIABLES: DEFINITIONS AND 
CONVENTIONS
3.1. Primary Endpoints
The primary endpoints are the test/reference ratios for AUCinf (if data permits), AUClast, and 
Cmax of nirmatrelvir and ritonavir. Treatment A will be the Reference treatment while 
Treatments B, C, D, E will be the Test treatments. 
3.2. Secondary Endpoints
The secondary endpoints are the following:

The test/reference ratios for AUCinf (if data permits), AUClast, and Cmax of nirmatrelvir 
and ritonavir, where Treatment D will be the Reference treatment while Treatment E 
will be the Test treatment.

Safety and tolerability data, discussed in Section 3.5.

Palatability data, collected using the sponsor-provided questionnaire. The scores for 
each attribute (mouth feel, bitterness, tongue/mouth burn, throat burn, overall liking) 
will be derived by measuring the length (using a scale with gradations of at least 0.1 
cm) of the “x” marked by the participant relative to the “good trait”.
 
 
 
 
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Other exploratory endpoints include the test/reference ratios for AUCinf (if data permits), 
AUClast, and Cmax of nirmatrelvir and ritonavir, where Treatment B will be the Reference 
treatment while Treatments C and D will be the Test treatments.
3.4. Baseline Variables
Baseline characteristics will be collected according to the schedule of activities (SoA) as 
specified in the protocol.
3.5. Safety Endpoints
The following data are considered in standard safety summaries (see protocol for collection
days, baseline assessment, and list of parameters):

adverse events (AE)

laboratory data

vital signs data

electrocardiogram (ECG) results
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3.5.1. Adverse Events
Any adverse events occurring following start of treatment will be considered as treatment 
emergent adverse event (TEAE). Events that occur during follow-up within the lag time of 
up to 28 days after the last of nirmatrelvir/ritonavir dose will be counted as treatment 
emergent and attributed to the last treatment taken. Events that occur during the washout 
period (up to 28 days from the last treatment) between study periods will be counted as 
treatment emergent and attributed to the previous treatment taken. The time period for 
collecting AEs (“active collection period”) for each participant begins from the time the 
participant provides informed consent.
3.5.2. Laboratory Data
Safety laboratory tests will be performed as described in the protocol. To determine if there 
are any clinically significant laboratory abnormalities, the haematological, clinical chemistry 
(serum) and urinalysis safety tests will be assessed against the criteria specified in the 
sponsor reporting standards. The assessment will not take into account whether each 
participants’s baseline test result is within or outside the laboratory reference range for the 
particular laboratory parameter.
The baseline measurement is the predose measurement on Day -1.
3.5.3. Vital Signs
Supine blood pressure (BP) and pulse rate (PR) will be measured at times specified in the 
SoA given in the protocol.
For each period, the baseline measurement is the predose measurement on Day 1.
3.5.4. Electrocardiograms
QT interval, QTcF, PR, QRS and heart rate (HR) will be recorded at each assessment time 
indicated in the SoA given in the protocol. QTcF will be derived using Fridericia’s heart rate 
correction formula:
QTcF = QT / (RR)^(1/3) where RR = 60/HR (if not provided)
The baseline measurement is the predose measurement on Period 1 Day 1.
4. ANALYSIS SETS (POPULATIONS FOR ANALYSIS)
Data for all participants will be assessed to determine if participants meet the criteria for 
inclusion in each analysis population prior to releasing the database and classifications will 
be documented per standard operating procedures.


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Participant Analysis Set
Description
Enrolled/Randomly
assigned to study
intervention
“Enrolled” means a participant's agreement to participate in 
a clinical study following completion of the informed consent
process and 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. A 
participant will be considered enrolled if the informed 
consent is not withdrawn prior to participating in any study 
activity after screening.
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 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 PK parameters of primary 
interest are reported.
5. GENERAL METHODOLOGY AND CONVENTIONS
Final analysis will be performed after study participant data set release following last 
participant last visit.
5.1. Hypotheses and Decision Rules
No statistical hypothesis will be tested in this study.
5.2. General Methods
5.2.1. Analyses for Binary/Categorical Endpoints
For binary or categorical variables, number of participants, numbers and percentages of 
participants meeting the categorical criteria will be presented in accordance with the Clinical 
Data Interchange Standards Consortium and Pfizer Standards (CaPS).
5.2.2. Analyses for Continuous Endpoints
For continuous variables, the data will be summarized using the number of participants, 
mean, median, standard deviation (SD), minimum, and maximum in accordance with the 
CaPS. For appropriate PK parameters, geometric mean and geometric coefficient of variation 
(%CV) will also be summarized.


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5.3. Methods to Manage Missing Data
5.3.1. Pharmacokinetic Data
Methods to handle missing PK data are described below. 
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.).
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.
An anomalous concentration value is one that, after verification of bioanalytical validity, is 
grossly inconsistent with other concentration data from the same individual or from other 
participants. For example, a BLQ concentration that is between quantifiable values from the 
same dose is considered as anomalous. Anomalous concentration values may be excluded 
from PK analysis at the discretion of the PK analyst.
PK 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 not be presented for a particular treatment group if more 
than 50% of the data are NC. For statistical analyses, PK parameters coded as NC will also 
be set to missing.
If an individual participant has a known biased estimate of a PK parameter (due for example 
to dosing error or an unexpected event such as vomiting before all the compound is 
adequately absorbed from the gastrointestinal tract), this will be footnoted in summary tables 
and will not be included in the calculation of summary statistics or statistical analyses.  For 
instance, if a participant has a vomiting event post dose that is within a duration of time that 
is 2-times the derived median Tmax for the population for the administered treatment, then the 


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pharmacokineticist should consider the exclusion of the PK concentration data collected 
following the initial vomiting event in that treatment period and the PK parameter data 
reported for that treatment period from the datasets used to calculate summary statistics or 
statistical analyses.
5.3.2. Safety Data
Missing values in standard summaries of AEs, laboratory data, vital signs, and ECGs will be 
imputed according to CaPS.
6. ANALYSES AND SUMMARIES
6.1. Primary Endpoints
For the estimation of rBA of nirmatrelvir/ritonavir oral powder in 3 different food delivery 
vehicles relative to the nirmatrelvir/ritonavir commercial tablets, natural log transformed 
AUCinf (if data permits), AUClast and Cmax 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. 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.
Residuals from the models 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 CSR. 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.
6.2. Secondary Endpoints
For the secondary endpoints on the assessment of food effect, same analyses as in the 
primary endpoints will be used, but with Treatment D as the Reference treatment and 
Treatment E as the Test treatment.
Analyses and summaries of safety data are described in Section 6.6.
For the taste assessment of the study, the data used in the analysis will be transcribed and 
rescaled to a score from 0 to 100 from the raw measurements on the questionnaire. The 
sensory attributes (mouthfeel, bitterness, tongue/mouth burn, throat burn, overall liking) from 
the taste questionnaires will be listed and descriptively summarized by treatment, and 
question across participants. Summary statistics (mean and 90% CI) will be calculated for the 
various questions. Radar plots for each of 4 time points, summarizing all attributes for each 
treatment will be generated. Boxplots of each attribute will be plotted against the time points.


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6.4. Subset Analyses
There are no planned subset analyses.
6.5. Baseline and Other Summaries and Analyses
6.5.1. Demographic Summaries
Demographic characteristics (age, gender, ethnicity, race, weight, height and body mass 
index) will be summarized for enrolled population in accordance with the CaPS.
6.5.2. Study Conduct and Participant Disposition
Participants evaluation groups will show end of study participant disposition. Frequency 
counts will be supplied for participant discontinuation(s) by treatment. Data will be reported 
in accordance with the CaPS.
6.5.3. Study Treatment Exposure
Study treatment exposure will be listed.
6.5.4. Concomitant Medications and Nondrug Treatments
All concomitant medication(s) as well as non-drug treatment(s) will be reported in the 
listings.
6.6. Safety Summaries and Analyses
All safety analyses will be performed on the Safety Analysis Set.
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Safety data will be presented in tabular and/or graphical format and summarized 
descriptively, where appropriate.
6.6.1. Adverse Events
Adverse events will be reported in accordance with the CaPS.
Participant discontinuations due to adverse events will be detailed by treatment. Data will be 
reported in accordance with the CaPS.
6.6.2. Laboratory Data
Laboratory data will be listed and summarized by treatment in accordance with the CaPS.
6.6.3. Vital Signs
Vital sign data will be databased and available upon request.
6.6.4. Electrocardiograms
ECG data will be databased and available upon request.
7. 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 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.


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APPENDICES
Appendix 1. SAS Code for Analyses
An example of the PROC MIXED code is provided below:
For primary objectives:
proc mixed data=tab.pk;
class seq period trt participant;
model l&var=seq period trt/ ddfm=KR;
random participant(seq) /subject=participant(seq);
lsmeans trt;
estimate 'B vs A' trt -1 1 0 0 0  /cl alpha=0.1;
estimate 'C vs A' trt -1 0 1 0 0  /cl alpha=0.1;
estimate 'D vs A' trt -1 0 0 1 0  /cl alpha=0.1;
estimate 'E vs A' trt -1 0 0 0 1  /cl alpha=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 
 tablets under fasted 
condition (Reference);
B: Single oral dose of nirmatrelvir/ritonavir 
 oral powder mixed in water 
under fasted condition (Test);
C: Single oral dose of nirmatrelvir/ritonavir 
 oral powder mixed in infant 
formula under fasted condition (Test);
D: Single oral dose of nirmatrelvir/ritonavir 
 oral powder mixed in vanilla 
pudding under fasted condition (Test);
E: Single oral dose of nirmatrelvir/ritonavir 
 oral powder mixed in vanilla 
pudding under fed condition (Test)
*/
For secondary objective:
proc mixed data=tab.pk;
where trt in (“D”, “E”);
class seq period trt participant;
model l&var= seq period trt / ddfm=KR;
random participant(seq) / subject=participant(seq);
lsmeans trt;
estimate 'E vs D' trt -1  1  /cl alpha=0.1;
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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;
D: Single oral dose of nirmatrelvir/ritonavir 
 oral powder mixed in vanilla 
pudding under fasted condition (Reference);
E: Single oral dose of nirmatrelvir/ritonavir 
 oral powder mixed in vanilla 
pudding under fed condition (Test)
*/
 
 
 
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Appendix 2. List of Abbreviations
Abbreviation
Term
%CV
coefficient of variation
AE
adverse event
AUCinf
area under the concentration-time curve from time 0 to infinity
AUClast
area under the concentration-time curve from 0 to time of last 
measurable concentration
BLQ
below the limit of quantitation
BP
blood pressure
CaPS
Clinical Data Interchange Standards Consortium and Pfizer 
Standards
CI
confidence interval
Clast
estimated plasma concentration at the last quantifiable time point
estimated form the log-linear regression analysis
Cmax
maximum observed plasma concentration
CSR
clinical study report
ECG
electrocardiogram
HR
heart rate
kel
the terminal phase rate constant calculated by a linear regression of 
the loglinear concentration-time curve
LLQ
lower limit of quantitation
mg
milligram
N/A
not applicable
NC
not calculated
ND
not done
NS
no sample
PK
pharmacokinetic(s)
PR
pulse rate
QRS
Combination of Q-, R- and S- wave on an electrocardiogram 
representing ventricular depolarization
QTc
corrected QT
QTcF
corrected QT (Fridericia method)
RR
respiratory rate
SAP
statistical analysis plan
SD
standard deviation
SoA
schedule of activities
TEAE
treatment emergent adverse event
C
CI
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