Clinical trial NCT05005312
Conditions: Hepatic Impairment
Keywords: COVID-19 SARS-CoV-2
Sponsor: Pfizer
Start date: 2021-08-31; Completion date: 2021-12-07
Enrollment: 17 participants; Allocation: NON_RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The study is to estimate the effect of hepatic impairment on the plasma PK of PF-07321332/ritonavir. Findings from this study will be used to develop dosing recommendations so that the dose and/or dosing interval may be adjusted appropriately in the presence of hepatic impairment.

Detailed description:

Arms: arm 1: Healthy Volunteer arm 2: Hepatic Impairment
Interventions: intervention 1: PF-07321332 intervention 2: Ritonavir
Intervention descriptions: intervention 1: Tablet intervention 2: PK Boosting agent

Protocol documents:
Prot_000.pdf: 
PF-07321332 
Protocol C4671010
Final Protocol, 25 June 2021
PFIZER CONFIDENTIAL
Page 1
A PHASE 1, NON-RANDOMIZED, OPEN-LABEL STUDY TO ASSESS THE 
PHARMACOKINETICS, SAFETY AND TOLERABILITY OF PF-07321332 
BOOSTED WITH RITONAVIR IN ADULT PARTICIPANTS WITH MODERATE 
HEPATIC IMPAIRMENT AND HEALTHY PARTICIPANTS WITH NORMAL 
HEPATIC FUNCTION
Study Intervention Number:
PF-07321332
Study Intervention Name:
Not applicable
US IND Number:
153517
EudraCT Number:
N/A
ClinicalTrials.gov ID:
N/A
Protocol Number:
C4671010
Phase:
1
Brief Title: Study to Estimate the Effects of Hepatic Impairment on the 
Pharmacokinetics of PF-07321332
This document and accompanying materials contain confidential information belonging to Pfizer. Except as 
otherwise agreed to in writing, by accepting or reviewing these documents, you agree to hold this 
information in confidence and not copy or disclose it to others (except where required by applicable law) or 
use it for unauthorized purposes. In the event of any actual or suspected breach of this obligation, Pfizer 
must be promptly notified.


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Document History
Document
Version Date
Original protocol
25 June 2021


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Final Protocol, 25 June 2021
PFIZER CONFIDENTIAL
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TABLE OF CONTENTS
LIST OF TABLES.....................................................................................................................8
LIST OF FIGURES ...................................................................................................................8
1. PROTOCOL SUMMARY.....................................................................................................9
1.1. Synopsis ....................................................................................................................9
1.2. Schema ....................................................................................................................12
1.3. Schedule of Activities .............................................................................................13
2. INTRODUCTION ...............................................................................................................16
2.1. Study Rationale .......................................................................................................16
2.2. Background .............................................................................................................16
2.2.1. Nonclinical Pharmacology..........................................................................16
2.2.2. Nonclinical Pharmacokinetics and Metabolism .........................................16
2.2.3. Nonclinical Safety ......................................................................................17
2.2.4. Clinical Overview.......................................................................................17
2.3. Benefit/Risk Assessment.........................................................................................19
2.3.2. Benefit Assessment.....................................................................................22
2.3.3. Overall Benefit/Risk Conclusion................................................................22
3. OBJECTIVES AND ENDPOINTS.....................................................................................22
4. STUDY DESIGN.................................................................................................................23
4.1. Overall Design.........................................................................................................23
4.2. Scientific Rationale for Study Design.....................................................................24
4.2.1. Choice of Contraception/Barrier Requirements .........................................25
4.2.2. Collection of Retained Research Samples..................................................25
4.3. Justification for Dose ..............................................................................................25
4.4. End of Study Definition ..........................................................................................25
5. STUDY POPULATION......................................................................................................25
5.1. Inclusion Criteria.....................................................................................................26
5.2. Exclusion Criteria....................................................................................................27
5.3. Lifestyle Considerations..........................................................................................31
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5.3.1. Meals and Dietary Restrictions...................................................................31
5.3.2. Caffeine, Alcohol, and Tobacco .................................................................31
5.3.3. Activity .......................................................................................................31
5.3.4. Contraception..............................................................................................32
5.4. Screen Failures ........................................................................................................32
6. STUDY INTERVENTION(S) AND CONCOMITANT THERAPY.................................32
6.1. Study Intervention(s) Administered........................................................................32
6.1.1. Administration............................................................................................33
6.2. Preparation, Handling, Storage, and Accountability...............................................33
6.2.1. Preparation and Dispensing........................................................................34
6.3. Measures to Minimize Bias: Randomization and Blinding.....................................34
6.3.1. Allocation to Study Intervention ................................................................34
6.4. Study Intervention Compliance...............................................................................34
6.5. Dose Modification...................................................................................................35
6.6. Continued Access to Study Intervention After the End of the Study......................35
6.7. Treatment of Overdose............................................................................................35
6.8. Concomitant Therapy..............................................................................................35
6.8.1. Participants with Healthy Liver Function (Cohort 1).................................36
6.8.2. Participants with Impaired Liver Function (Cohort 2) ...............................36
6.8.3. Rescue Medicine.........................................................................................36
7. DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL...........................................................................36
7.1. Discontinuation of Study Intervention ....................................................................36
7.2. Participant Discontinuation/Withdrawal From the Study.......................................37
7.2.1. Withdrawal of Consent...............................................................................38
7.3. Lost to Follow up ....................................................................................................38
8. STUDY ASSESSMENTS AND PROCEDURES...............................................................38
8.1. Efficacy Assessments..............................................................................................40
8.2. Safety Assessments .................................................................................................40
8.2.1. Physical Examinations................................................................................40
8.2.2. Vital Signs ..................................................................................................40
8.2.3. Electrocardiograms.....................................................................................41


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8.2.4. Clinical Safety Laboratory Assessments ....................................................41
8.2.5. COVID-19 specific assessments.................................................................42
8.2.6. Pregnancy Testing ......................................................................................42
8.3. Adverse Events, Serious Adverse Events, and Other Safety Reporting .................43
8.3.1. Time Period and Frequency for Collecting AE and SAE Information.......43
8.3.1.1. Reporting SAEs to Pfizer Safety...............................................44
8.3.1.2. Recording Nonserious AEs and SAEs on the CRF...................44
8.3.2. Method of Detecting AEs and SAEs ..........................................................44
8.3.3. Follow-up of AEs and SAEs.......................................................................44
8.3.4. Regulatory Reporting Requirements for SAEs...........................................44
8.3.5. Environmental Exposure, Exposure During Pregnancy or 
Breastfeeding, and Occupational Exposure.....................................................45
8.3.5.1. Exposure During Pregnancy......................................................45
8.3.5.2. Exposure During Breastfeeding ................................................47
8.3.5.3. Occupational Exposure .............................................................47
8.3.6. Cardiovascular and Death Events...............................................................47
8.3.7. Disease Related Events and/or Disease Related Outcomes Not 
Qualifying as AEs or SAEs..............................................................................47
8.3.8. Adverse Events of Special Interest.............................................................47
8.3.8.1. Lack of Efficacy........................................................................48
8.3.9. Medical Device Deficiencies......................................................................48
8.3.10. Medication Errors.....................................................................................48
8.4. Pharmacokinetics ....................................................................................................48
8.4.1. Plasma for Analysis of PF-07321332 
..................................48
8.7. Immunogenicity Assessments.................................................................................51
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8.8. Health Economics ...................................................................................................51
9. STATISTICAL CONSIDERATIONS ................................................................................51
9.1. Statistical Hypotheses .............................................................................................51
9.2. Analysis Sets ...........................................................................................................51
9.3. Statistical Analyses .................................................................................................51
9.3.1. Other Safety Analyses ................................................................................52
9.3.2.1. Pharmacokinetic Analyses ........................................................52
9.4. Interim Analyses .....................................................................................................54
10. SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS..........................................................................................................55
10.1. Appendix 1: Regulatory, Ethical, and Study Oversight Considerations...............55
10.1.1. Regulatory and Ethical Considerations ....................................................55
10.1.1.1. Reporting of Safety Issues and Serious Breaches of the 
Protocol or ICH GCP.........................................................................55
10.1.2. Financial Disclosure .................................................................................56
10.1.3. Informed Consent Process ........................................................................56
10.1.4. Data Protection .........................................................................................57
10.1.5. Committees Structure ...............................................................................57
10.1.5.1. Data Monitoring Committee ...................................................57
10.1.6. Dissemination of Clinical Study Data ......................................................57
10.1.7. Data Quality Assurance ............................................................................58
10.1.8. Source Documents....................................................................................59
10.1.9. Study and Site Start and Closure ..............................................................60
10.1.10. Publication Policy...................................................................................61
10.1.11. Sponsor’s Qualified Medical Personnel .................................................62
10.2. Appendix 2: Clinical Laboratory Tests .................................................................63
10.3. Appendix 3: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-Up, and Reporting .....................................................................64
10.3.1. Definition of AE .......................................................................................64
10.3.2. Definition of an SAE ................................................................................65
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10.3.3. Recording/Reporting and Follow-Up of AEs and/or SAEs During 
the Active Collection Period............................................................................66
10.3.4. Reporting of SAEs....................................................................................70
10.4. Appendix 4: Contraceptive and Barrier Guidance ................................................72
10.4.1. Male Participant Reproductive Inclusion Criteria....................................72
10.4.2. Female Participant Reproductive Inclusion Criteria.................................72
10.4.3. Woman of Childbearing Potential ............................................................73
10.4.4. Contraception Methods.............................................................................74
10.6. Appendix 6: Liver Safety: Suggested Actions and Follow-Up Assessments .......77
10.7. Appendix 7: ECG Findings of Potential Clinical Concern ...................................79
10.9. Appendix 9: Child-Pugh Classification (CPC) of Liver Dysfunction...................84
10.10. Appendix 10: Abbreviations ...............................................................................85
11. REFERENCES ..................................................................................................................89
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LIST OF TABLES
Table 1.
Hepatic Function Categories Based on Child-Pugh Score .......................23
Table 2.
Plasma PK Parameters..............................................................................53
Table 4.
Protocol-Required Safety Laboratory Assessments .................................63
Table 5.
Scoring for Child-Pugh Classification......................................................84
Table 6.
Derivation of Child-Pugh Classification Score ........................................84
Table 7.
Determination of Encephalopathy Grade .................................................84
LIST OF FIGURES
Figure 1.
Treatment and Schema .............................................................................12
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1. PROTOCOL SUMMARY 
1.1. Synopsis 
Brief Title: Study to Estimate the Effects of Hepatic Impairment on the Pharmacokinetics of 
PF-07321332.
Rationale
The purpose of this study is to estimate the effect of hepatic impairment on the plasma PK of 
PF-07321332/ritonavir. Findings from this study will be used to develop dosing 
recommendations so that the dose and/or dosing interval may be adjusted appropriately in the 
presence of hepatic impairment.
Objectives and Endpoints
Objectives
Endpoints
Primary:
Primary:
•
To compare the PK of PF-07321332, following 
a single oral dose administration of 
PF-07321332 pharmacokinetically boosted 
with ritonavir in adult participants with 
moderate hepatic impairment and age and body 
weight-matched participants without hepatic 
impairment.
•
Plasma PF-07321332 PK parameters: Cmax, 
AUClast, AUCinf (if data permit)
Secondary: 
Secondary: 
•
To evaluate the safety and tolerability of 
PF-07321332 and ritonavir, following a single 
oral dose administration of PF-07321332 
pharmacokinetically boosted with ritonavir, in 
participants with moderate hepatic impairment 
and in healthy participants with normal hepatic 
function.
•
Incidence of TEAEs, abnormal ECGs, vital 
signs, and laboratory values
 
 
 
 
 
 
 
 
 
 
 
 
 
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Overall Design
Brief Summary
This is a Phase 1, non-randomized, open-label study to investigate the effect of hepatic 
impairment on the plasma PK, safety and tolerability of a single oral dose of PF-07321332 in 
combination with the PK boosting agent ritonavir in approximately 16 participants. The 
study will be conducted in adult participants with stable, moderate hepatic impairment and a 
control group of participants with normal hepatic function. 
Enrollment will be in a staged manner such that participants with hepatic impairment 
(Cohort 2) will begin enrollment first. Participants without hepatic impairment (Cohort 1) 
will begin recruitment towards the end of Cohort 2 or earlier, at the sponsor’s discretion such 
that the enrollment in both cohorts may overlap. Participants in Cohort 1 will match the 
average demographics (at a minimum, age and weight; gender and race as much as 
practically possible) of participants in Cohort 2. 
All participants in both cohorts will provide informed consent and undergo Screening 
evaluations to determine their eligibility. Categorization of participants into hepatic 
impairment cohort, Cohort 2, will be done based on Child-Pugh scores as described in 
Appendix 9, at the Screening visit.
Participants who prematurely discontinue for non-safety related reasons may be replaced, at 
the discretion of the PI and sponsor study team.
Eligible participants will be admitted to the CRU on Day -1 (at least 12 hours prior to the 
dosing of PF-07321332 on Day 1) and will be confined in the CRU until Day 3. On the 
evening of Day -1, participants will receive a single 100 mg dose of ritonavir (-12 hour 
relative to PF-07321332 dosing). On the morning of Day 1, the participants will receive a 
single dose of 100 mg PF-07321332 with a 100 mg dose of ritonavir after an overnight (or a 
minimum of 6 hours) fast. Ritonavir, 100 mg, will continue to be dosed at 12 and 24 hours 
post PF-07321332 dosing to ensure maintenance of the PK boosting effect. Serial blood 
 
 samples at specified intervals will be collected up to 24 hours post-dose for PK 
assessments. 
Safety assessments will be performed during Screening, on Day -1 prior to dosing and on 
Day 3. Physical examinations, vital sign measurements, and clinical laboratory tests will be 
conducted, and AEs will be monitored to assess safety. The total participation time (eg, CRU 
confinement time for study procedures) for each participant in this study is approximately 
3 nights/4 days (excluding screening & Follow-Up contact). 
A safety follow-up call will be made to participants 28 to 35 days from administration of the 
last dose of PF-07321332.
Number of Participants
Approximately 16 participants will be enrolled to study intervention.
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Note: "Enrolled" means a participant's, or his or her legally authorized representative’s, 
agreement to participate in a clinical study following completion of the informed consent 
process and screening. A participant will be considered enrolled if the informed consent is 
not withdrawn prior to participating in any study activity after screening. Potential 
participants who are screened for the purpose of determining eligibility for the study, but do 
not participate in the study, are not considered enrolled, unless otherwise specified by the 
protocol.
Intervention Groups and Duration
Each enrolled participant will receive a single 100 mg dose of PF-07321332 administered 
orally in combination with the PK boosting agent ritonavir administered as a 100 mg dose 
at -12, 0, 12, and 24 hours relative to PF-07321332 dosing. 
The total planned duration of participation, from the Screening visit to the last Follow-up 
phone call, is approximately up to 9 weeks.
Data Monitoring Committee or Other Independent Oversight Committee: No
Statistical Methods
One-way ANOVA will be used to compare the natural log transformed AUClast, AUCinf (if 
data permit) and Cmax for PF-07321332 between Cohort 2 with moderate hepatic impairment 
(Test) and Cohort 1 with normal hepatic function (Reference). Estimates of the adjusted 
mean differences (Test-Reference) and corresponding 90% CI will be obtained from the 
model. The adjusted mean differences and 90% CIs for the differences will be exponentiated 
to provide estimates of the ratio of the adjusted geometric means (Test/Reference) and 
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1.2. Schema
Figure 1.
Treatment and Schema
≤ 28 days
Screen
Day -1
Admission to CRU
Administration of ritonavir
a
Day 1
Administration of PF-07321332 
and ritonavir
b
Day 2
Last dose of ritonavir
b
Day 3
CRU Discharge 
Inpatient Stay at CRU
Day 28 – 35 
Follow-up via 
telephone contact
c
a.
Admission can occur at any time of day; once admitted, participants to be provided inpatient meal(s). On the 
evening of Day -1, participants will receive a single 100 mg dose of ritonavir (-12-hour relative to PF-07321332 
dosing). 
b.
On the morning of Day 1, participants will receive a single dose of 100 mg PF-07321332 with a 100 mg dose of 
ritonavir after a fast of at least 6 hours, followed by ritonavir (100 mg) to be dosed at 12 and 24 hours post 
PF-07321332 dosing. 
c.
Contact may occur via telephone contact and must occur 28 to 35 days from administration of PF-07321332 or 
from the time of early termination/discontinuation. 


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1.3. Schedule of Activities
The SoA table provides an overview of the protocol visits and procedures. Refer to the STUDY ASSESSMENTS AND 
PROCEDURES section of the protocol for detailed information on each procedure and assessment required for compliance with the 
protocol. 
The investigator may schedule visits (unplanned visits) in addition to those listed in the SoA table, in order to conduct evaluations or 
assessments required to protect the well-being of the participant.
Visit Identifiera
Screening
Day -1
Day 1
Day 2
Day 3
Early 
Termination/
DC
Follow-up
Contact
Days Relative to Day 1
Abbreviations used in this table 
can be found in Appendix 10
Day -28 to Day -2
28-35 Daysb
Informed consent
X
Admission to CRU
X
Confinement to CRU
X


X
Inclusion/exclusion criteria
X
X
Medical history 
X
X
Demographyc
X
Physical examinationd
X
X
X
X
Height and weight assessment
X
Safety laboratory testse
X
X
X
X
Child-Pugh classificationf
X
History of illegal 
drug/tobacco/alcohol use
X
X
Urine alcohol test or alcohol 
breath test
X
X
Urine or serum pregnancy test 
(WOCBP only)
X
X
X
X
Contraception checkg
X
X
X
X
X
Serum FSH in post-menopausal 
females amenorrheic ≥12 months 
and under 60 years of age
X
Urine drug screen
X
X
Single supine 12-Lead ECGh
X
X
X
X


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Visit Identifiera
Screening
Day -1
Day 1
Day 2
Day 3
Early 
Termination/
DC
Follow-up
Contact
Days Relative to Day 1
Abbreviations used in this table 
can be found in Appendix 10
Day -28 to Day -2
28-35 Daysb
Single, seated vital signs (BP, 
and pulse rate)i
X
X
X
X
HIV, HBsAg, HBcAb, HCVAb 
testingj
X
PF-07321332 administration
X
Ritonavir administrationk
X
X
X
Plasma PK for PF-07321332
 
l
X
X
X
X
 
Prior/concomitant treatments
X
X
→
→
X
X
X
COVID-19 testingo
X
X
COVID-19 check temperaturep
X
X
X
X
X
COVID-19 questionnaireq
X
X
CRU discharge 
X
Serious and nonserious adverse 
event monitoring
X
X
→
→
X
X
X
Standard meals
X
Xr
X
X
a.
Day relative to start of PF-07321332 dosing (Day 1).
b.
Contact may occur via telephone contact and must occur 28 to 35 days from administration of PF-07321332 or from the time of early termination/discontinuation. 
c.
Demographics will include race, age, and gender.
d.
Complete physical examination will be performed at screening; and limited PE will be conducted on Day -1, Day 3, early termination, and at any time point as deemed 
necessary by the investigator.
e.
Safety laboratory assessments include chemistry, hematology, and urinalysis (and microscopy, if needed) and must be collected following at least a 4 hour fast. 
f.
The Child-Pugh classification (Appendix 9) will be used to define the participants of Cohort 2 with moderate hepatic impairment (Child-Pugh Class B) at Screening.
g.
Confirmation of the correct use of appropriate contraceptive method.
h.
Single 12-lead ECG readings will be taken pre-dose on Day 1 and at specified times. All ECG assessments will be made prior to any blood draws or vital sign 
measurements. 
i.
Single seated BP and PR will be performed pre-dose on Day 1 and at specified times. All BP and PR will be measured prior to collection of blood draws if scheduled at the 
same time, after collection of ECGs.
j.
Testing will be performed as described in Appendix 2.
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Visit Identifiera
Screening
Day -1
Day 1
Day 2
Day 3
Early 
Termination/
DC
Follow-up
Contact
Days Relative to Day 1
Abbreviations used in this table 
can be found in Appendix 10
Day -28 to Day -2
28-35 Daysb
k.
Ritonavir will be administered on Day -1 at -12 hours, Day 1 at 0 hours and 12 hours, and Day 2 at 24 hours, relative to PF-07321332 dosing.
l.
Blood samples are to be collected for plasma PK assessment of PF-07321332 
 on Day 1 at 0 (pre-dose for PF-07321332), 0.5, 1, 2, 3, 4, 6, 8, 10, and 12 hours, 
Day 2 at 24 and 36 hours, and Day 3 at 48 hours, relative to PF-07321332 dosing, and at early termination/DC (if before 48 hours post-dose for PF-07321332), if needed.
 
o.
Testing for COVID-19 pathogen will be performed prior to being admitted to the clinic for confinement, on Day -1, and if participant develops COVID-19 like symptoms.
p.
To be done at least daily during residence. 
q.
Check exposure to positive case, residence or travel in area of high incidence and COVID-19 related signs and symptoms.
r.
Meals/snacks to be served at clock times matching approximately 0H, 4H, 7H, 10H, and 14H (optional) relative to dosing on Day 1 (while inpatient).
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2. INTRODUCTION
PF-07321332 is a potent and selective inhibitor of the SARS-CoV-2 3CL protease that is 
currently being developed as an oral treatment of COVID-19. Ritonavir is a strong CYP3A4 
inhibitor being used to inhibit the metabolism of PF-07321332 in order to increase plasma 
concentrations of PF-07321332 to values that are anticipated to be efficacious.
2.1. Study Rationale 
PF-07321332/ritonavir is intended for short term (eg, 5 day) use, in patients with COVID-19,
some of whom may have some degree of impaired hepatic function. Therefore, the purpose 
of this study is to characterize the effect of hepatic impairment on the plasma PK of 
PF-07321332/ritonavir. Findings from this study will be used to develop dosing 
recommendations so that the dose and/or dosing interval may be adjusted appropriately in the 
presence of hepatic disease.
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 20 January 2020 and further characterized the 
disease outbreak as a pandemic on 11 March 2020.1
PF-07321332 is an orally bioavailable 3CLpro inhibitor shown to be effective against 
SARS-CoV-2 3CLpro (Ki = 0.00311 µM) in a biochemical enzymatic assay. Since the 
3CLpro from human coronaviruses are structurally similar and share a high degree of 
conservation at the active site of the enzyme, the ability of PF-07321332 to inhibit the 3CLpro
of other coronaviruses (SARS-CoV-1 and HCoV-229E, MERS, HCoV-OC43, HCoV-HKU1, 
and HCoV-NL63) was also confirmed, indicating a potential for broad spectrum 
anti-coronavirus activity. The coronavirus 3CL protease is a virally encoded enzyme that is 
critical to the SARS-CoV-2 replication cycle, analogous to other obligatory virally encoded 
proteases (eg, HIV Protease, HCV Protease).2 PF-07321332 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 PF-07321332 
in order to increase plasma concentrations of PF-07321332 to values that are anticipated to 
be efficacious. Ritonavir did not show SARS-CoV-2 antiviral activity in vitro up to 3 µM 
ritonavir and is being used only as a pharmacokinetic boosting agent.
2.2.1. Nonclinical Pharmacology
Details of the nonclinical pharmacology of PF-07321332 can be found in the current IB.3
2.2.2. Nonclinical Pharmacokinetics and Metabolism
Hepatic CYP450 enzymes were identified as the main pathway for clearance of PF-07321332 
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. In a 
reaction phenotyping study using human liver microsomes in the presence of selective CYP
inhibitors, CYP3A4 was predicted to be the major contributor (fm = 0.99) to the in vitro 


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oxidative metabolism of PF-07321332. No significant CYP3A5 contribution is expected to 
the metabolism of PF-07321332. Urinary excretion of PF-07321332 following single IV or 
oral doses in rats was approximately 11%, suggesting minor urinary contributions to the 
overall elimination of PF-07321332.
PF-07321332 is not extensively bound to human plasma proteins, with fu of 0.31 observed in 
the in vitro protein binding study.
Additional information of the nonclinical PK and metabolism of PF-07321332 is available in 
the current IB.3
2.2.3. Nonclinical Safety
There were no adverse findings observed in repeat-dose toxicity studies in rats and monkeys 
up to 2 weeks duration and the NOAELs were the highest dose administered (1000 mg/kg 
and 600 mg/kg in the rat and monkey studies, respectively). PF-07321332-related 
non-adverse, test article-related clinical findings included sporadic occurrence of emesis with 
slight body weight decreases in monkeys. Monitorable and reversible clinical pathology 
findings included those possibly suggestive of low-grade inflammation (in rats and monkeys) 
or alterations in the coagulation pathways (in rats only) without clinical or microscopic 
correlates. Other non-adverse clinical pathology findings were likely due to the emesis and 
subsequent dehydration in monkeys. In rats administered 1000 mg/kg/day, lower mean 
absolute and relative heart weights (females) and higher absolute and relative liver weights 
(both sexes) were observed relative to controls. The lower heart weights had no microscopic 
correlates and were fully reversed at the end of the 2-week recovery period. Higher liver 
weights correlated with reversible, non-adverse microscopic findings of minimal to mild 
severity in the liver and thyroid gland consistent with adaptive changes related to microsomal 
enzyme induction.
PF-07321332 was not mutagenic or clastogenic in in vitro genetic toxicity studies and was 
negative in the in vivo rat micronucleus assay incorporated into the GLP repeat-dose rat 
toxicity study. 
The nonclinical studies performed adequately support the oral administration of 
PF-07321332 in the clinic for up to 14 days.
Further details of the nonclinical safety program are provided in the current IB.3
2.2.4. Clinical Overview
Safety, tolerability and pharmacokinetics of PF-07321332 in healthy adult participants is 
currently being explored in an ongoing Phase 1 FIH study (C4671001). Study C4671001 is a 
4-part study consisting of SAD (PART-1), MAD (PART-2), relative bioavailability/food 
effect (PART-3) evaluations, and evaluation for metabolism and excretion (PART-4). 
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 
PF-07321332, respectively. PART-3 is randomized and open-label to evaluate relative 
bioavailability and food effect of an oral tablet formulation. PART-4 is an open-label, 


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non-randomized, single period to evaluate the metabolism and excretion of PF-07321332.
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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2.3. Benefit/Risk Assessment
PF-07321332/ritonavir is not expected to provide any clinical benefit to healthy participants 
or participants with hepatic impairment in this study. This study is designed primarily to 
characterize the effect of hepatic impairment on the plasma PK of a single dose of 
PF-07321332 pharmacokinetically enhanced with ritonavir. The data from this study are 
expected to provide the basis for development of dosing recommendations for target patient 
populations who may have hepatic impairment. 
Based on preliminary data from the ongoing Phase 1 study (C4671001) collected as of 
07 April 2021 in PART-1 and 14 April 2021 in PART-2 (data snapshot taken), the clinical 
safety profile of PF-07321332 appears to be acceptable at single doses up to 1500 mg alone 
and up to 750 mg administered with ritonavir (100 mg at -12h, 0h, 12h), and at repeated daily 
doses administered orally for 10 days of up to 500 mg PF-07321332 BID with 100 mg 
ritonavir BID. 
More detailed information about the known and expected benefits and risks and reasonably 
expected adverse events of PF-07321332 with ritonavir may be found in the IB and ritonavir
USPI4, which are the SRSDs for this study.
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2.3.2. Benefit Assessment
PF-07321332/ritonavir will not provide any clinical benefit to healthy participants or 
participants with hepatic impairment in this study. Any anticipated benefit to participants 
would be in terms of contribution to the process of developing a new therapy in an area of 
unmet medical need.
2.3.3. Overall Benefit/Risk Conclusion
Taking into account the measures to minimize risk to study participants, the potential risks 
identified in association with PF-07321332/ritonavir are justified by the anticipated benefits 
that may be afforded to participants with COVID-19.
3. OBJECTIVES AND ENDPOINTS
Objectives
Endpoints
Primary:
Primary:
•
To compare the PK of PF-07321332, following 
a single oral dose administration of 
PF-07321332 pharmacokinetically boosted 
with ritonavir in adult participants with 
moderate hepatic impairment and age and body 
weight-matched participants without hepatic 
impairment.
•
Plasma PF-07321332 PK parameters: Cmax, 
AUClast, AUCinf (if data permit)
Secondary: 
Secondary: 
•
To evaluate the safety and tolerability of 
PF-07321332 and ritonavir, following a single 
oral dose administration of PF-07321332 
pharmacokinetically boosted with ritonavir, in 
participants with moderate hepatic impairment 
and in healthy participants with normal hepatic 
function.
•
Incidence of TEAEs, abnormal ECGs, vital 
signs, and laboratory values
 
 
 
 
 
 
 
 
 
 
 
 
 
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4. STUDY DESIGN
4.1. Overall Design
This is a Phase 1, non-randomized, open-label, single-dose study to compare the 
pharmacokinetics of PF-07321332, given in combination with PK boosting agent, ritonavir, 
in adult participants with moderate hepatic impairment relative to participants without 
hepatic impairment. 
The study will have 2 cohorts: participants without hepatic impairment (Cohort 1) and 
participants with moderate hepatic impairment (Cohort 2).
Enrollment will be in a staged manner such that participants with hepatic impairment 
(Cohorts 2) will be enrolled first. Participants without hepatic impairment (Cohort 1) will 
begin recruitment towards the end of Cohort 2 or earlier, at the sponsor’s discretion, such that 
the enrollment in both cohorts may overlap. Participants in Cohort 1 will match the average
demographics (at a minimum, age and weight; and gender as much as practically possible) of 
participants in Cohort 2. Approval from the sponsor must be obtained before proceeding with 
recruitment for participants in Cohort 1.
Table 1.
Hepatic Function Categories Based on Child-Pugh Score
Cohort
Description
Child-Pugh Score
Number of Participants
1
Without hepatic impairment
Not Applicable
8
2
Moderate hepatic impairment
Class B (7 to 9 points)
8
The Child-Pugh classification (CPC; Appendix 9) will be used to define the participants of 
Cohort 2 with moderate hepatic impairment (Child-Pugh Class B). 
All participants will be required to provide their own consent to participate in this study, 
hence participants with clinically active Grade 3 or Grade 4 encephalopathy will be excluded. 
However, participants who have a previous history of Grade 3 or Grade 4 encephalopathy but 
are currently receiving an intervention [for example: lactulose or lactitol, alone or in 
combination with rifaximin, and/or neomycin] to control their encephalopathy related signs 
and symptoms are eligible provided the on-treatment encephalopathy grading at the 
Screening visit is Grade 2 or lower thereby permitting them to provide their own informed 
consent. 
Eligible participants will be admitted to the CRU on Day -1 (at least 12 hours prior to the 
dosing of PF-07321332 on Day 1) and will be confined in the CRU until Day 3. On the 
evening of Day -1, participants will receive a single 100 mg dose of ritonavir (-12 hour 
relative to PF-07321332 dosing). On the morning of Day 1, the participants will receive a 
single dose of 100 mg PF-07321332 with a 100 mg dose of ritonavir after an overnight (or a 
minimum 6 hour) fast. Ritonavir, 100 mg, will continue to be dosed at 12 and 24 hours post 
PF-07321332 dosing to ensure maintenance of the PK boosting effect. Serial blood 
 
samples at specified intervals will be collected for PK assessments as per SoA. Safety 
assessments will be performed during Screening, on Day -1 prior to dosing, and on Day 3. 
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Physical examinations and clinical laboratory tests will be conducted, and AEs will be 
monitored to assess safety. Vital signs and ECG measurements will be done on Day 1, prior 
to dosing. The total participation time (eg, CRU confinement time for study procedures) for 
each participant in this study is approximately 3 nights/4 days (excluding Screening & 
Follow-Up contact). 
A safety follow-up call will be made to participants 28 to 35 days from administration of the 
dose of study intervention.
Participants who prematurely discontinue for non-safety related reasons may be replaced, at 
the discretion of the PI and sponsor study team.
The overall study design is summarized in Figure 1. For individual participants, the total
duration of participation from the Screening visit to the Follow-Up visit will range from
5 weeks (minimum) to 9 weeks (maximum).
4.2. Scientific Rationale for Study Design
This study is a Phase 1, non-randomized, open-label study of PF-07321332 in participants
with moderate hepatic impairment and participants with normal hepatic function, matched for 
age, body weight and, to the extent possible, for gender composition. Details on age and 
body weight matching criteria are specified in Section 5.1. 
PF-07321332 alone is primarily eliminated through a CYP450 mediated oxidation with 
CYP3A4 as the major contributor (fm = 0.99). However, in the presence of the CYP3A4 
inhibitor ritonavir, preliminary data suggests renal excretion may play a significant role in 
PF-07321332 excretion. In FIH study, approximately 64.6% to 32.5% of the administered 
dose was excreted unchanged in urine and remaining drug may get eliminated via 
metabolism. Preliminary PBPK modeling suggests < 2 × increase in AUC in mild hepatic 
impaired participants (Child-Pugh A) and < 3 × increase in moderate (Child-Pugh B) hepatic 
impaired participants. Therefore, the PK will only be evaluated in moderately hepatic 
impaired participants. Ritonavir has not been studied in severe hepatic impaired patients and 
currently prohibited to be used in those population. Therefore, this study does not plan to 
evaluate PK in severely hepatically impaired participants.
A single dose of PF-07321332 was selected and is considered appropriate as available data 
do not indicate PF-07321332 PK are time-dependent, and hence, single dose data are 
considered predictive of steady state. As ritonavir is not eliminated renally, multiple doses of 
100 mg ritonavir will be administered at -12, 0, 12, and 24 hours relative to PF-07321332 
dosing to ensure adequate PK boosting effect over the duration of PF-07321332 exposure. 
PF-07321332 is not extensively bound to human plasma proteins, with fu of 0.31 observed in 
the in vitro protein binding study. Thus, no additional blood samples will be collected in this 
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4.2.1. Choice of Contraception/Barrier Requirements
Human reproductive safety data are limited for PF-07321332, 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).
 
4.3. Justification for Dose
A single oral dose of 100 mg PF-07321332, pharmacokinetically enhanced with ritonavir 
(100 mg at -12, 0, 12, and 24 hours relative to PF-07321332), is planned in this study. This is 
anticipated to be at the lower end of the clinically effective dose range, and below the
anticipated Phase 2/3 dose of PF-07321332/ritonavir of 300/100 mg. Although single doses 
up to 750 mg PF-07321332 with ritonavir have been evaluated, exposure increased less than 
dose proportional within the 250 mg to 750 mg dose range evaluated. Therefore, 100 mg 
PF-07321332 is appropriate considering systemic exposures of PF-07321332 may be 
increased when administered in hepatic impairment.
When co-administered with ritonavir, doses of PF-07321332 up to 750 mg single dose and 
500 mg q12h for 10 days were generally safe and well tolerated based on preliminary data 
from the Phase 1 Study C4671001. There have been no deaths or serious adverse events or 
SUSARs reported. Based on review of preliminary (unaudited) data, all reported adverse 
events have been of mild intensity. There were no clinically meaningful findings in vital 
signs, ECG, or potential Hy’s Law cases reported during the study. 
Using preliminary PBPK model, the projected AUC and Cmax at the proposed dose are
 which are below the highest observed exposures at safe and 
tolerate dose in study C4671001 and are approximately 19 × and 25 × below NOAEL 
exposures observed in toxicity studies in rats, respectively.
The dose of ritonavir to be used in this study is 100 mg administered BID. This dose is the 
typical dose of ritonavir when dosed as PK enhancer.
4.4. End of Study Definition
The end of the study is defined as the date of the last visit of the last participant in the study.
A participant is considered to have completed the study if he/she has completed all phases of 
the study, including the last visit. 
5. STUDY POPULATION
This study can fulfill its objectives only if appropriate participants are enrolled. 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
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taken into consideration when deciding whether a particular participant is suitable for this 
protocol.
Prospective approval of protocol deviations to recruitment and enrollment criteria, also 
known as protocol waivers or exemptions, is not permitted.
5.1. Inclusion Criteria
Participants are eligible to be included in the study only if all of the following criteria apply:
Age and Sex:
1. Participants must be 18 to 75 years of age, inclusive, at the time of signing the ICD.

[For Cohort 1 only] Each participant’s age is within ±10 years of the mean age of 
the hepatic impairment group. Attempts will be made to ensure that the male-to-
female distribution in Cohort 1 is comparable to that in hepatic impairment
cohort, Cohort 2.

Refer to Appendix 4 for reproductive criteria for male (Section 10.4.1) and female
(Section 10.4.2) participants.
Type of Participant and Disease Characteristics:
2. Participants who are willing and able to comply with all scheduled visits, treatment 
plan, laboratory tests, lifestyle considerations, and other study procedures.
3. [For Cohort 1 only] Male and female participants who are classically healthy having 
no clinically relevant abnormalities as determined by medical evaluation including 
medical history, physical examination including blood pressure and pulse rate 
measurement, 12-lead ECG, and laboratory tests. No known or suspected hepatic 
impairment. 
4. [for Cohort 2 only] Stable hepatic impairment that meets the criteria for Class B of 
the CPC (refer to Appendix 9) with no clinically significant change in disease status 
within the 28 days prior to the Screening visit, as documented by the participant’s 
recent medical history (for example: no worsening clinical signs of hepatic 
impairment, no worsening of total bilirubin or PT by more than 50%).
Weight:
5. BMI of 17.5 to 40 kg/m2; and a total body weight >50 kg (110 lb).

[For Cohort 1 only] Each participant’s body weight within ±15 kg of the mean 
body weight of hepatic impairment group.


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Informed Consent:
6. Capable of giving signed informed consent as described in Appendix 1, which 
includes compliance with the requirements and restrictions listed in the ICD and in 
this protocol.
5.2. Exclusion Criteria
Participants are excluded from the study if any of the following criteria apply:
Medical Conditions:
1. 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).
2. Any condition possibly affecting drug absorption (eg, prior bariatric surgery, 
gastrectomy, ileal resection).
NOTE: Participants who have undergone cholecystectomy and/or appendectomy are
eligible for this study so long as the surgery occurred more than 6 months prior to 
Screening.
3. At screening, participants with a positive result for HIV antibodies. 
4. [For Cohort 1 only] Participants with chronic liver disease including history of 
hepatitis, hepatitis B, or hepatitis C or evidence of active disease, at screening.
NOTE: Participants with a previously positive hepatitis B surface antibody result due 
to vaccination are deemed eligible.
5. [For Cohort 2 only] 

Hepatic carcinoma or hepatorenal syndrome or limited predicted life expectancy 
(defined as less than 1 year).

A diagnosis of hepatic dysfunction secondary to any acute ongoing hepatocellular 
process that is documented by medical history, physical examination, liver 
biopsy, hepatic ultrasound, computerized tomography scan, or MRI.

Signs of clinically active Grade 3 or Grade 4 hepatic encephalopathy 
(ie, > Grade 2 Portal Systemic Encephalopathy score; refer to Appendix 9).

Severe ascites and/or pleural effusion.

History of kidney, liver, or heart transplantation.


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6. Other medical or psychiatric condition including recent (within the past year) or 
active suicidal ideation/behavior or laboratory abnormality or other conditions or 
situations related to COVID-19 pandemic (eg, Contact with positive case, residence, 
or travel to an area with high incidence) that may increase the risk of study 
participation or, in the investigator’s judgment, make the participant inappropriate for 
the study.
Prior/Concomitant Therapy:
7. Participants who have been vaccinated with COVID-19 vaccines within the past 
1 week of dosing.
8. 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 investigational 
product used in this study (whichever is longer).
9. 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 6.8 Concomitant Therapy for additional details).
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. 
For participants with hepatic impairment, stable concomitant medications (including 
herbal supplements) may be given following approval by the sponsor if they are 
considered necessary for the welfare of the study participants (eg, standard therapy 
for underlying diseases), are not contraindicated with the IP, and are unlikely to 
interfere with the PK of the IP.
10. Current use of any prohibited concomitant medication(s) or those unwilling/unable to 
use a permitted concomitant medication(s) (Refer to Section 6.8 Concomitant 
Therapy for additional details).
Prior/Concurrent Clinical Study Experience:
11. 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).
12. Participants with known prior participation (ie, randomized and received at least 
1 dose of investigational product) in a study involving PF-07321332.
Diagnostic Assessments:
13. A positive urine drug test at Screening or on Day -1.


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NOTE: Participants in Cohort 2 who have been medically prescribed opiates/opioids 
or benzodiazepines and report the use of these drugs to the investigator at Screening 
may be allowed to participate if approved by the sponsor.
14. In females of childbearing potential, a positive urine pregnancy test at Screening or 
Day -1.
15. Vital sign measurements at Screening that demonstrates:
[For Cohort 1 only] Screening seated BP ≥140 mm Hg (systolic) or ≥90 mm Hg 
(diastolic), following at least 5 minutes of rest. 
[For Cohort 2 only] 

Screening seated BP ≥180 mm Hg and/or ≥100 mm Hg (diastolic) following at 
least 5 minutes of rest.
NOTE: If SBP is ≥140 mm Hg (for Cohort 1) or ≥180 mm Hg (for Cohort 2) or if 
DBP ≥90 mm Hg (for Cohort 1) or ≥100 mm Hg (for Cohort 2), 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.

For participants with SBP ≥160 (and <180) mm Hg or DBP ≥95 (and 
<100) mm Hg, the period between Screening and Day -1 must be used to refine 
the doses of the agents used for management of BP with the aim to have stable BP 
by Day -1. Participants must have measurement on Day 1 of SBP ≤160 mm Hg 
and DBP <95 mm Hg.
16. Screening standard 12-lead ECG that demonstrates:

Clinically relevant abnormalities requiring treatment (eg, acute myocardial 
infarction, serious tachy- or brady-arrhythmias) or indicating serious underlying 
heart disease (eg, prolonged PR interval, cardiomyopathy, underlying structural 
heart disease, Wolff Parkinson-White syndrome); 
[For Cohort 1 only] Screening supine 12-lead ECG demonstrating QTcF interval 
>450 msec or a QRS interval >120 msec;
[For Cohort 2 only] Screening supine 12-lead ECG demonstrating a QTcF 
interval >470 msec or a QRS interval >120 msec;
NOTE: If QTcF exceeds 450 msec (for Cohort 1) or 480 msec (for Cohort 2), 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 eligibility.


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17. 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:

eGFR <60 mL/min/1.73m2 based on the CKD-EPI equation, with single repeat
allowed.

[For Cohort 1 only]

AST or ALT level ≥ULN;

Albumin > ULN;

Prothrombin time > ULN;

Total bilirubin level ≥1.5 × ULN;
NOTE: Participants with a history of Gilbert syndrome (and hence elevated 
total bilirubin) are eligible provided direct bilirubin level is ≤ULN;

[For Cohort 2 only] ALT or AST >5 × ULN
18. In the opinion of the investigator or Pfizer (or designee), have any clinically 
significant laboratory abnormality that that could affect interpretation of study data or 
the participant’s participation in the study.
Other Exclusions:
19. 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).

At Screening or Day -1, a positive breath alcohol test or urine test.
20. Female participants of childbearing potential who are unwilling or unable to use 
highly effective methods of contraception as outlined in Section 5.3.4 for the duration 
of the study and for at least 28 days after the administration of investigational 
product, pregnant female participants, female participants planning to become 
pregnant during the duration of the study until 28 days after the administration of 
investigational product, breastfeeding female participants.
21. Blood donation (excluding plasma donations) of approximately 1 pint (500 mL) or 
more within 60 days prior to dosing.


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22. History of sensitivity reactions to ritonavir, or any of the formulation components of 
PF-07321332 or ritonavir.
23. History of sensitivity to heparin or heparin induced thrombocytopenia, only if heparin 
is used to flush intravenous catheters used during serial blood collections.
24. Unwilling or unable to comply with the criteria in the Lifestyle Considerations
section of this protocol.
25. Investigator site staff or Pfizer employees directly involved in the conduct of the 
study, site staff otherwise supervised by the investigator, and their respective family 
members.
5.3. Lifestyle Considerations
The following guidelines are provided:
5.3.1. 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 overnight (at least 6 hours) prior to the 
collection of the predose PK sample and PF-07321332 administration on Day 1.
There will be no restriction to breakfast on the other days provided other restrictions 
are followed.

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.

Participants will refrain from consuming red wine, grapefruit, or grapefruit-related 
citrus fruits (eg, Seville oranges, pomelos) 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.
5.3.2. Caffeine, Alcohol, and Tobacco

Consumption of caffeinated drinks and tobacco (or nicotine containing products) is 
permitted during participation in the study; however, there may be a need for brief 
interruption while at the site, depending on local site policy.
5.3.3. 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.


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
In order to standardize the conditions on PK sampling days, participants will be 
required to refrain from lying down (except when required for BP, pulse rate, and 
ECG measurements), eating, and drinking beverages other than water during the first 
4 hours after dosing of PF-07321332 (does not apply to ritonavir dosing).
5.3.4. Contraception
The investigator or his or her designee, in consultation with the participant, will confirm that 
the participant has selected an appropriate method of contraception for the individual 
participant and his or her partner(s) from the permitted list of contraception methods (see 
Appendix 4 Section 10.4.4) and will confirm that the participant has been instructed in its 
consistent and correct use. At time points indicated in the schedule of activities (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 or if pregnancy is known or suspected in the participant or partner.
5.4. Screen Failures
Screen failures are defined as participants who consent to participate in the clinical study but 
are not subsequently enrolled in the study. Screen failure data are collected and remain as 
source and are not reported to the clinical database.
Individuals who do not meet the criteria for participation in this study (screen failure) may be 
rescreened if prior reason for not meeting the eligibility criteria has been resolved. 
Rescreening may only occur with sponsor approval. In the event that the participation of a 
participant in the study is delayed, outdated screening procedures can be repeated. 
Rescreened participants should be assigned the same participant number as for the initial 
screening.
6. STUDY INTERVENTION(S) AND CONCOMITANT THERAPY
Study intervention is defined as any investigational intervention(s), marketed product(s), 
placebo, medical device(s), or study procedure(s) intended to be administered to a study 
participant according to the study protocol.
For the purposes of this protocol, study intervention refers to PF-07321332 and ritonavir. 
6.1. Study Intervention(s) Administered
For this study, the investigational products are PF-07321332 (provided as 100 mg tablets) 
and ritonavir (provided as 100 mg tablets).
PF-07321332 100 mg tablets and ritonavir 100 mg tablets will be supplied by Pfizer to the 
CRU in bulk along with individual dosing containers for unit dosing.


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6.1.1. Administration
Investigational products will be administered orally and according to the conditions 
described in the SoA section and Protocol Section 5.3.1 Meals and Dietary Restrictions.
On Day -1, 12 hours prior to dosing of PF-07321332, participants will receive a 100 mg 
ritonavir tablet (as 1 × 100 mg) with approximately 240 mL ambient temperature water. On 
Day 1, following an overnight fast of at least 6 hours, participants will receive 100 mg 
PF-07321332 (as 1 × 100 mg tablet) at approximately 0800 hours (plus or minus 2 hours) 
and 100 mg ritonavir (as 1 × 100 mg tablet). Participants will receive 2 additional doses of 
100 mg ritonavir (as 1 × 100 mg tablet) at 12 and 24 hours after receiving PF-07321332. 
Investigator site personnel will administer study intervention with ambient temperature water 
to a total volume of approximately 240 mL. Participants will swallow the study intervention 
whole and will not manipulate or chew the study intervention prior to swallowing. 
In order to standardize the conditions of PK sampling, all participants will be required to 
refrain from lying down (except when required for ECG measurements), eating, and drinking 
beverages other than water during the first 4 hours after dosing of PF-07321332.
6.2. Preparation, Handling, Storage, and Accountability
1. The investigator or designee must confirm appropriate temperature conditions have 
been maintained during transit for all study interventions received and any 
discrepancies are reported and resolved before use of the study intervention. 
2. Only participants enrolled in the study may receive study intervention and only 
authorized site staff may supply or administer study intervention. All study 
interventions must be stored in a secure, environmentally controlled, and monitored 
(manual or automated recording) area in accordance with the labeled storage 
conditions with access limited to the investigator and authorized site staff. At a 
minimum, daily minimum and maximum temperatures for all site storage locations 
must be documented and available upon request. Data for nonworking days must 
indicate the minimum and maximum temperatures since previously documented for 
all site storage locations upon return to business.
3. Any excursions from the study intervention label storage conditions should be 
reported to Pfizer upon discovery along with any actions taken. The site should 
actively pursue options for returning the study intervention to the storage conditions 
described in the labeling, as soon as possible. Once an excursion is identified, the 
study intervention must be quarantined and not used until Pfizer provides permission 
to use the study intervention. Specific details regarding the definition of an excursion 
and information the site should report for each excursion will be provided to the site 
in the IP manual. 
4. Any storage conditions stated in the SRSD will be superseded by the storage 
conditions stated on the label.
5. Study interventions should be stored in their original containers.


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6. The investigator, institution, or the head of the medical institution (where applicable) 
is responsible for study intervention accountability, reconciliation, and record 
maintenance (ie, receipt, reconciliation, and final disposition records), such as the 
IPAL or sponsor-approved equivalent. All study interventions will be accounted for 
using a study intervention accountability form/record.
7. Further guidance and information for the final disposition of unused study 
interventions are provided in the IP manual. All destruction must be adequately 
documented. If destruction is authorized to take place at the investigator site, the 
investigator must ensure that the materials are destroyed in compliance with 
applicable environmental regulations, institutional policy, and any special instructions 
provided by Pfizer.
Upon identification of a product complaint, notify the sponsor within 1 business day of 
discovery as described in the IP manual.
6.2.1. Preparation and Dispensing
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.
PF-07321332 and ritonavir tablets 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). The tablets will be provided to the participant in unit 
dose containers and labeled in accordance with Pfizer regulations and the clinical site’s 
labeling requirements. 
6.3. Measures to Minimize Bias: Randomization and Blinding
6.3.1. Allocation 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. All participants enrolled will receive treatment according to the dose/schedule.
6.4. Study Intervention Compliance
When participants are dosed at the site, they will receive study intervention directly from the 
investigator or designee, under medical supervision. The date and time of each dose
administered in the clinic will be recorded in the source documents and recorded in the CRF.
The dose of study intervention and study participant identification will be confirmed at the 
time of dosing by a member of the study site staff other than the person administering the 


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study intervention. Study site personnel will examine each participant’s mouth to ensure that 
the study intervention was ingested.
6.5. Dose Modification
Dose modifications for PF-07321332 and ritonavir are not allowed. 
6.6. Continued Access to Study Intervention After the End of the Study
No intervention will be provided to study participants at the end of their study participation.
6.7. Treatment of Overdose
For this study, any dose of PF-07321332 greater than 100 mg or ritonavir greater than 
200 mg within a 24-hour time period will be considered an overdose.
There is no specific treatment for an overdose.
In the event of an overdose, the investigator should:
1. Contact the medical monitor within 24 hours.
2. Closely monitor the participant for any AEs/SAEs and laboratory abnormalities for at 
least 5 half-lives or 28 calendar days after the overdose of PF-07321332 or ritonavir 
(whichever is longer).
3. Document the quantity of the excess dose as well as the duration of the overdose in 
the CRF.
4. Overdose is reportable to Pfizer Safety only when associated with an SAE.
5. Obtain a blood sample for PK analysis within 2 days from the date of the last dose of 
study intervention if requested by the medical monitor (determined on a case-by-case 
basis).
6.8. Concomitant Therapy
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.
Hormonal contraceptives that meet the requirements of this study are allowed to be used in 
participants who are WOCBP (see Appendix 4).
As PF-07321332 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 investigational product. Additionally, ritonavir and PF-07321332 


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are inhibitors of CYP3A4. Therefore, medications highly dependent on CYP3A4 for 
clearance and for which elevated plasma concentrations may be associated with serious 
and/or life-threatening events are not permitted during dosing of PF-07321332/ritonavir. A 
non-exhaustive list of prohibited and precautionary medications is provided in Appendix 8. If 
a medication is not listed, it should not automatically be assumed it is safe to co-administer.
All concomitant treatments taken during the study must be recorded with indication, daily 
dose, and start and stop dates of administration. All participants will be questioned about 
concomitant treatment at each clinic visit.
Treatments taken within 28 days before the first dose of study intervention will be 
documented as a prior treatment. Treatments taken after the first dose of study intervention 
will be documented as concomitant treatments.
6.8.1. Participants with Healthy Liver Function (Cohort 1)
In general, participants will abstain from all concomitant treatments (prescription or over the 
counter) as described in Section 6.8, except for the treatment of AEs. Of note, the following 
restrictions apply:
•
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 
after approval by the sponsor.
6.8.2. Participants with Impaired Liver Function (Cohort 2) 
Participants are permitted to be on stable doses (at least up to 5 half-lives) of background 
medications if they are considered necessary for the welfare of the study participants (eg, 
standard therapy for the underlying disease), are not contraindicated with the investigational 
product, and are unlikely to interfere with the PK of the investigational product. Whenever 
possible, attempts must be made to not alter the doses and regimens of the concomitant 
medications after Day 1 and until the end of study on Day 3.
•
Approved concomitant medications should be administered to hepatically impaired 
participants at least 2 hours prior to dosing or withheld until 4 hours after 
PF-07321332 dosing.
6.8.3. Rescue Medicine
There is no rescue therapy to reverse the AEs observed with PF-07321332 or ritonavir˗
standard medical supportive care must be provided to manage the AEs. 
7. DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL
7.1. Discontinuation of Study Intervention
It may be necessary for a participant to permanently discontinue study intervention. Reasons 
for permanent discontinuation of study intervention include the following.


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
AEs requiring discontinuation in investigator’s view;

Pregnancy;

Positive COVID-19 test.
Note that discontinuation of study intervention does not represent withdrawal from the study.
If study intervention is permanently discontinued, the participant will remain in the study to 
be evaluated for safety and PK, if possible. See the SoA for data to be collected at the time of 
discontinuation of study intervention and follow-up for any further evaluations that need to 
be completed.
In the event of discontinuation of study intervention, it must be documented on the 
appropriate CRF/in the medical records whether the participant is discontinuing further 
receipt of study intervention or also from study procedures, posttreatment study follow-up, 
and/or future collection of additional information.
7.2. Participant Discontinuation/Withdrawal From the Study
A participant may withdraw from the study at any time at his/her own request. Reasons for 
discontinuation from the study include the following:

Refused further study procedures;

Lost to follow-up;

Death;

Study terminated by sponsor;
At the time of discontinuing from the study, if possible, an early discontinuation visit should 
be conducted. See the SoA for assessments to be collected at the time of study 
discontinuation and follow-up and for any further evaluations that need to be completed. 
The early discontinuation visit applies only to participants who are enrolled/randomized and 
then are prematurely withdrawn from the study. Participants should be questioned regarding 
their reason for withdrawal.
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.


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If the participant withdraws from the study and also withdraws consent (see Section 7.2.1) 
for disclosure of future information, no further evaluations should be performed and no 
additional data should be collected. The sponsor may retain and continue to use any data 
collected before such withdrawal of consent.
7.2.1. Withdrawal of Consent 
Participants who request to discontinue receipt of study intervention will remain in the study 
and must continue to be followed for protocol specified follow-up procedures. The only 
exception to this is when a participant specifically withdraws consent for any further contact 
with him or her or persons previously authorized by the participant to provide this 
information. Participants should notify the investigator in writing of the decision to withdraw 
consent from future follow-up, whenever possible. The withdrawal of consent should be 
explained in detail in the medical records by the investigator, as to whether the withdrawal is 
only from further receipt of study intervention or also from study procedures and/or 
posttreatment study follow-up, and entered on the appropriate CRF page. In the event that 
vital status (whether the participant is alive or dead) is being measured, publicly available 
information should be used to determine vital status only as appropriately directed in 
accordance with local law.
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 return to the clinic for/attend a 
required study visit:

The site must attempt to contact the participant and reschedule the missed visit as 
soon as possible. Counsel the participant on the importance of maintaining the 
assigned visit schedule and ascertain whether the participant wishes to and/or should 
continue in the study;

Before a participant is deemed lost to follow-up, the investigator or designee must 
make every effort to regain contact with the participant (where possible, 3 telephone 
calls and, if necessary, a certified letter to the participant’s last known mailing 
address or local equivalent methods). These contact attempts should be documented 
in the participant’s medical record;

Should the participant continue to be unreachable, he/she will be considered to have 
withdrawn from the study. 
8. STUDY ASSESSMENTS AND PROCEDURES
The investigator (or an appropriate delegate at the investigator site) must obtain a signed and 
dated ICD before performing any study -specific procedures.


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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 
(pulse rate and BP) should be collected prior to the insertion of the catheter.
For samples being collected and shipped, detailed collection, processing, storage, and 
shipment instructions and contact information will be provided to the investigator site prior 
to initiation of the study.
The total blood sampling volume for individual participants in this study is approximately 
90 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 60 consecutive days.
To prepare for study participation, participants will be instructed on the information in 
Section 5.3 Lifestyle Considerations and Section 6.8 Concomitant Therapy sections of the 
protocol.


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8.1. Efficacy Assessments
Not Applicable.
8.2. Safety Assessments
Planned time points for all safety assessments are provided in the SoA. Unscheduled clinical 
laboratory measurements may be obtained at any time during the study to assess any 
perceived safety issues.
8.2.1. 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 8.3.1 to 8.3.3.
8.2.2. Vital Signs
Seated BP will be measured with the participant’s arm supported at the level of the heart and 
recorded to the nearest mm Hg after approximately 5 minutes of rest. The same arm 
(preferably the dominant arm) will be used throughout the study. Participants should be 
instructed not to speak during measurements.
The same properly sized and calibrated BP cuff will be used to measure BP each time. The 
use of an automated device for measuring BP and pulse rate is acceptable; however, when 
done manually, pulse rate will be measured in the brachial/radial artery for at least 
30 seconds. When the timing of these measurements coincides with a blood collection, BP 
and pulse rate should be obtained prior to the nominal time of the blood collection.
Additional collection times, or changes to collection times, of BP and pulse rate will be 
permitted, as necessary, to ensure appropriate collection of safety data.


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8.2.3. 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 
postdose QTcF interval is increased by ≥30 msec from the baseline and is >450 msec for 
participants with normal hepatic function and >470 msec for participants with impaired 
hepatic function; 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 postdose QTcF interval remains ≥30 msec from the baseline and is >450 msec for 
participants with normal hepatic function and >470 msec for participants with impaired 
hepatic function; or b) an absolute QT value is ≥500 msec for any scheduled ECG for greater 
than 4 hours (or sooner, at the discretion of the investigator); or c) QTcF intervals get 
progressively longer, the participant should undergo continuous ECG monitoring. 
A cardiologist should be consulted if QTcF intervals do not return to less than the criteria
listed above after 8 hours of monitoring (or sooner, at the discretion of the investigator).
In some cases, it may be appropriate to repeat abnormal ECGs to rule out improper lead 
placement as contributing to the ECG abnormality. It is important that leads be placed in the 
same positions each time in order to achieve precise ECG recordings. If a machine read QTc 
value is prolonged, as defined above, repeat measurements may not be necessary if a 
qualified medical provider’s interpretation determines that the QTcF values are in the 
acceptable range.
ECG values of potential clinical concern are listed in Appendix 7.
8.2.4. 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.


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The investigator must review the laboratory report, document this review, and record any 
clinically relevant changes occurring during the study in the AE section of the CRF.
Clinically significant abnormal laboratory findings are those which are not associated with 
the underlying disease, unless judged by the investigator to be more severe than expected for 
the participant's condition.
All laboratory tests with values considered clinically significantly abnormal during 
participation in the study or within 28 calendar days after the last dose of study intervention 
should be repeated until the values return to normal or baseline or are no longer considered 
clinically significant by the investigator or medical monitor.
If such values do not return to normal/baseline within a period of time judged reasonable by 
the investigator, the etiology should be identified and the sponsor notified.
See Appendix 6 for suggested actions and follow-up assessments in the event of potential 
drug-induced liver injury.
If laboratory values from non-protocol specified laboratory assessments performed at the 
institution’s local laboratory require a change in participant management or are considered 
clinically significant by the investigator (eg, SAE or AE or dose modification), then the 
results must be recorded in the CRF.
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. 
8.2.5. COVID-19 specific assessments
Participants will be tested for SARS-CoV-2 infection as per site-specific regulations prior to 
being admitted to the clinic for confinement and a subsequent COVID-19 test will be 
performed if they develop COVID-19 like symptoms. Additional testing may be required by 
local regulations or by the Principal Investigator.
8.2.6. Pregnancy Testing
Pregnancy tests may be urine or serum tests, but must have a sensitivity of at least 
25 mIU/mL. Pregnancy tests will be performed in WOCBP at the times listed in the SoA.
Following a negative pregnancy test result at screening, appropriate contraception must be 
commenced 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.


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8.3. Adverse Events, Serious Adverse Events, and Other Safety Reporting
The definitions of an AE and an SAE can be found in Appendix 3.
AEs may arise from symptoms or other complaints reported to the investigator by the 
participant (or, when appropriate, by a caregiver, surrogate, or the participant's legally 
authorized representative), or they may arise from clinical findings of the Investigator or 
other healthcare providers (clinical signs, test results, etc.).
The investigator and any qualified designees are responsible for detecting, documenting, and 
recording events that meet the definition of an AE or SAE and remain responsible to pursue 
and obtain adequate information both to determine the outcome and to assess whether the 
event meets the criteria for classification as an SAE or caused the participant to discontinue 
the study (see Section 7.1). 
During the active collection period as described in Section 8.3.1, each participant will be 
questioned about the occurrence of AEs in a nonleading manner.
In addition, the investigator may be requested by Pfizer Safety to obtain specific follow-up
information in an expedited fashion.
8.3.1. Time Period and Frequency for Collecting AE and SAE Information
The time period for actively eliciting and collecting AEs and SAEs (“active collection 
period”) for each participant begins from the time the participant provides informed consent, 
which is obtained before the participant’s participation in the study (ie, before undergoing 
any study related procedure and/or receiving study intervention), through and including a 
minimum of 28 calendar days, after the last administration of the study intervention.
Follow-up by the investigator continues throughout and after the active collection period and 
until the AE or SAE or its sequelae resolve or stabilize at a level acceptable to the 
investigator.
For participants who are screen failures, the active collection period ends when screen failure 
status is determined.
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 because of an AE 
or SAE, the AE or SAE must be recorded on the CRF and the SAE reported using the CT 
SAE Report Form.
Investigators are not obligated to actively seek information on AEs or SAEs after the 
participant has concluded study participation. However, if the investigator learns of any SAE, 
including a death, at any time after a participant has completed the study, and he/she 
considers the event to be reasonably related to the study intervention, the investigator must 
promptly report the SAE to Pfizer using the CT SAE Report Form.


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8.3.1.1. Reporting SAEs to Pfizer Safety
All SAEs occurring in a participant during the active collection period as described in 
Section 8.3.1 are reported to Pfizer Safety on the CT SAE Report Form immediately upon 
awareness and under no circumstance should this exceed 24 hours, as indicated in 
Appendix 3. The investigator will submit any updated SAE data to the sponsor within 
24 hours of it being available.
8.3.1.2. Recording Nonserious AEs and SAEs on the CRF
All nonserious AEs and SAEs occurring in a participant during the active collection period, 
which begins after obtaining informed consent as described in Section 8.3.1, will be recorded 
on the AE section of the CRF.
The investigator is to record on the CRF all directly observed and all spontaneously reported 
AEs and SAEs reported by the participant.
Reporting of AEs and SAEs for participants who fail screening are subject to the CRF 
requirements as described in Section 5.4.
8.3.2. Method of Detecting AEs and SAEs
The method of recording, evaluating, and assessing causality of AEs and SAEs and the 
procedures for completing and transmitting SAE reports are provided in Appendix 3.
Care will be taken not to introduce bias when detecting AEs and/or SAEs. Open-ended and 
nonleading verbal questioning of the participant is the preferred method to inquire about 
AE occurrences.
8.3.3. Follow-up of AEs and SAEs
After the initial AE or SAE report, the investigator is required to proactively follow each 
participant at subsequent visits/contacts. For each event, the investigator must pursue and 
obtain adequate information until resolution, stabilization, the event is otherwise explained, 
or the participant is lost to -follow-up (as defined in Section 7.3).
In general, follow-up information will include a description of the event in sufficient detail to 
allow for a complete medical assessment of the case and independent determination of 
possible causality. Any information relevant to the event, such as concomitant medications 
and illnesses, must be provided. In the case of a participant death, a summary of available 
autopsy findings must be submitted as soon as possible to Pfizer Safety. 
Further information on follow-up procedures is given in Appendix 3.
8.3.4. Regulatory Reporting Requirements for SAEs
Prompt notification by the investigator to the sponsor of an SAE is essential so that legal 
obligations and ethical responsibilities toward the safety of participants and the safety of a 
study intervention under clinical investigation are met.


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The sponsor has a legal responsibility to notify both the local regulatory authority and other 
regulatory agencies about the safety of a study intervention under clinical investigation. The 
sponsor will comply with country specific regulatory requirements relating to safety 
reporting to the regulatory authority, IRBs/ECs, and investigators.
Investigator safety reports must be prepared for SUSARs according to local regulatory 
requirements and sponsor policy and forwarded to investigators as necessary.
An investigator who receives SUSARs or other specific safety information (eg, summary or 
listing of SAEs) from the sponsor will review and then file it along with the SRSD(s) for the 
study and will notify the IRB/EC, if appropriate according to local requirements.
8.3.5. Environmental Exposure, Exposure During Pregnancy or Breastfeeding, and 
Occupational Exposure
Environmental exposure, occurs when a person not enrolled in the study as a participant 
receives unplanned direct contact with or exposure to the study intervention. Such exposure 
may or may not lead to the occurrence of an AE or SAE. Persons at risk for environmental 
exposure include healthcare providers, family members, and others who may be exposed. An 
environmental exposure may include exposure during pregnancy, exposure during 
breastfeeding, and occupational exposure.
Any such exposure to the study intervention under study are reportable to Pfizer Safety 
within 24 hours of investigator awareness.
8.3.5.1. Exposure During Pregnancy
An EDP occurs if: 

A female participant is found to be pregnant while receiving or after discontinuing 
study intervention.

A male participant who is receiving or has discontinued study intervention exposes a 
female partner prior to or around the time of conception.

A female is found to be pregnant while being exposed or having been exposed to 
study intervention due to environmental exposure. Below are examples of 
environmental EDP:

A female family member or healthcare provider reports that she is pregnant after 
having been exposed to the study intervention by ingestion.

A male family member or healthcare provider who has been exposed to the study 
intervention by ingestion then exposes his female partner prior to or around the 
time of conception.
The investigator must report EDP to Pfizer Safety within 24 hours of the investigator’s 
awareness, irrespective of whether an SAE has occurred. The initial information submitted 


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should include the anticipated date of delivery (see below for information related to 
termination of pregnancy). 

If EDP occurs in a participant or a participant’s partner, the investigator must report 
this information to Pfizer Safety on the CT SAE Report Form and an EDP 
Supplemental Form, regardless of whether an SAE has occurred. Details of the 
pregnancy will be collected after the start of study intervention and until 28 days after 
the last dose.

If EDP occurs in the setting of environmental exposure, the investigator must report 
information to Pfizer Safety using the CT SAE Report Form and EDP Supplemental 
Form. Since the exposure information does not pertain to the participant enrolled in 
the study, the information is not recorded on a CRF; however, a copy of the 
completed CT SAE Report Form is maintained in the investigator site file.
Follow-up is conducted to obtain general information on the pregnancy and its outcome for 
all EDP reports with an unknown outcome. The investigator will follow the pregnancy until 
completion (or until pregnancy termination) and notify Pfizer Safety of the outcome as a 
follow-up to the initial EDP Supplemental Form. In the case of a live birth, the structural 
integrity of the neonate can be assessed at the time of birth. In the event of a termination, the 
reason(s) for termination should be specified and, if clinically possible, the structural 
integrity of the terminated fetus should be assessed by gross visual inspection (unless 
preprocedure test findings are conclusive for a congenital anomaly and the findings are 
reported).
Abnormal pregnancy outcomes are considered SAEs. If the outcome of the pregnancy meets 
the criteria for an SAE (ie, ectopic pregnancy, spontaneous abortion, intrauterine fetal 
demise, neonatal death, or congenital anomaly in a live-born baby, a terminated fetus, an 
intrauterine fetal demise, or a neonatal death), the investigator should follow the procedures 
for reporting SAEs. Additional information about pregnancy outcomes that are reported to 
Pfizer Safety as SAEs follows: 

Spontaneous abortion including miscarriage and missed abortion;

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.


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8.3.5.2. Exposure During Breastfeeding
An exposure during breastfeeding occurs if:

A female participant is found to be breastfeeding while receiving or after 
discontinuing study intervention.

A female is found to be breastfeeding while being exposed or having been exposed to 
study intervention (ie, environmental exposure). An example of environmental 
exposure during breastfeeding is a female family member or healthcare provider who 
reports that she is breastfeeding after having been exposed to the study intervention 
by ingestion.
The investigator must report exposure during breastfeeding to Pfizer Safety within 24 hours 
of the investigator’s awareness, irrespective of whether an SAE has occurred. The 
information must be reported using the CT SAE Report Form. When exposure during 
breastfeeding occurs in the setting of environmental exposure, the exposure information does 
not pertain to the participant enrolled in the study, so the information is not recorded on a 
CRF. However, a copy of the completed CT SAE Report Form is maintained in the 
investigator site file.
An exposure during breastfeeding report is not created when a Pfizer drug specifically 
approved for use in breastfeeding women (eg, vitamins) is administered in accord with 
authorized use. However, if the infant experiences an SAE associated with such a drug, the 
SAE is reported together with the exposure during breastfeeding.
8.3.5.3. Occupational Exposure
The investigator must report any instance of occupational exposure to Pfizer Safety within 24 
hours of the investigator’s awareness using the CT SAE Report Form regardless of whether 
there is an associated SAE. Since the information about the occupational exposure does not 
pertain to a participant enrolled in the study, the information is not recorded on a CRF; 
however, a copy of the completed CT SAE Report Form must be maintained in the 
investigator site file.
8.3.6. Cardiovascular and Death Events
Not applicable.
8.3.7. Disease Related Events and/or Disease Related Outcomes Not Qualifying as AEs 
or SAEs
Not applicable.
8.3.8. Adverse Events of Special Interest
Not applicable.


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8.3.8.1. Lack of Efficacy
This section is not applicable because efficacy is not expected in the study population.
8.3.9. Medical Device Deficiencies
Not applicable.
8.3.10. Medication Errors
Medication errors may result from the administration or consumption of the study 
intervention by the wrong participant, or at the wrong time, or at the wrong dosage strength.
Exposures to the study intervention under study may occur in clinical trial settings, such as 
medication errors.
Safety Event
Recorded on the CRF
Reported on the CT SAE Report 
Form to Pfizer Safety Within 
24 Hours of Awareness
Medication errors All (regardless of whether 
associated with an AE)
Only if associated with an SAE
Medication errors include:
•
Medication errors involving participant exposure to the study intervention;
•
Potential medication errors or uses outside of what is foreseen in the protocol that do 
or do not involve the study participant.
Such medication errors occurring to a study participant are to be captured on the medication 
error page of the CRF, which is a specific version of the AE page.
In the event of a medication dosing error, the sponsor should be notified within 24 hours.
Whether or not the medication error is accompanied by an AE, as determined by the 
investigator, the medication error is recorded on the medication error page of the CRF and, if 
applicable, any associated AE(s), serious and nonserious, are recorded on the AE page of the 
CRF.
Medication errors should be reported to Pfizer Safety within 24 hours on a CT SAE Report 
Form only when associated with an SAE.
8.4. Pharmacokinetics 
8.4.1. Plasma for Analysis of PF-07321332
Blood samples of approximately 4 mL, to provide a minimum of 1.5 mL plasma, will be
collected for measurement of concentrations of PF-07321332 
 as specified in the 
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SoA. Instructions for the collection and handling of biological samples will be provided in 
the laboratory manual or by the sponsor. The actual date and time (24-hour clock time) of 
each sample will be recorded.
The actual times may change, but the number of samples will remain the same. All efforts 
will be made to obtain the samples at the exact nominal time relative to dosing. Collection of 
samples up to and including 10 hours after dose administration that are obtained within 
10% of the nominal time relative to dosing (eg, within 6 minutes of a 60-minute sample) will 
not be captured as a protocol deviation, as long as the exact time of the collection is noted on 
the source document and the data collection tool (eg, CRF/DCT). 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 data collection tool 
(eg, CRF/DCT). This protocol deviation window does not apply to samples to be collected 
more than 10 hours after dose administration at outpatient/follow-up visits with visit 
windows.
Samples will be used to evaluate the PK of PF-07321332
. Each plasma sample 
will be divided into 2 aliquots. Samples collected for analyses of PF-07321332 
 
plasma concentration may also be used to evaluate safety or efficacy aspects related to 
concerns arising during or after the study, for metabolite identification and/or evaluation of 
the bioanalytical method, 
.
Genetic analyses will not be performed on these plasma samples. Participant confidentiality 
will be maintained.
Samples collected for measurement of plasma concentrations of PF-07321332
 
will be analyzed using a validated analytical method in compliance with applicable SOPs.
Potential metabolites may be analyzed with either validated or exploratory methods.
The PK samples must be processed and shipped as indicated in the instructions provided to 
the investigator site to maintain sample integrity. Any deviations from the PK sample 
handling procedure (eg, sample collection and processing steps, interim storage or shipping 
conditions), including any actions taken, must be documented and reported to the sponsor.
On a case-by-case basis, the sponsor may make a determination as to whether sample 
integrity has been compromised.
 
 
 
 
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8.7. Immunogenicity Assessments
Immunogenicity assessments are not included in this study.
8.8. Health Economics
Health economics/medical resource utilization and health economics parameters are not 
evaluated in this study.
9. STATISTICAL CONSIDERATIONS
Detailed methodology for summary and statistical analyses of the data collected in this study 
is outlined here and further detailed in a SAP, which will be maintained by the sponsor. The 
SAP may modify what is outlined in the protocol where appropriate; however, any major 
modifications of the primary endpoint definitions or their analyses will also be reflected in a 
protocol amendment.
9.1. Statistical Hypotheses
No statistical hypothesis will be tested in this study.
9.2. Analysis Sets
For purposes of analysis, the following analysis sets are defined:
Participant Analysis 
Set
Description
PK Concentration
The PK concentration population is defined as all participants 
assigned to investigational product and treated who have at 
least 1 concentration measured.
PK Parameter
The PK parameter analysis population is defined as all 
participants assigned to investigational product and treated 
who have at least 1 of the PK parameters of primary interest 
measured.
Safety Analysis Set
All participants randomly assigned to study intervention and 
who take at least 1 dose of study intervention. Participants 
will be analyzed according to the product they actually 
received.
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.
One-way ANOVA will be used to compare the natural log transformed AUClast, AUCinf (if 
data permit) and Cmax for PF-07321332 between Cohort 2 with moderate hepatic impairment 


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(Test) and Cohort 1 with normal hepatic function (Reference). Estimates of the adjusted 
mean differences (Test-Reference) and corresponding 90% CIs will be obtained from the 
model. The adjusted mean differences and 90% CIs for the differences will be exponentiated 
to provide estimates of the ratio of the adjusted geometric means (Test/Reference) and 
90% CIs for the ratios. 
Box and whisker plots for individual participant parameters (AUCinf and Cmax) will be
constructed by cohort and overlaid with geometric means.
For summary statistics and median/mean plots by sampling time, the nominal PK sampling 
time will be used. For individual participant plots by time, the actual PK sampling time will 
be used.
9.3.1. Other Safety Analyses
All safety analyses will be performed on the safety population.
AEs, 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 pulse 
rate abnormalities of potential clinical concern will be described. Safety data will be 
presented in tabular and/or graphical format and summarized descriptively, where 
appropriate.
Medical history and physical examination and neurological examination information, as 
applicable, collected during the course of the study will be considered source data and will 
not be required to be reported, unless otherwise noted. However, any untoward findings 
identified on physical and/or neurological examinations conducted during the active 
collection period will be captured as AEs, if those findings meet the definition of an AE.
Data collected at screening that are used for inclusion/exclusion criteria, such as laboratory 
data, ECGs, and vital signs, will be considered source data, and will not be required to be 
reported, unless otherwise noted. Demographic data collected at screening will be reported.
 
9.3.2.1. Pharmacokinetic Analyses
9.3.2.1.1. Analysis Population
The PK concentration population will be defined as all participants treated in whom at least 
1 plasma concentration value is reported.
The PK parameter analysis population is defined as all participants dosed who have at least 
1 of the PK parameters of primary interest.
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9.3.2.1.2. Derivation of Pharmacokinetic Parameters Prior to Analysis
The plasma PK parameters for PF-07321332 will be derived from the concentration time 
profiles as detailed in Table 2. Actual PK sampling times will be used in the derivation of PK 
parameters. In the case that actual PK sampling times are not available, nominal PK sampling 
time will be used in the derivation of PK parameters.
Table 2.
Plasma PK Parameters
Parameter
Analyte
Definition
Method of Determination
AUClast
PF-07321332
Area under the plasma 
concentration-time profile from 
time 0 to the time of Clast
Linear/Log trapezoidal method.
 
AUCinf*
PF-07321332
Area under the plasma 
concentration-time profile from 
time 0 extrapolated to infinite 
time
AUClast + (Clast*/kel), Where Clast* is 
the predicted plasma concentration 
at the last quantifiable time point 
estimated from the log-linear 
regression analysis.
Cmax
PF-07321332, 
ritonavir
Maximum plasma concentration
Observed directly from data.
 
 
 
 
 
 
*
As data permit.
 
 
 
 
 
 
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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. 
 
 
 
 
 
 
 
 
 
 
 
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10. SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS
10.1. Appendix 1: Regulatory, Ethical, and Study Oversight Considerations
10.1.1. Regulatory and Ethical Considerations
This study will be conducted in accordance with the protocol and with the following:

Consensus ethical principles derived from international guidelines, including the 
Declaration of Helsinki and CIOMS International Ethical Guidelines;

Applicable ICH GCP guidelines;

Applicable laws and regulations, including applicable privacy laws.
The protocol, protocol amendments, ICD, SRSD(s), and other relevant documents 
(eg, advertisements) must be reviewed and approved by the sponsor, submitted to an IRB/EC 
by the investigator, and reviewed and approved by the IRB/EC before the study is initiated.
Any amendments to the protocol will require IRB/EC approval before implementation of 
changes made to the study design, except for changes necessary to eliminate an immediate 
hazard to study participants.
Protocols and any substantial amendments to the protocol will require health authority 
approval prior to initiation except for changes necessary to eliminate an immediate hazard to 
study participants.
The investigator will be responsible for the following:

Providing written summaries of the status of the study to the IRB/EC annually or 
more frequently in accordance with the requirements, policies, and procedures 
established by the IRB/EC;

Notifying the IRB/EC of SAEs or other significant safety findings as required by 
IRB/EC procedures;

Providing oversight of the conduct of the study at the site and adherence to 
requirements of 21 CFR, ICH GCP guidelines, the IRB/EC, European regulation 
536/2014 for clinical studies (if applicable), European Medical Device Regulation 
2017/745 for clinical device research (if applicable), and all other applicable local 
regulations.
10.1.1.1. Reporting of Safety Issues and Serious Breaches of the Protocol or ICH GCP
In the event of any prohibition or restriction imposed (ie, clinical hold) by an applicable 
regulatory authority in any area of the world, or if the investigator is aware of any new 
information that might influence the evaluation of the benefits and risks of the study 
intervention, Pfizer should be informed immediately.


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In addition, the investigator will inform Pfizer immediately of any urgent safety measures 
taken by the investigator to protect the study participants against any immediate hazard, and 
of any serious breaches of this protocol or of the ICH GCP guidelines that the investigator 
becomes aware of.
10.1.2. Financial Disclosure
Investigators and subinvestigators will provide the sponsor with sufficient, accurate financial 
information as requested to allow the sponsor to submit complete and accurate financial 
certification or disclosure statements to the appropriate regulatory authorities. Investigators 
are responsible for providing information on financial interests during the course of the study 
and for 1 year after completion of the study.
10.1.3. Informed Consent Process
The investigator or his/her representative will explain the nature of the study, including the 
risks and benefits, to the participant and answer all questions regarding the study. The 
participant should be given sufficient time and opportunity to ask questions and to decide 
whether or not to participate in the trial.
Participants must be informed that their participation is voluntary. Participants will be 
required to sign a statement of informed consent that meets the requirements of 21 CFR 50, 
local regulations, ICH guidelines, privacy and data protection requirements, where 
applicable, and the IRB/EC or study center.
The investigator must ensure that each study participant is fully informed about the nature 
and objectives of the study, the sharing of data related to the study, and possible risks 
associated with participation, including the risks associated with the processing of the 
participant’s personal data. 
The participant must be informed that his/her personal study-related data will be used by the 
sponsor in accordance with local data protection law. The level of disclosure must also be 
explained to the participant.
The participant must be informed that his/her medical records may be examined by Clinical 
Quality Assurance auditors or other authorized personnel appointed by the sponsor, by 
appropriate IRB/EC members, and by inspectors from regulatory authorities.
The investigator further must ensure that each study participant is fully informed about his or 
her right to access and correct his or her personal data and to withdraw consent for the 
processing of his or her personal data.
The medical record must include a statement that written informed consent was obtained 
before the participant was enrolled in the study and the date on which the written consent was 
obtained. The authorized person obtaining the informed consent must also sign the ICD.
Participants must be reconsented to the most current version of the ICD(s) during their 
participation in the study.


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A copy of the ICD(s) must be provided to the participant.
Participants who are rescreened are required to sign a new ICD.
10.1.4. Data Protection
All parties will comply with all applicable laws, including laws regarding the implementation 
of organizational and technical measures to ensure protection of participant data.
Participants’ personal data will be stored at the study site in encrypted electronic form and 
will be password-protected to ensure that only authorized study staff have access. The study 
site will implement appropriate technical and organizational measures to ensure that the 
personal data can be recovered in the event of disaster. In the event of a potential personal 
data breach, the study site will be responsible for determining whether a personal data breach 
has in fact occurred and, if so, providing breach notifications as required by law.
To protect the rights and freedoms of participants with regard to the processing of personal 
data, participants will be assigned a single, participant specific numerical code. Any 
participant records or data sets that are transferred to the sponsor will contain the numerical 
code; participant names will not be transferred. All other identifiable data transferred to the 
sponsor will be identified by this single, participant specific code. The study site will 
maintain a confidential list of participants who participated in the study, linking each 
participant’s numerical code to his or her actual identity and medical record ID. In case of 
data transfer, the sponsor will protect the confidentiality of participants’ personal data 
consistent with the clinical study agreement and applicable privacy laws.
10.1.5. Committees Structure
10.1.5.1. Data Monitoring Committee 
This study will not use a 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, and/or 
www.pfizer.com, and other public registries in accordance with applicable local 
laws/regulations. In addition, Pfizer reports study results outside of the requirements of local 
laws/regulations pursuant to its SOPs.
In all cases, study results are reported by Pfizer in an objective, accurate, balanced, and 
complete manner and are reported regardless of the outcome of the study or the country in 
which the study was conducted.
www.clinicaltrials.gov
Pfizer posts clinical trial results on www.clinicaltrials.gov for Pfizer-sponsored interventional 
studies (conducted in patients) that evaluate the safety and/or efficacy of a product, 


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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
Pfizer posts clinical trial results on EudraCT for Pfizer-sponsored interventional studies in 
accordance with the format and timelines set forth by EU requirements.
www.pfizer.com
Pfizer posts public disclosure synopses (CSR synopses in which any data that could be used 
to identify individual participants have been removed) on www.pfizer.com for 
Pfizer-sponsored interventional studies at the same time the corresponding study results are
posted to www.clinicaltrials.gov.
Documents within marketing authorization packages/submissions
Pfizer complies with the European Union Policy 0070, the proactive publication of clinical 
data to the EMA website. Clinical data, under Phase 1 of this policy, includes clinical 
overviews, clinical summaries, CSRs, and appendices containing the protocol and protocol 
amendments, sample CRFs, and statistical methods. Clinical data, under Phase 2 of this 
policy, includes the publishing of individual participant data. Policy 0070 applies to new 
marketing authorization applications submitted via the centralized procedure since 
01 January 2015 and applications for line extensions and for new indications submitted via 
the centralized procedure since 01 July 2015.
Data sharing
Pfizer provides researchers secure access to patient-level data or full CSRs for the purposes 
of “bona-fide scientific research” that contributes to the scientific understanding of the 
disease, target, or compound class. Pfizer will make data from these trials available 
24 months after study completion. Patient-level data will be anonymized in accordance with 
applicable privacy laws and regulations. CSRs will have personally identifiable information 
redacted.
Data requests are considered from qualified researchers with the appropriate competencies to 
perform the proposed analyses. Research teams must include a biostatistician. Data will not 
be provided to applicants with significant conflicts of interest, including individuals 
requesting access for commercial/competitive or legal purposes.
10.1.7. Data Quality Assurance
All participant data relating to the study will be recorded on printed or electronic CRF unless 
transmitted to the sponsor or designee electronically (eg, laboratory data). The investigator is 
responsible for verifying that data entries are accurate and correct by physically or 
electronically signing the CRF.


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Guidance on completion of CRFs will be provided in the CRF Completion Requirements 
document.
The investigator must ensure that the CRFs are securely stored at the study site in encrypted 
electronic form and are password-protected to prevent access by unauthorized third parties.
The investigator must permit study-related monitoring, audits, IRB/EC review, and 
regulatory agency inspections and provide direct access to source data documents. This 
verification may also occur after study completion. It is important that the investigator(s) and 
their relevant personnel are available during the monitoring visits and possible audits or 
inspections and that sufficient time is devoted to the process.
Monitoring details describing strategy, including definition of study critical data items and 
processes (eg, risk-based initiatives in operations and quality, such as risk management and 
mitigation strategies and analytical risk-based monitoring), methods, responsibilities, and 
requirements, including handling of noncompliance issues and monitoring techniques 
(central, virtual, or on-site monitoring), are provided in the data management plan and 
monitoring plan maintained and utilized by the sponsor or designee.
The sponsor or designee is responsible for the data management of this study, including 
quality checking of the data.
Records and documents, including signed ICDs, pertaining to the conduct of this study must 
be retained by the investigator for 15 years after study completion unless local regulations or 
institutional policies require a longer retention period. No records may be destroyed during 
the retention period without the written approval of the sponsor. No records may be 
transferred to another location or party without written notification to the sponsor. The 
investigator must ensure that the records continue to be stored securely for as long as they are 
maintained.
When participant data are to be deleted, the investigator will ensure that all copies of such 
data are promptly and irrevocably deleted from all systems.
The investigator(s) will notify the sponsor or its agents immediately of any regulatory 
inspection notification in relation to the study. Furthermore, the investigator will cooperate 
with the sponsor or its agents to prepare the investigator site for the inspection and will allow 
the sponsor or its agent, whenever feasible, to be present during the inspection. The 
investigator site and investigator will promptly resolve any discrepancies that are identified 
between the study data and the participant's medical records. The investigator will promptly 
provide copies of the inspection findings to the sponsor or its agent. Before response 
submission to the regulatory authorities, the investigator will provide the sponsor or its 
agents with an opportunity to review and comment on responses to any such findings.
10.1.8. Source Documents
Source documents provide evidence for the existence of the participant and substantiate the 
integrity of the data collected. Source documents are filed at the investigator site.


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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 clinical 
monitoring plan, which is maintained by the sponsor.
Description of the use of the computerized system is documented in the Data Management 
Plan, which is maintained by the sponsor.
The investigator must maintain accurate documentation (source data) that supports the 
information entered in the CRF.
Study monitors will perform ongoing source data verification to confirm that data entered 
into the CRF by authorized site personnel are accurate, complete, and verifiable from source 
documents; that the safety and rights of participants are being protected; and that the study is 
being conducted in accordance with the currently approved protocol and any other study 
agreements, ICH GCP guidelines, and all applicable regulatory requirements.
10.1.9. Study and Site Start and Closure
The study start date is the date on which the clinical study will be open for recruitment of 
participants.
The first act of recruitment is the date of the first participant’s first visit and will be the study 
start date.
The sponsor designee reserves the right to close the study site or terminate the study at any 
time for any reason at the sole discretion of the sponsor. Study sites will be closed upon study 
completion. A study site is considered closed when all required documents and study 
supplies have been collected and a study-site closure visit has been performed.
The investigator may initiate study-site closure at any time upon notification to the sponsor 
or designee/CRO if requested to do so by the responsible IRB/EC or if such termination is 
required to protect the health of study participants.


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Reasons for the early closure of a study site by the sponsor may include but are not limited 
to:

Failure of the investigator to comply with the protocol, the requirements of the 
IRB/EC or local health authorities, the sponsor's procedures, or the ICH GCP 
guidelines;

Inadequate recruitment of participants by the investigator;

Discontinuation of further study intervention development.
If the study is prematurely terminated or suspended, the sponsor shall promptly inform the 
investigators, the ECs/IRBs, the regulatory authorities, and any CRO(s) used in the study of 
the reason for termination or suspension, as specified by the applicable regulatory 
requirements. The investigator shall promptly inform the participant and should assure 
appropriate participant therapy and/or follow-up.
Study termination is also provided for in the clinical study agreement. If there is any conflict 
between the contract and this protocol, the contract will control as to termination rights.
10.1.10. Publication Policy
The results of this study may be published or presented at scientific meetings by the
investigator after publication of the overall study results or 1 year after the end of the study 
(or study termination), whichever comes first. 
The investigator agrees to refer to the primary publication in any subsequent publications,
such as secondary manuscripts, and submits all manuscripts or abstracts to the sponsor 
30 days before submission. This allows the sponsor to protect proprietary information and to 
provide comments, and the investigator will, on request, remove any previously undisclosed 
confidential information before disclosure, except for any study- or Pfizer-intervention
related information necessary for the appropriate scientific presentation or understanding of
the study results.
For all publications relating to the study, the investigator will comply with recognized ethical 
standards concerning publications and authorship, including those established by the 
International Committee of Medical Journal Editors.
The sponsor will comply with the requirements for publication of the overall study results 
covering all investigator sites. In accordance with standard editorial and ethical practice, the 
sponsor will support publication of multicenter studies only in their entirety and not as 
individual site data. In this case, a coordinating investigator will be designated by mutual 
agreement.
Authorship of publications for the overall study results will be determined by mutual 
agreement and in line with International Committee of Medical Journal Editors authorship 
requirements. 


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


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10.2. Appendix 2: Clinical Laboratory Tests
The following safety laboratory tests will be performed at times defined in the SoA section of 
this protocol. Additional laboratory results may be reported on these samples as a result of 
the method of analysis or the type of analyzer used by the clinical laboratory, or as derived 
from calculated values. These additional tests would not require additional collection of 
blood. Unscheduled clinical laboratory measurements may be obtained at any time during the 
study to assess any perceived safety issues.
Table 4.
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/urea and creatinine
Glucose
Calcium
Sodium
Potassium
Chloride
Total CO2 (bicarbonate)
AST, ALT
Alkaline phosphatase
Total bilirubin
Direct bilirubina
Indirect bilirubina
Uric acid
Albumin
Total protein
Local Dipstick:
pH
Glucose (qual)
Protein (qual)
Blood (qual)
Ketones
Nitrites
Leukocyte esterase
Urobilinogen
Urine bilirubin
Laboratory:
Microscopyb
•
SARS-CoV-2 RT-PCRc
•
Urine drug screeningd
•
Breath or urine alcohol 
teste
•
Pregnancy test (β-hCG)f
At Screening Onlyg:
•
PT
•
aPTT
•
PT-INR
•
HIV
•
HbsAg
•
HbcAbh
•
HCVAbi
•
FSHj
a.
Direct and indirect bilirubin assessed when total bilirubin is > ULN, only.
b.
Only if urine dipstick is positive for blood, protein, nitrites, or leukocyte esterase.
c.
Testing for COVID-19 pathogen will be performed prior to being admitted to the clinic for confinement, on 
Day -1, and if participant develops COVID-19 like symptoms.
d.
At Screening and Day -1; The minimum requirement for drug screening includes cocaine, THC, opiates/opioids, 
benzodiazepines, and amphetamines (others are site and study specific).
e.
At Screening and Day -1.
f.
Local urine testing will be standard for the protocol unless serum testing is required by local regulation or 
IRB/EC. Serum or urine β-hCG for female participants of childbearing potential. 
g.
Tests will only be performed at Screening. 
h.
HBsAb will be performed as reflex testing for any participant who is HBsAg negative and HBcAb positive.
i.
HCV RNA will be performed as reflex testing for any participant who is HCV Ab positive.
j.
At Screening for confirmation of postmenopausal status only.
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.
 
Samples to be used for this 
purpose will be shipped to either a Pfizer-approved BBS facility or other designated 
laboratory and retained for up to 1 year following the completion of the study.
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10.3. Appendix 3: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-Up, and Reporting
10.3.1. Definition of AE
AE Definition

An AE is any untoward medical occurrence in a patient or clinical study
participant, temporally associated with the use of study intervention, whether or 
not considered related to the study intervention.

Note: An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease (new or exacerbated) 
temporally associated with the use of study intervention.
Events Meeting the AE Definition

Any abnormal laboratory test results (hematology, clinical chemistry, or 
urinalysis) or other safety assessments (eg, ECG, radiological scans, vital sign 
measurements), including those that worsen from baseline, considered clinically 
significant in the medical and scientific judgment of the investigator. Any 
abnormal laboratory test results that meet any of the conditions below must be 
recorded as an AE:

Is associated with accompanying symptoms;

Requires additional diagnostic testing or medical/surgical intervention;

Leads to a change in study dosing (outside of any protocol-specified dose 
adjustments) or discontinuation from the study, significant additional 
concomitant drug treatment, or other therapy.

Exacerbation of a chronic or intermittent preexisting condition, including either 
an increase in frequency and/or intensity of the condition.

New condition detected or diagnosed after study intervention administration,
even though it may have been present before the start of the study.

Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction.

Signs, symptoms, or the clinical sequelae of a suspected overdose of either study 
intervention or a concomitant medication. Overdose per se will not be reported as 
an AE or SAE unless it is an intentional overdose taken with possible 
suicidal/self-harming intent. Such overdoses should be reported regardless of 
sequelae.


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


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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, is considered serious.
The event may be suspected from clinical symptoms or laboratory findings 
indicating an infection in a participant exposed to a Pfizer product. The terms 
“suspected transmission” and “transmission” are considered synonymous. These 
cases are considered unexpected and handled as serious expedited cases by 
pharmacovigilance personnel. Such cases are also considered for reporting as 
product defects, if appropriate.
g. Other situations:

Medical or scientific judgment should be exercised by the investigator in 
deciding whether SAE reporting is appropriate in other situations, such as 
significant medical events that may jeopardize the participant or may require 
medical or surgical intervention to prevent one of the other outcomes listed in the 
above definition. These events should usually be considered serious.

Examples of such events include invasive or malignant cancers, intensive 
treatment in an emergency room or at home for allergic bronchospasm, blood 
dyscrasias or convulsions that do not result in hospitalization, or development of 
drug dependency or drug abuse.
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 exposure during 
pregnancy or breastfeeding
Note: Instances of EDP or 
EDB not associated with an 
AE or SAE are not captured 
in the CRF.
All instances of EDP are 
reported (whether or not 
there is an associated 
SAE)*
All instances of EDB are 
reported (whether or not 
there is an associated 
SAE). **
Environmental or 
occupational exposure 
to the product under 
study to a non-
participant (not 
involving EDP or EDB).
None. Exposure to a study 
non-participant is not 
collected on the CRF.
The exposure (whether or 
not there is an associated 
AE or SAE) must be 
reported.***
*
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.


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
It is not acceptable for the investigator to send photocopies of the participant’s 
medical records to Pfizer Safety in lieu of completion of the CT SAE Report 
Form/AE or SAE CRF page.

There may be instances when copies of medical records for certain cases are 
requested by Pfizer Safety. In this case, all participant identifiers, with the 
exception of the participant number, will be redacted on the copies of the medical 
records before submission to Pfizer Safety.

The investigator will attempt to establish a diagnosis of the event based on signs,
symptoms, and/or other clinical information. Whenever possible, the diagnosis 
(not the individual signs/symptoms) will be documented as the AE or SAE.
Assessment of Intensity
The investigator will make an assessment of intensity for each AE and SAE reported 
during the study and assign it to 1 of the following categories: 

Mild: Asymptomatic or mild symptoms; clinical or diagnostic observations only; 
intervention not indicated.

Moderate: Minimal, local or noninvasive intervention indicated; limiting age-
appropriate instrumental ADL. Instrumental ADL refers to preparing meals, 
shopping for groceries or clothes, using the telephone, managing money, etc.

Severe: Severe or medically significant but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling, limiting 
self care ADL. Self care ADL refers to bathing, dressing and undressing, feeding 
self, using the toilet, taking medications, and not bedridden.
An event is defined as “serious” when it meets at least 1 of the predefined outcomes as 
described in the definition of an SAE, NOT when it is rated as severe.
If required on the AE page of the CRF, the investigator will use the adjectives 
MILD, MODERATE, SEVERE, or VERY SEVERE to describe the maximum 
intensity of the AE. The severity of the AE should be determined using the Toxicity 
Grading Scale: 
MILD
Does not interfere with participant's usual function.
MODERATE
Interferes to some extent with participant's usual function.
SEVERE
Interferes significantly with participant's usual function.


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VERY SEVERE
Unacceptable and intolerable events or events which are 
irreversible or cause the participant to be in imminent danger of 
death.
Assessment of Causality

The investigator is obligated to assess the relationship between study intervention 
and each occurrence of each AE or SAE. The investigator will use clinical 
judgment to determine the relationship.

A “reasonable possibility” of a relationship conveys that there are facts, 
evidence, and/or arguments to suggest a causal relationship, rather than a 
relationship cannot be ruled out.

Alternative causes, such as underlying disease(s), concomitant therapy, and other 
risk factors, as well as the temporal relationship of the event to study intervention 
administration, will be considered and investigated.

The investigator will also consult the IB and/or product information, for 
marketed products, in his/her assessment.

For each AE or SAE, the investigator must document in the medical notes that 
he/she has reviewed the AE or SAE and has provided an assessment of causality.

There may be situations in which an SAE has occurred and the investigator has 
minimal information to include in the initial report to the sponsor. However, it is 
very important that the investigator always make an assessment of causality 
for every event before the initial transmission of the SAE data to the 
sponsor.

The investigator may change his/her opinion of causality in light of follow-up 
information and send an SAE follow-up report with the updated causality 
assessment.

The causality assessment is one of the criteria used when determining regulatory 
reporting requirements.

If the investigator does not know whether or not the study intervention caused the 
event, then the event will be handled as “related to study intervention” for 
reporting purposes, as defined by the sponsor. In addition, if the investigator 
determines that an SAE is associated with study procedures, the investigator 
must record this causal relationship in the source documents and CRF, and report 
such an assessment in the dedicated section of the CT SAE Report Form and in 
accordance with the SAE reporting requirements.


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Follow-Up of AEs and SAEs

The investigator is obligated to perform or arrange for the conduct of 
supplemental measurements and/or evaluations, as medically indicated or as 
requested by the sponsor, to elucidate the nature and/or causality of the AE or 
SAE as fully as possible. This may include additional laboratory tests or 
investigations, histopathological examinations, or consultation with other 
healthcare providers.

If a participant dies during participation in the study or during a recognized 
follow-up period, the investigator will provide Pfizer Safety with a copy of any 
postmortem findings, including histopathology.

New or updated information will be recorded in the originally submitted 
documents.

The investigator will submit any updated SAE data to the sponsor within 24 
hours of receipt of the information.
10.3.4. Reporting of SAEs
SAE Reporting to Pfizer Safety via an Electronic Data Collection Tool

The primary mechanism for reporting an SAE to Pfizer Safety will be the 
electronic data collection tool.

If the electronic system is unavailable, then the site will use the paper SAE data 
collection tool (see next section) to report the event within 24 hours.

The site will enter the SAE data into the electronic system as soon as the data
become available.

After the study is completed at a given site, the electronic data collection tool 
will be taken off-line to prevent the entry of new data or changes to existing data.

If a site receives a report of a new SAE from a study participant or receives 
updated data on a previously reported SAE after the electronic data collection 
tool has been taken off-line, then the site can report this information on a paper 
SAE form (see next section) or to Pfizer Safety by telephone.


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


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10.4. Appendix 4: Contraceptive and Barrier Guidance
10.4.1. Male Participant Reproductive Inclusion Criteria
Male participants are eligible to participate if they agree to the following requirements during 
the intervention period and for at least 28 days after the last dose of study intervention, which
corresponds to the time needed to eliminate reproductive safety risk of the study 
intervention(s):

Refrain from donating sperm.
PLUS either:

Be abstinent from heterosexual intercourse with a female of childbearing potential as 
their preferred and usual lifestyle (abstinent on a long-term and persistent basis) and 
agree to remain abstinent.
OR

Must agree to use contraception/barrier as detailed below:

Agree to use a male condom and should also be advised of the benefit for a 
female partner to use a highly effective method of contraception as a condom may 
break or leak when having sexual intercourse with a woman of childbearing 
potential who is not currently pregnant.

In addition to male condom use, a highly effective method of contraception may be
considered in WOCBP partners of male participants (refer to the list of highly 
effective methods below in Section 10.4.4).
10.4.2. Female Participant Reproductive Inclusion Criteria
A female participant is eligible to participate if she is not pregnant or breastfeeding, and at 
least 1 of the following conditions applies:

Is not a WOCBP (see definitions below in Section 10.4.3).
OR

Is a WOCBP and using a contraceptive method that is highly effective (with a failure 
rate of <1% per year), as described below during the intervention period and for at 
least 28 days after the last dose of PF-07321332, which corresponds to the time 
needed to eliminate any reproductive safety risk of the study intervention. If a highly 
effective method that is user dependent is chosen, a second effective method of 
contraception, as described below (except options 5 and 6), must also be used. The 
investigator should evaluate the effectiveness of the contraceptive method in 
relationship to the first dose of study intervention.


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The investigator is responsible for review of medical history, menstrual history, and recent 
sexual activity to decrease the risk for inclusion of a woman with an early undetected 
pregnancy. 
10.4.3. Woman of Childbearing Potential
A woman is considered fertile following menarche and until becoming postmenopausal 
unless permanently sterile (see below).
If fertility is unclear (eg, amenorrhea in adolescents or athletes) and a menstrual cycle cannot 
be confirmed before the first dose of study intervention, additional evaluation should be 
considered.
Women in the following categories are not considered WOCBP:
1. Premenopausal female with 1 of the following:

Documented hysterectomy;

Documented bilateral salpingectomy;

Documented bilateral oophorectomy.
For individuals with permanent infertility due to an alternate medical cause other than 
the above, (eg, mullerian agenesis, androgen insensitivity), investigator discretion 
should be applied to determining study entry.
Note: Documentation for any of the above categories can come from the site 
personnel’s review of the participant’s medical records, medical examination, or 
medical history interview. The method of documentation should be recorded in the 
participant’s medical record for the study.
2. Postmenopausal female.

A postmenopausal state is defined as no menses for 12 months without an 
alternative medical cause. In addition:

A high FSH level in the postmenopausal range must be used to confirm a 
postmenopausal state in women under 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 nonestrogen hormonal highly effective contraception methods if they 
wish to continue their HRT during the study. Otherwise, they must discontinue 
HRT to allow confirmation of postmenopausal status before study enrollment.


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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.
Highly Effective Methods That Have Low User Dependency
1. Implantable progestogen-only hormone contraception associated with inhibition of 
ovulation.
2. Intrauterine device.
3. Intrauterine hormone-releasing system.
4. Bilateral tubal occlusion (eg, bilateral tubal ligation).
5. Vasectomized partner.

A vasectomized partner is a highly effective contraceptive method provided that 
the partner is the sole sexual partner of the 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;

Intravaginal;

Transdermal.
7. Progestogen-only hormone contraception associated with inhibition of ovulation.

Oral;

Injectable.
8. Sexual abstinence.

Sexual abstinence is considered a highly effective method only if defined as 
refraining from heterosexual intercourse during the entire period of risk associated 
with the study intervention. The reliability of sexual abstinence needs to be 
evaluated in relation to the duration of the study and the preferred and usual 
lifestyle of the participant.


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One of the following effective barrier methods must be used in addition to the highly 
effective methods listed above that are user dependent:

Male or female condom with or without spermicide;

Cervical cap, diaphragm, or sponge with spermicide;

A combination of male condom with either cervical cap, diaphragm, or sponge with 
spermicide (double-barrier methods).


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10.6. Appendix 6: Liver Safety: Suggested Actions and Follow-Up Assessments
Potential Cases of Drug-Induced Liver Injury
Humans exposed to a drug who show no sign of liver injury (as determined by elevations in 
transaminases) are termed “tolerators,” while those who show transient liver injury but adapt 
are termed “adaptors.” In some participants, transaminase elevations are a harbinger of a 
more serious potential outcome. These participants fail to adapt and therefore are 
"susceptible" to progressive and serious liver injury, commonly referred to as DILI.
Participants who experience a transaminase elevation above 3 × ULN should be monitored 
more frequently to determine if they are “adaptors” or are “susceptible.”
In the majority of DILI cases, elevations in AST and/or ALT precede TBili elevations 
(>2 × ULN) by several days or weeks. The increase in TBili typically occurs while AST/ALT 
is/are still elevated above 3 × ULN (ie, AST/ALT and TBili values will be elevated within 
the same laboratory sample). In rare instances, by the time TBili elevations are detected, 
AST/ALT values might have decreased. This occurrence is still regarded as a potential DILI.
Therefore, abnormal elevations in either AST OR ALT in addition to TBili that meet the 
criteria outlined below are considered potential DILI (assessed per Hy’s law criteria) cases
and should always be considered important medical events, even before all other possible 
causes of liver injury have been excluded.
The threshold of laboratory abnormalities for a potential DILI case depends on the 
participant’s individual baseline values and underlying conditions. Participants who present 
with the following laboratory abnormalities should be evaluated further as potential DILI 
(Hy’s law) cases to definitively determine the etiology of the abnormal laboratory values:

Participants with AST/ALT and TBili baseline values within the normal range who 
subsequently present with AST OR ALT values >3 × ULN AND a TBili value 
>2 × ULN with no evidence of hemolysis and an alkaline phosphatase value 
<2 × ULN or not available.

For participants with baseline AST OR ALT OR TBili values above the ULN, the 
following threshold values are used in the definition mentioned above, as needed, 
depending on which values are above the ULN at baseline:

Preexisting AST or ALT baseline values above the normal range: AST or ALT 
values >2 times the baseline values AND >3 × ULN; or >8 × ULN (whichever is 
smaller).

Preexisting values of TBili above the normal range: TBili level increased from 
baseline value by an amount of at least 1 × ULN or if the value reaches 
>3 × ULN (whichever is smaller).
Rises in AST/ALT and TBili separated by more than a few weeks should be assessed 
individually based on clinical judgment; any case where uncertainty remains as to whether it 
represents a potential Hy’s law case should be reviewed with the sponsor. 


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The participant should return to the investigator site and be evaluated as soon as possible, 
preferably within 48 hours from awareness of the abnormal results. This evaluation should 
include laboratory tests, detailed history, and physical assessment. 
In addition to repeating measurements of AST and ALT and TBili for suspected Hy’s law 
cases, additional laboratory tests should include albumin, CK, direct and indirect bilirubin, 
GGT, PT/INR, total bile acids, and alkaline phosphatase. Consideration should also be given 
to drawing a separate tube of clotted blood and an anticoagulated tube of blood for further 
testing, as needed, for further contemporaneous analyses at the time of the recognized initial 
abnormalities to determine etiology. A detailed history, including relevant information, such 
as review of ethanol, acetaminophen/paracetamol (either by itself or as a coformulated 
product in prescription or over-the-counter medications), recreational drug, or supplement 
(herbal) use and consumption, family history, sexual history, travel history, history of contact 
with a jaundiced person, surgery, blood transfusion, history of liver or allergic disease, and 
potential occupational exposure to chemicals, should be collected. Further testing for acute 
hepatitis A, B, C, D, and E infection, liver imaging (eg, biliary tract), and collection of serum 
samples for acetaminophen/paracetamol drug and/or protein adduct levels may be warranted. 
All cases demonstrated on repeat testing as meeting the laboratory criteria of AST/ALT and 
TBili elevation defined above should be considered potential DILI (Hy’s law) cases if no 
other reason for the LFT abnormalities has yet been found. Such potential DILI (Hy’s law) 
cases are to be reported as SAEs, irrespective of availability of all the results of the 
investigations performed to determine etiology of the LFT abnormalities.
A potential DILI (Hy’s law) case becomes a confirmed case only after all results of 
reasonable investigations have been received and have excluded an alternative etiology.


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10.7. Appendix 7: ECG Findings of Potential Clinical Concern
ECG Findings That May Qualify as AEs

Marked sinus bradycardia (rate <40 bpm) lasting minutes.

New PR interval prolongation >280 msec.

New prolongation of QTcF to >480 msec (absolute) or by ≥60 msec from 
baseline.

New-onset atrial flutter or fibrillation, with controlled ventricular response rate: ie, 
rate <120 bpm.

New-onset type I second-degree (Wenckebach) AV block of >30 seconds’
duration.

Frequent PVCs, triplets, or short intervals (<30 seconds) of consecutive 
ventricular complexes.
ECG Findings That May Qualify as SAEs

QTcF prolongation >500 msec.

New ST-T changes suggestive of myocardial ischemia.

New-onset left bundle branch block (QRS >120 msec).

New-onset right bundle branch block (QRS >120 msec).

Symptomatic bradycardia.

Asystole:

In awake, symptom-free 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 
(heart rate <40 bpm), accelerated idioventricular rhythm (HR >40 bpm to
<100 bpm), and monomorphic/polymorphic ventricular tachycardia (HR 
>100 bpm (such as torsades de pointes)).

Type II second-degree (Mobitz II) AV block.

Complete (third-degree) heart block.
ECG Findings That Qualify as SAEs

Change in pattern suggestive of new myocardial infarction.

Sustained ventricular tachyarrhythmias (>30 seconds’ duration).

Second- or third-degree AV block requiring pacemaker placement.

Asystolic pauses requiring pacemaker placement.

Atrial flutter or fibrillation with rapid ventricular response requiring 
cardioversion.

Ventricular fibrillation/flutter.

At the discretion of the investigator, any arrhythmia classified as an adverse 
experience.
The enumerated list of major events of potential clinical concern are recommended as “alerts” or 
notifications from the core ECG laboratory to the investigator and Pfizer study team, and not to be 
considered as all inclusive of what to be reported as AEs/SAEs.


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10.9. Appendix 9: Child-Pugh Classification (CPC) of Liver Dysfunction 
Table 5.
Scoring for Child-Pugh Classification
Cohort
CPC
Level of dysfunction
Total Score 
(tally based on assessment of 
parameters in Table 6)
1
Not Applicable
Without hepatic impairment
Not Applicable
NA
A
Mild
5-6
2
B
Moderate
7-9
NA
C
Severe
≥10
Table 6.
Derivation of Child-Pugh Classification Score
Assessment 
Parameters
Assigned score for observed findings
1 point
2 points
3 points
Encephalopathy gradea
(refer to Table 7 below)
0
1 or 2
3 or 4a
Ascites
Absent
Asymptomatic
Requiring intervention
Serum total bilirubin, 
mg/dL
<2
2 to 3
>3
Serum albumin, g/dL
>3.5
2.8 to 3.5
<2.8
Prothrombin time, sec 
prolongedb
<4
4 to 6
>6
a.
Participants with a prior history of Grade 3 or Grade 4 encephalopathy who are currently receiving 
an intervention [for example: lactulose or lactitol, alone or in combination with rifaximin, and/or neomycin] to 
manage encephalopathy-related signs and symptoms should be scored for encephalopathy grading based on their 
presentation while on intervention at the Screening visit and can be included in this study as long as they do not
have clinically active Grade 3 or Grade 4 encephalopathy.
b.
As assessed relative to PT control (or upper limit of normal).
Table 7.
Determination of Encephalopathy Grade
Encephalopathy Grade
Definition
0
Normal consciousness, personality, neurological exam
1
Restless, sleep disturbed, irritable/agitated, tremor, impaired handwriting
2
Lethargic, time disoriented, inappropriate, asterixis, ataxia
3a
Somnolent, stuporous, place disoriented, hyperactive reflexes, rigidity
4a
Unrousable coma, no personality/behavior, decerebrate
a.
Participants with clinically active Grade 3 or 4 encephalopathy are excluded.
CPC should be assessed at Screening to determine the classification of a given 
participant.


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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
3CLpro
3C-like protein
Ab
antibody
Abs
absolute
ADL
activities of daily living
AE
adverse event
 
 
ALT
alanine aminotransferase
ANOVA
analysis of variance
aPTT
activated partial thromboplastin time
AST
aspartate aminotransferase
AUC
area under the curve
 
 
AUCinf
area under the plasma concentration-time profile from time 0 
extrapolated to infinite time
AUClast
area under the plasma concentration-time profile from time 0 to 
the time of Clast
AV
atrioventricular
β-hCG
beta-human chorionic gonadotropin
BBS
Biospecimen Banking System
BID
twice a day
BMI
body mass index
BP
blood pressure
bpm
beats per minute
BUN
blood urea nitrogen
CFR
Code of Federal Regulations
CI
confidence interval
CIOMS
Council for International Organizations of Medical Sciences
CK
creatine kinase
CKD
chronic kidney disease
CKD-EPI 
Chronic Kidney Disease-Epidemiology Collaboration
Clast
predicted plasma concentration at the last quantifiable time point
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Abbreviation
Term
Cmax
maximum plasma concentration
CO2
carbon dioxide (bicarbonate)
COVID-19
coronavirus disease 2019
CPC
Child-Pugh score
CRF
case report form
CRO
contract research organization
CRU
clinical research unit
CSR
Clinical Study Report
CT
clinical trial
CYP
cytochrome P450 
CYP3A4
cytochrome P450 3A4 
DBP
diastolic blood pressure
DC
discontinuation
DCT
data collection tool
DDI
drug-drug interaction 
DILI
drug-induced liver injury
DMC
Data Monitoring Committee
DNA
deoxyribonucleic acid
EC
ethics committee
ECC
Emergency Contact Card
ECG
electrocardiogram
eCRF
electronic case report form
EDB
exposure during breastfeeding
EDP
exposure during pregnancy
eGFR
estimated glomerular filtration rate
EMA
European Medicines Agency
EU
European Union
EudraCT
European Clinical Trials Database
FDA
Food and Drug Administration
FIH
first-in-human
fm
fraction metabolized
FSH
follicle stimulating hormone
fu
fraction unbound
GCP
Good Clinical Practice
GGT
gamma-glutamyl transferase
GLP
Good Laboratory Practice
H
hour
HBcAb 
hepatitis B core antibody
HBsAb
hepatitis B surface antibody
HBsAg 
hepatitis B surface antigen
HCoV-OC43
human coronavirus OC43
HCoV-229E
human coronavirus 229E
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Abbreviation
Term
HCoV-HKU1
human coronavirus HKU1
HCoV-NL63
human coronavirus NL63
HCVAb
hepatitis C antibody
HCV
hepatitis C virus
hep C
hepatitis C
HI
hepatic impairment 
HIV
human immunodeficiency virus
HMG CoA reductase
3-hydroxy-3-methyl-glutaryl-CoA reductase
HR
heart rate
HRT
hormone replacement therapy
IB
Investigator's Brochure
ICD
informed consent document
ICH
International Council for Harmonisation
IMP
investigational medicinal product
IND
Investigational New Drug 
INR
international normalized ratio
IP
investigational product
IP manual
investigational product manual
IPAL
Investigational Product Accountability Log
IRB
Institutional Review Board
IV
intravenous
kel
elimination rate constant
Ki
inhibition constant
LFT
liver function test
MAD
multiple ascending dose
MCH
mean corpuscular hemoglobin
MCHC
mean corpuscular hemoglobin concentration
MCV
mean corpuscular volume
MERS
Middle East respiratory syndrome 
MRI
magnetic resonance imaging
N/A
not applicable
NHP
non-human primate
NNRT
non-nucleoside reverse transcriptase
NOAEL
no observed adverse effect level
NTI
narrow therapeutic index
PAH
pulmonary arterial hypertension
PBPK
physiologically based pharmacokinetic
PD
pharmacodynamic(s)
PE
physical examination
pH
potential of hydrogen
PI
principle investigator
PK
pharmacokinetic(s)
PR
pulse rate


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Abbreviation
Term
PT
prothrombin time
PT-INR
prothrombin time-international normalized ratio
PVC
premature ventricular contraction/complex
q12h
every 12 hours
QT
time from the beginning of the QRS complex to the end of the 
T wave
QTc
corrected QT interval
QTcF
corrected QT (Fridericia method)
qual
qualitative
RBC
red blood cell
RNA
ribonucleic acid
RT-PCR
reverse-transcriptase polymerase chain reaction
SAD
single ascending dose
SAE
serious adverse event
SAP
Statistical Analysis Plan
SARS-CoV-1
severe acute respiratory syndrome coronavirus 1
SARS-CoV-2 
severe acute respiratory syndrome coronavirus 2
SBP
systolic blood pressure
SoA
schedule of activities
SOP
standard operating procedure
SRSD
single-reference safety document
SToD 
Study Team on Demand
SUSAR
suspected unexpected serious adverse reaction
T4
thyroxine
TBili 
total bilirubin
TEAE
treatment emergent adverse event
THC
tetrahydrocannabinol
TIPS
transjugular intrahepatic portosystemic shunt
TSH
thyroid stimulating hormone
ULN
upper limit of normal
US
United States
USPI
United States Prescribing Information
WBC
white blood cell
WHO
World Health Organization
WOCBP
woman/women of childbearing potential
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11. REFERENCES
1
WHO Situation Report 51. 11 March 2020 Available from: 
https://www.who.int/emergencies/diseases/novel-coronavirus-2019/situation-reports. 
Accessed: 29 March 2020.
2
Anand K, Ziebuhr J, Wadhwani P, et al. Coronavirus main proteinase (3CLpro) structure: 
basis for design of anti-SARS drugs. Science. 2003;300:1763-7.
3
Investigator’s Brochure, PF-07321332. (June 2021)
4
Ritonavir [package insert]. North Chicago, IL: AbbVie Inc; 2017. Available from: 
https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/209512lbl.pdf. Accessed: 
24 June 2021.
5
US Department of Health and Human Services, Food and Drug Administration, Center 
for Drug Evaluation and Research, Center for Biologics Evaluation and Research. 
Guidance for industry: pharmacokinetics in patients with impaired hepatic function: 
study design, data analysis and impact on dosing and labeling. Rockville, MD: US 
Department of Health and Human Services;  May 2003. Available from: 
https://www.fda.gov/regulatory-information/search-fda-guidance-
documents/pharmacokinetics-patients-impaired-hepatic-function-study-design-data-
analysis-and-impact-dosing-and. Accessed: 24 June 2021.

SAP_001.pdf: 
Protocol C4671010 (PF-07321332) Statistical Analysis Plan
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PFIZER GENERAL BUSINESS 
Protocol C4671010
A PHASE 1, NON-RANDOMIZED, OPEN-LABEL STUDY TO ASSESS 
THE PHARMACOKINETICS, SAFETY AND TOLERABILITY OF 
PF-07321332 BOOSTED WITH RITONAVIR IN ADULT PARTICIPANTS 
WITH MODERATE HEPATIC IMPAIRMENT AND HEALTHY 
PARTICIPANTS WITH NORMAL HEPATIC FUNCTION
Statistical Analysis Plan 
(SAP)
Version:
1.0
SAP Author: 
(
 
, Mumbai)
Date:
29-Nov-2021
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Revision History
Version
Date
Author(s)
Summary of Changes/Comments
Final
November 29, 2021
Not Applicable
NOTE: Italicized text within this document has been taken verbatim from the Protocol.
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TABLE OF CONTENTS 
LIST OF TABLES.....................................................................................................................4
LIST OF FIGURES ...................................................................................................................4
1. AMENDMENTS FROM PREVIOUS VERSION(S) ...........................................................6
2. INTRODUCTION .................................................................................................................6
2.1. Study Design .............................................................................................................6
2.2. Study Objectives .......................................................................................................7
2.2.1. Primary Objective.........................................................................................7
2.2.2. Secondary Objective.....................................................................................7
3. INTERIM ANALYSES, FINAL ANALYSES AND UNBLINDING..................................7
4. HYPOTHESES AND DECISION RULES...........................................................................7
4.1. Statistical Hypotheses ...............................................................................................7
4.2. Statistical Decision Rules..........................................................................................8
5. ANALYSIS SETS .................................................................................................................8
5.1. Enrolled Set...............................................................................................................8
5.2. Pharmacokinetic (PK) Analysis Set ..........................................................................8
5.2.1. Concentration Analysis Set...........................................................................8
5.2.2. Parameter Analysis Set.................................................................................8
5.3. Pharmacodynamic Analysis Set................................................................................8
5.4. Safety Analysis Set....................................................................................................8
5.5. Other Analysis Sets ...................................................................................................8
5.6. Treatment Misallocations..........................................................................................8
5.7. Protocol Deviations...................................................................................................9
5.7.1. Deviations Assessed Prior to Randomization...............................................9
5.7.2. Deviations Assessed Post-Randomization....................................................9
6. ENDPOINTS AND COVARIATES .....................................................................................9
6.1. Efficacy Endpoint(s) .................................................................................................9
6.2. Safety Endpoints .......................................................................................................9
6.3. Other Endpoints.........................................................................................................9
6.3.1. PK Endpoints................................................................................................9
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6.3.2. PD Endpoints..............................................................................................10
6.4. Covariates................................................................................................................10
7. HANDLING OF MISSING VALUES ................................................................................10
7.1. Concentrations Below the Limit of Quantification.................................................10
7.2. Deviations, Missing Concentrations and Anomalous Values .................................10
7.3. Pharmacokinetic Parameters ...................................................................................11
8. STATISTICAL METHODOLOGY AND STATISTICAL ANALYSES ..........................11
8.1. Statistical Methods ..................................................................................................11
8.2. Statistical Analyses .................................................................................................11
8.3. Safety Analysis........................................................................................................13
8.3.1. Treatment and Disposition of Subjects.......................................................13
8.3.2. Demographic and Clinical Examination Data............................................13
8.3.3. Discontinuation(s).......................................................................................13
8.3.4. Adverse Events...........................................................................................13
8.3.5. Laboratory Data..........................................................................................14
8.3.6. Vital Signs Data..........................................................................................14
8.3.7. ECG Data....................................................................................................14
8.3.8. COVID-19 Data..........................................................................................14
8.3.9. Other Safety Data .......................................................................................14
8.3.10. Concomitant Treatments...........................................................................14
8.3.11. Screening and Other Special Purpose Data ..............................................14
9. REFERENCES ....................................................................................................................15
10. APPENDICES ...................................................................................................................16
LIST OF TABLES
Table 1.
Hepatic Function Categories Based on Child-Pugh Score .........................7
Table 2.
Noncompartmental PK Parameters...........................................................10
Table 3.
PK Parameters to be Summarized Descriptively by Group......................12
LIST OF FIGURES
None.


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APPENDICES
Appendix 1. SAS CODE FOR ANALYSES...........................................................................16


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1. AMENDMENTS FROM PREVIOUS VERSION(S) 
None.
2. INTRODUCTION
PF-07321332/ritonavir is intended for short-term (eg, 5 day) use, in patients with 
COVID-19, some of whom may have some degree of impaired hepatic function. The purpose 
of this study is to estimate the effect of hepatic impairment on the plasma PK of 
PF-07321332/ritonavir. Findings from this study will be used to develop dosing
recommendations so that the dose and/or dosing interval may be adjusted appropriately in 
the presence of hepatic impairment.
2.1. Study Design
This is a Phase 1, non-randomized, open-label study to investigate the effect of hepatic 
impairment on the plasma PK, safety and tolerability of a single oral dose of PF-07321332 
in combination with the PK boosting agent ritonavir in approximately 16 participants. The 
study will be conducted in adult participants with stable, moderate hepatic impairment and a 
control group of participants with normal hepatic function. 
Enrollment will be in a staged manner such that participants with hepatic impairment 
(Cohort 2) will begin enrollment first. Participants without hepatic impairment (Cohort 1) 
will begin recruitment towards the end of Cohort 2 or earlier, at the sponsor’s discretion 
such that the enrollment in both cohorts may overlap. Participants in Cohort 1 will match 
the average demographics (at a minimum, age and weight; gender and race as much as 
practically possible) of participants in Cohort 2. 
All participants in both cohorts will provide informed consent and undergo Screening 
evaluations to determine their eligibility. Categorization of participants into hepatic 
impairment cohort, Cohort 2, will be done based on Child-Pugh scores.
Participants who prematurely discontinue for non-safety related reasons may be replaced, at 
the discretion of the PI and sponsor study team.
Each enrolled participant will receive a single 100 mg dose of PF-07321332 administered 
orally in combination with the PK boosting agent ritonavir administered as a 100 mg dose 
at -12, 0, 12, and 24 hours relative to PF-07321332 dosing. 
The total planned duration of participation, from the Screening visit to the last Follow-up 
phone call, is approximately up to 9 weeks.


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Table 1.
Hepatic Function Categories Based on Child-Pugh Score
Cohort
Description
Child-Pugh Score
Number of Participants
1
Without hepatic impairment
Not Applicable
8
2
Moderate hepatic impairment
Class B (7 to 9 points)
8
2.2. Study Objectives
2.2.1. Primary Objective
•
To compare the PK of PF-07321332, following a single oral dose administration of 
PF-07321332 pharmacokinetically boosted with ritonavir in adult participants with 
moderate hepatic impairment and age and body weight-matched participants without 
hepatic impairment.
2.2.2. Secondary Objective
•
To evaluate the safety and tolerability of PF-07321332 and ritonavir, following a 
single oral dose administration of PF-07321332 pharmacokinetically boosted with 
ritonavir, in participants with moderate hepatic impairment and in healthy 
participants with normal hepatic function.
 
 
3. INTERIM ANALYSES, FINAL ANALYSES AND UNBLINDING
No formal interim analysis will be conducted for this study. As this is an open-label study, 
the sponsor may conduct unblinded reviews of the data during the course of the study for the 
purpose of safety assessment, facilitating PK/PD modeling, and/or supporting clinical 
development. 
Final analysis will follow the official database release.  As this will be an open-label study, 
there is no formal unblinding of the randomization code.
4. HYPOTHESES AND DECISION RULES
4.1. Statistical Hypotheses
No hypotheses are required.
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4.2. Statistical Decision Rules
No decision rules are required.
5. ANALYSIS SETS
5.1. Enrolled Set
"Enrolled" means a participant's, or his or her legally authorized representative’s, 
agreement to participate in a clinical study following completion of the informed consent 
process and screening. A participant will be considered enrolled if the informed consent is 
not withdrawn prior to participating in any study activity after screening. Potential 
participants who are screened for the purpose of determining eligibility for the study, but do 
not participate in the study, are not considered enrolled, unless otherwise specified by the 
protocol.
5.2. Pharmacokinetic (PK) Analysis Set
5.2.1. Concentration Analysis Set
The PK concentration population is defined as all participants assigned to investigational 
product and treated who have at least 1 concentration measured.
5.2.2. Parameter Analysis Set
The PK parameter analysis population is defined as all participants assigned to 
investigational product and treated who have at least 1 of the PK parameters of primary 
interest measured.
5.3. Pharmacodynamic Analysis Set
None.
5.4. Safety Analysis Set
All participants randomly assigned to study intervention and who take at least 1 dose of 
study intervention. Participants will be analyzed according to the product they actually 
received.
5.5. Other Analysis Sets
None.
5.6. Treatment Misallocations 
All analyses will be performed on an “as-treated” basis and will not include data from 
subjects who are randomized but not treated.


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5.7. Protocol Deviations
Subjects who experience events that may affect their PK profile (eg lack of compliance with 
dosing) may be excluded from the PK analysis.  At the discretion of the pharmacokineticist a 
concentration value may also be excluded if the deviation in sampling time is of sufficient 
concern or if the concentration is anomalous for any other reason.
A full list of protocol deviations will be compiled and reviewed to identify major and minor 
deviations prior to database closure.
5.7.1. Deviations Assessed Prior to Randomization
At Screening, the investigator will assess subjects against the inclusion and exclusion criteria 
as set out in Sections 5.1 and 5.2 of the protocol.
5.7.2. Deviations Assessed Post-Randomization
A full list of protocol deviations for the study report will be compiled prior to database 
closure.  Any significant deviation from the protocol will be reviewed prior to database 
closure and a decision taken regarding evaluation for each analysis population.
6. ENDPOINTS AND COVARIATES
6.1. Efficacy Endpoint(s)
None.
6.2. Safety Endpoints
Any events occurring following start of treatment (of PF-07321332) or increasing in severity 
will be counted as treatment emergent.
Events that occur in a non-treatment period (for example, Follow-up) will be counted as 
treatment emergent and attributed to the previous treatment taken.
The following data are considered in standard safety summaries (see protocol for collection 
days and list of parameters):
•
adverse events,
•
laboratory data.
6.3. Other Endpoints
6.3.1. PK Endpoints
Blood 
samples for PK analysis of PF-07321332 
 
 will be taken according to the Schedule of Activities given in the protocol.
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The following PK parameters will be calculated for PF-07321332 (if possible) 
 
 from the concentration-time data using standard noncompartmental 
methods:
Table 2.
Noncompartmental PK Parameters
PK Parameter
Analysis Scale
PF-07321332
AUCinf*
ln
A, D
AUClast
ln
A, D
Cmax
ln
A, D
Key:
A=analyzed using statistical model, D=displayed with descriptive statistics,
ln=natural-log transformed, NA=not applicable, 
 *=if data 
permits.
6.3.2. PD Endpoints
None.
6.4. Covariates
None.
7. HANDLING OF MISSING VALUES
For the analysis of safety endpoints, the sponsor data standard rules for imputation will be 
applied.
7.1. Concentrations Below the Limit of Quantification
In all data presentations (except listings), concentrations below the limit of quantification 
(BLQ) will be set to zero.  (In listings BLQ values will be reported as “<LLQ”, where LLQ 
will be replaced with the value for the lower limit of quantification).
7.2. Deviations, Missing Concentrations and Anomalous Values
In summary tables and plots of median profiles, statistics will be calculated having set 
concentrations to missing if 1 of the following cases is true:
1. A concentration has been collected as ND (ie, not done) or NS (ie, no sample);
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2. A deviation in sampling time is of sufficient concern or a concentration has been 
flagged anomalous by the pharmacokineticist.
Note that summary statistics will not be presented at a particular time point if more than 
50% of the data are missing.
7.3. Pharmacokinetic Parameters
Actual PK sampling times will be used in the derivation of PK parameters.
If a PK parameter cannot be derived from a subject’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 subject discontinues). 
In summary tables, statistics will be calculated by setting NC values to missing; and statistics 
will be presented for a particular hepatic function group with ≥3 evaluable measurements.  
For statistical analyses (ie analysis of variance), PK parameters coded as NC will also be set 
to missing; and analyses will not be performed for a particular parameter if more than 50% of 
the data are NC.
If an individual subject has a known biased estimate of a PK parameter (due for example to 
an unexpected event such as vomiting before all the compound is adequately absorbed in the 
body), this will be footnoted in summary tables and will not be included in the calculation of 
summary statistics or statistical analyses.
8. STATISTICAL METHODOLOGY AND STATISTICAL ANALYSES
8.1. Statistical Methods
The effect of the hepatic impairment on PK parameters will be assessed by constructing 
90% confidence intervals around the estimated difference between each of the Test (impaired 
groups) and the Reference (normal hepatic function group) using a one-way ANOVA model 
based on natural log transformed data and assuming unequal variances.
8.2. Statistical Analyses
One-way ANOVA will be used to compare the natural log transformed AUClast, AUCinf (if 
data permit) and Cmax for PF-07321332 between Cohort 2 with moderate hepatic impairment 
(Test) and Cohort 1 with normal hepatic function (Reference). Estimates of the adjusted 
mean differences (Test-Reference) and corresponding 90% CIs will be obtained from the 
model. The adjusted mean differences and 90% CIs for the differences will be exponentiated 
to provide estimates of the ratio of the adjusted geometric means (Test/Reference) and 
90% CIs for the ratios.
Box and whisker plots for individual participant parameters (AUCinf, AUClast and Cmax) will 
be constructed by cohort and overlaid with geometric means.


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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 clinical study report.  If there are major 
deviations from normality or outliers then the effect of these on the conclusions will be 
investigated through alternative transformations and/or analyses excluding outliers.  
Justification for any alternative to the planned analysis will be given in the report of the 
study.
The following PK parameters will be summarized by analyte and hepatic function group as 
applicable:
Table 3.
PK Parameters to be Summarized Descriptively by Group
Parameter
Summary Statistics
, AUClast, 
AUCinf, Cmax,
 
N, arithmetic mean, median, cv%, standard deviation, minimum, 
maximum, geometric mean and geometric cv%.
 
Supporting data from the estimation of t½ and AUCinf will be listed by group:  terminal phase 
rate constant (kel); goodness of fit statistic from the log-linear regression (r2); the percent of 
AUCinf based on extrapolation (AUCextrap%); and the first, last, and number of time points
used in the estimation of kel. This data may be included in the clinical study report.
Presentations for PF-07321332 
 (where applicable) concentrations will include:
•
A listing of all concentrations sorted by hepatic function group (present in heading), 
subject id and nominal time postdose.  The concentration listing will also include the 
actual times.  Deviations from the nominal time will be given in a separate listing.
•
A summary of concentrations by hepatic function group and nominal time postdose, 
where the set of statistics will include n, mean, median, standard deviation, 
coefficient of variation (cv), minimum, maximum and the number of concentrations 
above the lower limit of quantification.
•
Median concentrations time plots (on both linear and semi-log scales) against 
nominal time postdose by hepatic function group (all hepatic function groups on the 
same plot per scale, based on the summary of concentrations by hepatic function 
group and time postdose).
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•
Mean concentrations time plots (on both linear and semi-log scales) against nominal 
time postdose by hepatic function group (all hepatic function groups on the same plot 
per scale, based on the summary of concentrations by hepatic function group and time 
postdose).
•
Individual concentration time plots by hepatic function group (on both linear and 
semi-log scales) against actual time postdose (there will be separate spaghetti plots 
for each hepatic function group per scale).
•
 
.
For summary statistics, median and mean plots by sampling time, the nominal PK sampling 
time will be used, for individual subject plots by time, the actual PK sampling time will be 
used.
8.3. Safety Analysis
A set of summary tables split by hepatic function group will be produced to evaluate any 
potential risk associated with the safety and toleration of administering PF-07321332.
8.3.1. Treatment and Disposition of Subjects
Subject evaluation groups will show end of study subject disposition and will show which 
subjects were analyzed for pharmacokinetics, as well as for safety (adverse events and 
laboratory data).  Frequency counts will be supplied for subject discontinuation(s) by hepatic 
function group.
Data will be reported in accordance with the sponsor reporting standards.
8.3.2. Demographic and Clinical Examination Data
A break down of demographic data will be provided for age, race, weight, body mass index, 
and height.  Each will be summarized by sex at birth and ‘All Subjects’ in accordance with 
the sponsor reporting standards by cohort.
8.3.3. Discontinuation(s)
Subject discontinuations, temporary discontinuations or dose reductions due to adverse 
events will be detailed and summarized by hepatic function group.
Data will be reported in accordance with the sponsor reporting standards.
8.3.4. Adverse Events
Adverse events will be reported in accordance with the sponsor reporting standards by 
hepatic function group.
CCI


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8.3.5. Laboratory Data
The baseline measurement is the last planned predose measurement.
For each planned timepoint, baseline values and change from baseline values within each 
hepatic function group will be summarized with descriptive statistics (using sponsor default 
standards).
These data will be listed in accordance with the sponsor reporting standards.
8.3.6. Vital Signs Data
Supine blood pressure and pulse rate will be measured at the time points as mentioned in the 
schedule of activities in the protocol.
The baseline measurement is the last planned predose measurement.
Vital Signs data will be databased and available upon request.
8.3.7. ECG Data
The baseline measurement is the last planned predose measurement.
ECG data will be databased and available upon request.
8.3.8. COVID-19 Data
These data will be listed in accordance with the sponsor reporting standards.
8.3.9. Other Safety Data
None.
8.3.10. Concomitant Treatments
All concomitant medication(s) as well as non-drug treatment(s) will be provided in the 
listings.
8.3.11. Screening and Other Special Purpose Data
If such data will be brought in-house, then it will not be listed.


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9. REFERENCES
None.


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10. APPENDICES
Appendix 1. SAS CODE FOR ANALYSES
An example of the PROC GLM code is provided below:
proc mixed data = tab.pk covtest alpha=0.1;
class group;
model l&var = group / S covb alpha=0.1 CL DDFM=KR;
repeated/type=un subject=subjid group=group R;
lsmeans group;
estimate 'Moderate vs Normal'
group 1 -1;
ods output lsmeans = lsmeans&var;
ods output solutionf = solution&var;
run;
/* Letter assignments for group within the estimate statement above are as follows;
A = Moderate (Test);
B = Normal (Reference);  */;