Clinical trial NCT04756531
Conditions: Healthy Participants
Sponsor: Pfizer
Start date: 2021-02-11; Completion date: 2021-09-01
Enrollment: 70 participants; Allocation: RANDOMIZED; Intervention model: CROSSOVER

Brief summary:
A Phase 1, double blind, sponsor open, single and multiple ascending dose study to evaluate safety, tolerability and pharmacokinetics of PF-07321332 in healthy participants.

Detailed description:
Combined 5-part study. Part-1: Single Ascending dose Part-2: Multiple Ascending Dose Part-3: Relative bioavailability and food effect Part-4: Metabolism and Excretion Part-5: Supra-therapeutic Exposure Part-1,2 and 5 are double blind, sponsor open and Part-3 and 4 are open label study.

Arms: arm 1: Dose level 1 of PF-07321332 arm 2: Dose level 2 of PF-07321332 arm 3: Dose level 3 of PF-07321332 arm 4: Dose level 4 of PF-07321332 arm 5: Dose level 5 of PF-07321332 arm 6: Dose level 4 of PF-07321332 with high fat meal
Interventions: intervention 1: PF-07321332 Dose 1 intervention 2: PF-07321332 Dose 2 intervention 3: PF-07321332 Dose 3 intervention 4: PF-07321332 Dose 4 intervention 5: PF-07321332 Dose 5 intervention 6: PF-07321332 Dose 4 or Placebo (Fed)
Intervention descriptions: intervention 1: PF-07321332 Dose 1 or Placebo intervention 2: PF-07321332 Dose 2 or Placebo intervention 3: PF-07321332 Dose 3 or Placebo intervention 4: PF-07321332 Dose 4 or Placebo intervention 5: PF-07321332 Dose 5 or Placebo intervention 6: PF-07321332 Dose 5 or Placebo with high fat meal

Protocol documents:
Prot_000.pdf: 
PF-07321332
Protocol C4671001
Final Protocol Amendment 3, 24 June 2021
PFIZER CONFIDENTIAL
Page 1
A PHASE 1, RANDOMIZED, DOUBLE-BLIND, SPONSOR-OPEN, PLACEBO
CONTROLLED, SINGLE- AND MULTIPLE-DOSE ESCALATION STUDY TO 
EVALUATE THE SAFETY, TOLERABILITY, AND PHARMACOKINETICS OF 
PF-07321332 IN HEALTHY ADULT PARTICIPANTS
Study Intervention Number:
PF-07321332
Study Intervention Name:
N/A
US IND Number:
EudraCT Number:
2020-006073-30
Protocol Number:
C4671001
Phase:
Phase 1
Short Title: A Phase 1 Single Ascending Dose and Multiple Ascending Dose Study of 
PF-07321332 in Healthy Adult Participants
This document and accompanying materials contain confidential information belonging to Pfizer.  Except as 
otherwise agreed to in writing, by accepting or reviewing these documents, you agree to hold this 
information in confidence and not copy or disclose it to others (except where required by applicable law) or 
use it for unauthorized purposes.  In the event of any actual or suspected breach of this obligation, Pfizer 
must be promptly notified.
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Protocol Amendment Summary of Changes Table
Document History
Document
Version Date
Summary and Rationale for Changes
Amendment 3
24 June 2021
•
 
 
 
 
 
 
 
  
Amendment 2
02 June 2021
•
 
 
 
 
 
 
 
Amendment 1
05 March 2021
•
 
 
 
 
 
 
Original protocol
28 January 2021
N/A
This amendment incorporates all revisions to date, including amendments made at the 
request of country health authorities and IRBs/ECs. 
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Final Protocol Amendment 3, 24 June 2021
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TABLE OF CONTENTS
LIST OF TABLES.....................................................................................................................8
LIST OF FIGURES ...................................................................................................................9
1. PROTOCOL SUMMARY...................................................................................................10
1.1. Synopsis ..................................................................................................................10
1.2. Schema ....................................................................................................................18
1.3. Schedule of Activities .............................................................................................19
2. INTRODUCTION ...............................................................................................................34
2.1. Study Rationale .......................................................................................................34
2.2. Background .............................................................................................................34
 
2.3. Benefit/Risk Assessment.........................................................................................41
2.3.2. Benefit Assessment.....................................................................................44
2.3.3. Overall Benefit/Risk Conclusion................................................................44
3. OBJECTIVES AND ENDPOINTS.....................................................................................44
4. STUDY DESIGN.................................................................................................................47
4.1. Overall Design.........................................................................................................47
4.2. Scientific Rationale for Study Design.....................................................................52
4.3. Justification for Dose ..............................................................................................55
4.3.1. Justification of Dose for PART-1, PART-2 and PART-3 (Original 
Protocol, 28 January 2021) ..............................................................................55
4.3.2. Justification of Dose for PART-4:Metabolism and Excretion 
(Protocol Amendment 2, 2 June 2021) ............................................................58
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4.3.3. Justification of Dose for PART-5: Supratherapeutic Exposure 
(Protocol Amendment 3, 24 June 2021) ..........................................................58
4.4. End of Study Definition ..........................................................................................59
5. STUDY POPULATION......................................................................................................59
5.1. Inclusion Criteria.....................................................................................................59
5.2. Exclusion Criteria....................................................................................................60
5.3. Lifestyle Considerations..........................................................................................62
5.3.1. Meals and Dietary Restrictions...................................................................62
5.3.1.1. Dietary Fiber Supplementation (PART-4 and PART-5 
only)...................................................................................................66
5.3.2. Caffeine, Alcohol, and Tobacco .................................................................66
5.3.3. Activity .......................................................................................................66
5.3.4. Contraception..............................................................................................67
5.4. Screen Failures ........................................................................................................67
6. STUDY INTERVENTION..................................................................................................67
6.1. Study Intervention(s) Administered........................................................................67
6.1.1. Administration............................................................................................68
6.2. Preparation/Handling/Storage/Accountability ........................................................70
6.2.1. Preparation and Dispensing........................................................................71
6.3. Measures to Minimize Bias: Randomization and Blinding.....................................72
6.3.1. Allocation to Study Intervention ................................................................72
6.3.2. Breaking the Blind......................................................................................73
6.4. Study Intervention Compliance...............................................................................73
6.5. Concomitant Therapy..............................................................................................73
6.5.1. Rescue Medicine.........................................................................................74
6.6. Dose Modification...................................................................................................74
6.6.1. Dose Escalation and Stopping Rules..........................................................74
6.7. Intervention After the End of the Study..................................................................75
7. DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL...........................................................................75
7.1. Discontinuation of Study Intervention ....................................................................75
7.2. Participant Discontinuation/Withdrawal From the Study.......................................77


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7.2.1. Withdrawal of Consent...............................................................................78
7.3. Lost to Follow-up....................................................................................................78
8. STUDY ASSESSMENTS AND PROCEDURES...............................................................78
8.1. Efficacy Assessments..............................................................................................80
8.2. Safety Assessments .................................................................................................80
8.2.1. Physical Examinations................................................................................80
8.2.2. Vital Signs ..................................................................................................80
8.2.2.1. Respiratory Rate........................................................................81
8.2.2.2. Temperature ..............................................................................81
8.2.3. Electrocardiograms.....................................................................................81
8.2.3.1. Continuous Cardiac Monitoring by Telemetry (PART-1 
and PART-5 only) .............................................................................82
8.2.4. Clinical Safety Laboratory Assessments ....................................................82
8.2.5. Pregnancy Testing ......................................................................................83
8.3. Adverse Events and Serious Adverse Events..........................................................83
8.3.1. Time Period and Frequency for Collecting AE and SAE Information.......84
8.3.1.1. Reporting SAEs to Pfizer Safety...............................................84
8.3.1.2. Recording Nonserious AEs and SAEs on the CRF...................84
8.3.2. Method of Detecting AEs and SAEs ..........................................................85
8.3.3. Follow-up of AEs and SAEs.......................................................................85
8.3.4. Regulatory Reporting Requirements for SAEs...........................................85
8.3.5. Exposure During Pregnancy or Breastfeeding, and Occupational 
Exposure ..........................................................................................................85
8.3.5.1. Exposure During Pregnancy......................................................86
8.3.5.2. Exposure During Breastfeeding ................................................87
8.3.5.3. Occupational Exposure .............................................................88
8.3.6. Cardiovascular and Death Events...............................................................88
8.3.7. Disease-Related Events and/or Disease-Related Outcomes Not 
Qualifying as AEs or SAEs..............................................................................88
8.3.8. Adverse Events of Special Interest.............................................................88
8.3.8.1. Lack of Efficacy........................................................................88
8.3.9. Medical Device Deficiencies......................................................................88


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8.3.10. Medication Errors.....................................................................................88
8.4. Treatment of Overdose............................................................................................89
8.5. Pharmacokinetics ....................................................................................................90
8.5.1. Plasma for Analysis of PF-07321332 PK, 19F-NMR measurement 
and Metabolic Profiling ...................................................................................90
8.5.2. Urine Pharmacokinetics (PART-2 only) ....................................................91
8.5.3. Urine and Feces for Measurement of Drug-Related Material by 19F-
NMR and Metabolic Profiling (PART-1: Cohort-1, Period 2 only)................92
8.5.4. Urine and Feces for Measurement of Drug-Related Material and 
Metabolic Profiling (PART-4 only).................................................................92
8.6. Pharmacodynamics..................................................................................................93
8.9. Immunogenicity Assessments.................................................................................94
8.10. Health Economics .................................................................................................94
9. STATISTICAL CONSIDERATIONS ................................................................................94
9.1. Statistical Hypotheses .............................................................................................94
9.2. Sample Size Determination.....................................................................................94
9.2.1. PART-1: SAD.............................................................................................94
9.2.2. PART-2: MAD ...........................................................................................95
9.2.3. PART-3: Relative Bioavailability/Food Effect ..........................................95
9.2.4. PART-4: Metabolism and Excretion ..........................................................95
9.2.5. PART-5: Supratherapeutic Exposures........................................................95
9.3. Analysis Sets ...........................................................................................................96
9.4. Statistical Analyses .................................................................................................96
9.4.1. General Considerations...............................................................................96
9.4.2. Primary Endpoint(s)....................................................................................97
9.4.3. Secondary Endpoint(s)................................................................................97
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9.4.3.1. PK Analysis...............................................................................97
9.4.3.2. Statistical Methods for PK Data................................................99
9.4.4. Tertiary/Exploratory Endpoint(s) .............................................................100
9.4.5. Safety Analyses ........................................................................................100
9.4.5.1. Standard Safety Analyses........................................................100
9.4.5.2. Electrocardiogram Analyses....................................................101
9.5. Interim Analyses ...................................................................................................102
9.6. Data Monitoring Committee or Other Independent Oversight Committee...........102
10. SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS........................................................................................................103
10.1. Appendix 1: Regulatory, Ethical, and Study Oversight Considerations.............103
10.1.1. Regulatory and Ethical Considerations ..................................................103
10.1.1.1. Reporting of Safety Issues and Serious Breaches of the 
Protocol or ICH GCP.......................................................................103
10.1.2. Informed Consent Process ......................................................................104
10.1.3. Data Protection .......................................................................................105
10.1.4. Dissemination of Clinical Study Data ....................................................105
10.1.5. Data Quality Assurance ..........................................................................106
10.1.6. Source Documents..................................................................................108
10.1.7. Study and Site Start and Closure ............................................................108
10.1.8. Publication Policy...................................................................................109
10.1.9. Sponsor’s Qualified Medical Personnel .................................................109
10.2. Appendix 2: Clinical Laboratory Tests ...............................................................111
10.3. Appendix 3: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting ....................................................................113
10.3.1. Definition of AE .....................................................................................113
10.3.2. Definition of SAE...................................................................................114
10.3.3. Recording/Reporting and Follow-up of AEs and/or SAEs.....................115
10.3.4. Reporting of SAEs..................................................................................118
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10.4. Appendix 4: Contraceptive Guidance .................................................................120
10.4.1. Male Participant Reproductive Inclusion Criteria..................................120
10.4.2. Female Participant Reproductive Inclusion Criteria...............................120
10.4.3. Woman of Childbearing Potential ..........................................................121
10.4.4. Contraception Methods...........................................................................121
10.6. Appendix 6: Liver Safety: Suggested Actions and Follow-up Assessments ......125
10.7. Appendix 7: ECG Findings of Potential Clinical Concern .................................127
10.9. Appendix 9: Abbreviations .................................................................................134
11. REFERENCES ................................................................................................................139
LIST OF TABLES
Table 1.
PART-1: Single Ascending Dose Cohorts ...............................................19
Table 2.
PART-2: Multiple Ascending Dose Cohorts (Including Optional 
Japanese Cohort).......................................................................................22
Table 3.
PART-2: PK Days (Day 1, Day 5, Day 10) in MAD Cohorts..................25
Table 4.
PART-3: Relative Bioavailability/Food Effect Cohort ............................27
Table 5.
PART-4: Metabolism and Excretion Cohort............................................29
Table 6.
Provisional Dosing Scheme in Part-1:SAD..............................................48
Table 7.
Randomization Sequence in Relative Bioavailability/Food Effect 
Cohort .......................................................................................................50
Table 8.
Provisional Dosing Scheme in Part-5:Supratherpeutic Exposure ............51
 
 
Table 11.
Probable 90% CI with 80% coverage probability for Varying SDs, 
Effect Sizes and Sample Sizes – in PART-3: Relative 
Bioavailability...........................................................................................95
Table 12.
Plasma PF‑07321332 PK Parameters For PART-1: Single 
Ascending Doses, PART-3: Relative Bioavailability/Food Effect, 
PART-4: Metabolism and Excretion and PART-5: Supratherapeutic 
Exposure ...................................................................................................97
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Table 13.
Plasma and Urine PF‑07321332 PK Parameters for PART-2: 
Multiple Ascending Doses........................................................................99
Table 14.
Safety QTcF Assessment........................................................................101
Table 15.
Protocol -Required Safety Laboratory Assessments ..............................111
LIST OF FIGURES
Figure 1.
C4671001 Study Design...........................................................................18


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Final Protocol Amendment 3, 24 June 2021
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1. PROTOCOL SUMMARY 
1.1. Synopsis 
Short Title: A Phase 1 Single Ascending Dose and Multiple Ascending Dose Study of 
PF-07321332 in Healthy Adult Participants
Rationale
The current study is the first clinical administration with PF-07321332. It is a 5-part study 
combining PART-1: SAD, PART-2: MAD, PART-3: relative bioavailability/food effect,
PART-4: metabolism and excretion (M&E) and PART-5: Supratherapeutic Exposure (SE). 
PART-1 and 2 are randomized, double-blind, sponsor-open, placebo-controlled trial to 
evaluate safety, tolerability and PK of single and multiple escalating oral doses of 
PF-07321332 in healthy adult participants and PART-3 is a randomized open label study to 
evaluate relative bioavailability and food effect of an oral tablet formulation. PART-2 of the 
study may also evaluate the safety tolerability and PK in Japanese participants. PART-4 is an 
open-label, non-randomized, single period to evaluate the metabolism and excretion of 
PF-07321332. PART-5 is a double-blind, sponsor-open, randomized, cross-over study to 
evaluate safety and tolerability at supratherapeutic exposures. 
Objectives and Endpoints
PART-1: SAD
Objectives
Endpoints
Primary: 
Primary: 

To assess the safety and tolerability 
following a single dose of 
PF-07321332 alone or in combination 
with a PK boosting agent (ritonavir).

Frequency, severity, and causal relationship of TEAEs and 
withdrawals due to TEAEs.

Frequency and magnitude of abnormal laboratory findings.

Changes from baseline in vital sign measurements and 
12-lead ECG parameters.
Secondary: 
Secondary: 

To assess the plasma PK profile of 
PF-07321332 following single 
ascending doses of PF-07321332 
alone or in combination with a PK 
boosting agent (ritonavir).

Plasma PK parameters of PF-07321332: 

Cmax, Tmax, AUClast, Cmax(dn), AUClast(dn).

If data permit, AUCinf, AUCinf(dn), t½, Vz/F, and 
CL/F.
Tertiary/Exploratory: 
Tertiary/Exploratory: 

To explore metabolites in plasma, 
urine, and feces, if data permit.

Qualitative characterization of metabolites of 
PF‑07321332 in pooled plasma, urine, and feces if data 
permit.

Quantitative excretion of drug-related 
material using 19F-NMR spectroscopy, 
if data permit.

Total excretion of drug-related material in urine and feces 
separately, and both routes combined, expressed as a 
percent of total dose administered, if data permit.


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
To determine the oral bioavailability 
of a tablet formulation of 
PF-07321332 relative to suspension, if 
evaluated (Optional).

The ratio of AUClast, AUCinf and Cmax of tablet formulation 
and suspension.

To evaluate the effect of food (high fat 
meal) on the exposure of 
PF-07321332 following a single oral 
dose of PF-07321332 tablet 
formulation, if evaluated (Optional).

The ratio of AUClast, AUCinf and Cmax under fed condition 
and fasted condition.
PART-2: MAD (including optional Japanese cohort)
Objectives
Endpoints
Primary: 
Primary: 

To assess the safety and tolerability 
following multiple ascending doses of 
PF-07321332 alone or in combination 
with a PK boosting agent (ritonavir).

Frequency, severity, and causal relationship of TEAEs 
and withdrawals due to TEAEs.

Frequency and magnitude of abnormal laboratory 
findings.

Changes from baseline in vital sign measurements and 
12-lead ECG parameters.
Secondary: 
Secondary: 

To assess the plasma PK profile of 
PF-07321332 on Days 1, 5 and 10 
following multiple ascending doses of 
PF-07321332 alone or in combination 
with a PK boosting agent (ritonavir).

Plasma PK parameters of PF-07321332: 

Cmax, Tmax, AUCtau (where tau=8 hours for TID 
dosing or 12 hours for BID dosing), Cmin, Cmax(dn), 
AUCtau(dn), Cav, Rac, Rac,Cmax, PTR,CL/F and Vz/F.

If data permit, t½.

To assess the urinary PK profile of 
PF-07321332 on Day 10 following 
multiple ascending doses of 
PF-07321332 alone or in combination 
with a PK boosting agent (ritonavir).

PF-07321332 urinary PK parameters: 

Aetau and Aetau%, CLr.
Tertiary/Exploratory: 
Tertiary/Exploratory: 

To explore metabolites in plasma if data 
permit.

Qualitative characterization of metabolites of 
PF‑07321332 in pooled plasma if data permit.

To explore PK by microsampling 
technique(s), if evaluated (Optional).

Concentration of PF-07321332, if evaluated.


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PART-3: Relative Bioavailability/Food Effect Cohort
Objectives
Endpoints
Primary: 
Primary: 
•
To determine the oral bioavailability of a 
tablet formulation of PF-07321332 relative 
to suspension.
•
The ratio of AUClast, AUCinf and Cmax of tablet 
formulation and suspension.
Secondary: 
Secondary: 
•
To evaluate the effect of food (high-fat 
high-calorie meal) on the exposure of 
PF-07321332 following a single oral dose 
of PF-07321332 tablet formulation.
•
The ratio of AUClast, AUCinf and Cmax of tablet 
formulation under fed condition and fasted condition.
•
To determine the pharmacokinetics of 
PF-07321332 following oral 
administration of tablet and suspension of 
PF-07321332.
•
Plasma PK parameters of PF-07321332: Tmax, Cmax,
AUClast, Cmax(dn), AUClast(dn), if data permit AUCinf, 
AUCinf(dn), t½, CL/F, Vz/F.
•
To determine the safety and tolerability of 
PF-07321332 following oral 
administration of tablet and suspension of 
PF-07321332.
•
Frequency, severity, and causal relationship of TEAEs 
and withdrawals due to TEAEs.
•
Frequency and magnitude of abnormal laboratory 
findings.
•
Changes from baseline in vital sign measurements and 
12-lead ECG parameters.
 
 
 
 
 
PART-4: Metabolism and Excretion 
Objectives
Endpoints
Primary: 
Primary: 
•
To determine the extent of excretion of 
drug related material in urine and feces 
after a single oral administration of 
PF-07321332 with PK boosting agent 
ritonavir.
•
Total recovery of drug related material in urine and 
feces separately, and both routes combined, expressed 
as a percent of total oral dose administered.
Secondary: 
Secondary: 
•
To determine the pharmacokinetics of 
PF-07321332 following oral 
administration of PF-07321332 with PK 
boosting agent ritonavir.
•
Plasma PK parameters of PF-07321332: Tmax, Cmax, 
AUClast, if data permit AUCinf, t½, CL/F, Vz/F. 
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
To determine the safety and tolerability of 
PF-07321332 after a single oral 
administration of PF-07321332 with PK 
boosting agent ritonavir.

Frequency, severity, and causal relationship of TEAEs 
and withdrawals due to TEAEs.

Frequency and magnitude of abnormal laboratory 
findings.

Changes from baseline in vital sign measurements and 
12-lead ECG parameters.
Tertiary/Exploratory: 
Tertiary/Exploratory: 

To characterize the metabolic profile and 
identify circulating and excreted 
metabolites following administration of a 
single oral dose of PF-07321332 with PK 
boosting agent ritonavir, if possible.

Metabolic profiling/identification and determination 
of relative abundance of PF-07321332 and the 
metabolites of PF-07321332 in plasma, urine, and 
feces, if possible.
PART-5: Supratherapeutic Exposure (NH CRU only)
Objectives
Endpoints
Primary: 
Primary: 

To assess the safety and tolerability of a 
supratherapeutic exposure of PF-07321332 
with a PK boosting agent (ritonavir)
administered as split dosing.

Frequency, severity, and causal relationship of TEAEs 
and withdrawals due to TEAEs.

Frequency and magnitude of abnormal laboratory 
findings.

Changes from baseline in vital sign measurements and 
12-lead ECG parameters.
Secondary: 
Secondary: 

To assess the plasma PK of PF-07321332 
at a supratherapeutic exposure of 
PF-07321332 with a PK boosting agent 
(ritonavir) administered as split dosing.

Plasma PK parameters of PF-07321332: 

Cmax, Tmax, AUClast

If data permit, AUCinf, t½.
Overall Design
The study will combine PART-1: single ascending dose (SAD), PART-2: multiple ascending 
dose (MAD, including optional Japanese cohort), PART-3: relative bioavailability and food 
effect cohort, PART-4: metabolism and excretion study and PART-5: supratherapeutic 
exposure cohort. PART-1 and 2 are randomized, double-blind (participant and investigator 
blinded), sponsor open, placebo controlled, single and multiple dose escalation study.
PART-3 is a randomized open label study to evaluate relative bioavailability and food effect.
PART-4 is an open-label, non-randomized, single period to evaluate the metabolism and 
excretion of PF-07321332. PART-5 is a double-blind, sponsor-open, randomized, cross-over 
study to evaluate safety and tolerability at supratherapeutic exposures to be conducted at NH 
CRU only.  


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PART-1: SAD
SAD will include 2 interleaving cohorts with a total of approximately 12 participants planned 
(approximately 6 participants in each cohort), with 4-period cross-over in each cohort. 
Period 3 and 4 are optional periods which may be used to further explore PK at additional 
doses or PK in combination with ritonavir or relative bioavailability of a new formulation or 
food effect (high-fat high-calorie meal), etc, based on emerging safety, tolerability and PK 
assessments.
There will be a washout interval of ≥5 days between dosing to a given participant. 
Participants will be required to stay at the CRU for the duration of the washout interval. 
However, they may be released at the discretion of the investigator. The washout interval 
may be adjusted based on data emerging from previous cohorts/periods.
PART-2:MAD
The first MAD cohort may start after a same total daily dose, which provides comparable or 
higher total daily exposure (24 h) in SAD than the projected total daily steady-state exposure
(over 24 h) at the starting dose in MAD, is found safe and well tolerated in PART-1 of the 
study. The proposed MAD study design will be parallel cohorts, with 10 days of dosing.
PART-2 will consist of approximately 2 to 5 cohorts including up to 3 optional cohorts 
(Cohort 5, 6 and 7) with approximately 6 participants in each cohort. Cohort 7 is an optional 
Japanese participants cohort.
PART-3: RBA and Food effect
If conducted, this cohort will be an open label, randomized, 3-period, 3-sequence cross-over 
single dose cohort evaluating the relative bioavailability of PF-07321332 tablet compared to 
PF-07321332 oral suspension and to evaluate the effect of food on the bioavailability of the 
PF-07321332 tablet in healthy adult participants. A maximum of 18 participants may be 
enrolled in PART-3 of the study with approximately equal number of participants 
randomized to each sequence. There will be a washout interval of at least 2 days between 
dosing in each period. Participants will be required to stay at the CRU until discharge in the 
last period. The washout interval may be adjusted based on data emerging from SAD and 
MAD cohorts.
PART-4: Metabolism and Excretion
This part will include a single cohort of approximately 6 male participants with at least 
4 completers. All participant will receive 4 doses of 100 mg ritonavir as specified in the SoA. 
Each participant will receive a single dose of 300 mg of PF-07321332 on Day 1 0h along
with 100 mg of ritonavir after at least 10h of fasting. The participants will be discharged on 
Day 11. 


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In PART-1 and 2, treatment sequences, actual doses, dose increments and dosing regimen 
may be adjusted, and intermediate or alternative dose levels may be substituted during the 
study based on emerging safety, tolerability, and PK data.
PART-5: Supratherapeutic Exposure (NH CRU only)
This cohort will include up to 12 participants in a 4-period (Periods 3 and 4 are optional), 
double-blind, sponsor-open, randomized, 2-sequence, cross-over design to explore safety, 
tolerability and PK at supratherpeutic exposure. For each period, participants will receive 
split dosing administration (3 doses) of PF-07321332 or placebo at short intervals 
(approximately 2 h of the previous dose) after at least 2 hours after the breakfast on Day 1. 
Baseline ECGs, vitals 
 will be collected before breakfast. The first 2 periods 
will be a cross-over where participants will be given PF-07321332 at 0, 2 and 4 hours at the 
dose of 750 mg (or placebo) with ritonavir. Periods 3 and 4 (if conducted) will only be 
conducted if supratherapeutic concentrations are not reached in Period 1. In periods 3 and 4 
(if conducted) doses may be given up to 4 times for a total daily dose not exceeding 3000 
mg, with or without food.
Number of Participants
A total of up to 78 participants (12 in PART-1: SAD, up to 30 [with 2 cohorts and 3 optional 
cohorts] in PART-2: MAD, a maximum of 18 in PART-3: Relative Bioavailability/Food 
Effect cohort,6 participants in PART-4: Metabolism and Excretion cohort and up to 
12 participants in PART-5: Supratherapeutic Exposure) are planned to be randomized in this 
study. At the discretion of the sponsor and investigator, participant who were enrolled in 
PART-2 may be enrolled in PART-5. 
Intervention Groups and Duration
In all 5 parts, participants will be screened within 28 days of their first dose of investigational 
product. Participants will be admitted to the CRU on Day -1 or earlier and may be discharged 
at investigator discretion following completion of assessments per SoA. 
PART-1: SAD
For each period, approximately 4 participants will receive a single oral dose of PF-07321332, 
and approximately 2 participants will receive placebo after at least 10h of fast. Each 
participant may receive either a single dose of PF-07321332 or a placebo during each period. 
In each period, participants on active treatment in Cohort 1 will receive D1, D3, D5 and D7
(optional) dose levels (Section 4.3, Table 9) and Cohort 2 will receive D2, D4, D6 and D8
(optional) dose levels (Section 4.3) in dose escalation format. In SAD cohorts requiring 
co-administration of PF-07321332/placebo with ritonavir, all participants (active and 
placebo) will receive 3 doses of 100 mg of ritonavir at -12h, 0h (coadministered with 
PF-07321332) and 12h.
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Protocol C4671001
Final Protocol Amendment 3, 24 June 2021
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Page 16
PART-2: MAD 
In each cohort, approximately 4 participants will receive one of the escalating doses of
PF-07321332 and approximately 2 participants will receive matching placebo after at least 
7h of fast for the morning dose and 2h of fast for the next dose(s). From Day 1 – Day 9, 
PF-07321332/placebo will be administered every 8h (ie, TID) when administered alone and 
every 12h (ie, BID) when co-administered with ritonavir; however, PF-07321332/placebo
alone may also be administered every 12h (ie, BID), if needed, based on emerging PK data. 
On Day 10, PF-07321332/placebo will be administered at approximately 0h for TID or BID 
regimen. In MAD cohorts requiring co-administration of PF-07321332/placebo with 
ritonavir, all participants (active and placebo) will receive 100 mg of ritonavir as specified in 
the SoA.
PART-3: RBA and Food effect
The dose level to be evaluated in relative bioavailability/food effect cohort will be 
determined based on emerging PK and safety data from SAD and MAD cohorts. The 
selected dose will be equal or lower than the highest tolerated dose already evaluated in 
SAD. There will be a washout interval of at least 2 days between dosing in each period.
Participants will be required to stay at the CRU until the discharge in last period. The 
washout interval may be adjusted based on data emerging from SAD and MAD cohorts. 
PART-4: Metabolism and Excretion
This part will include a single cohort of approximately 6 male participants with at least 
4 completers. All participants will receive 4 doses of 100 mg ritonavir as specified in the 
SoA. Each participant will receive a single dose of 300 mg of PF-07321332 on Day 1 0h 
along with 100 mg of ritonavir after at least 10h of fasting. The plasma for PK and metabolic 
profiling will be collected as specified in SoA. The urine and feces will be collected for 
10 days as specified in SoA to determine excretion routes and metabolite profiling. Dietary 
fiber supplementation and use of laxative (Section 5.3.1.1) should be considered with the 
goal to facilitate at least once daily bowel movement. The participants will be discharged on 
Day 11. 
PART-5: Supratherapeutic Exposure
In this part, for each period, participants will receive split dosing (3 doses) of PF-07321332
or placebo at short intervals (within 2 h of the previous dose). Participants will receive first 
split dose of PF-07321332/placebo oral suspension at approximately 08:00 hours (±2 hours)
at least 2h after the morning breakfast per the So. The second and third split doses will be 
administered at approximately 2h and 4h after the first dose, respectively. 
A total of 3 doses of 100 mg ritonavir tablet will be administered as a PK boosting agent as 
per SoA (approximately 12 hours before the first split dose, concurrently with the first split
dose and approximately 12 hours after the first split dose).  


PF-07321332
Protocol C4671001
Final Protocol Amendment 3, 24 June 2021
PFIZER CONFIDENTIAL
Page 17
For all Parts, a telephone follow-up contact will occur between 28 to 35 days from the day of 
last administration of study intervention. At the discretion of the investigator, telephone 
follow-up contact may be substituted with an on-site visit in case of additional follow-up of 
open AEs or clinically significant laboratory findings. 
The total planned duration of participation, from Screening visit to the Follow-up phone call, 
may be approximately 12 weeks for PART-1 and PART-5, 10 weeks for PART-2 and 
PART-3 and 8 weeks for PART-4.
Data Monitoring Committee or Other Independent Oversight Committee: No
Statistical Methods
The sample size for PART-1 and PART-2 of the study has been chosen based on the need to 
minimize exposure of healthy participants to a new chemical entity and the requirements to 
provide adequate safety and toleration and PK information at each dose level.
For PART-3, the sample size will provide adequate precision to compare the relative 
bioavailability of a tablet formulation of PF-07321332 relative to oral suspension.
For Part 4: A sample size of approximately 6 male participants (with at least 4 completers) is 
chosen based on the industry standard sample size for metabolism and excretion studies. This 
sample size was not justified by any empirical data or hypothesis testing criteria.
For Part 5: A sample size of up to 12 participants (with at least 10 completers) is chosen 
based on the need to provide adequate safety, tolerability and PK information at each dose 
level and/or administration schedule.
The data from the 5 parts of this study will be analyzed and reported separately in a single 
CSR.
All safety analyses will be performed on the safety analysis set, which is defined as all 
participants randomly assigned to study intervention and who receive at least one dose of 
study intervention. Participants will be analyzed according to the product they actually 
received. Safety data will be presented in tabular and/or graphical format and summarized 
descriptively, where appropriate. Plasma concentrations will be listed and summarized 
descriptively by PK sampling time and treatment. The plasma PK parameters will be 
summarized descriptively by dose. No formal inferential statistics will be applied to the PK 
data apart from the comparisons of formulation and food effect in either PART-1 or PART-3, 
if conducted.


PF-07321332
Protocol C4671001
Final Protocol Amendment 3, 24 June 2021
PFIZER CONFIDENTIAL
Page 18
1.2. Schema
Figure 1.
C4671001 Study Design
*Optional dose levels in SAD/MAD may be used to explore higher doses or food effect or relative 
bioavailability or in combination with ritonavir (see more details in Section 4.1). Dosing with food may be done 
in one or more cohorts in SAD/MAD based on the emerging PK/safety data. PART-4: Metabolism and 
Excretion (M&E) is an open-label single dose cohort (see more details in Section 4.1). PART-5:
supratherapeutic exposure (SE) is a double-blind, sponsor-open, randomized, cross-over cohort (See more 
details in Section 4.1).
SAD dose levels D1 to D8 and MAD dosing regimens DR1 to DR4 are listed in Table 9 and Table 10, 
respectively in Section 4.3.


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Protocol C4671001
Final Protocol Amendment 3, 24 June 2021
PFIZER CONFIDENTIAL
Page 19
1.3. Schedule of Activities
The SoA table provides an overview of the protocol visits and procedures. Refer to the STUDY ASSESSMENTS AND 
PROCEDURES section of the protocol for detailed information on each procedure and assessment required for compliance with the 
protocol. 
The investigator may schedule visits (unplanned visits) in addition to those listed in the SoA table, in order to conduct evaluations or 
assessments required to protect the well-being of the participant.
Table 1.
PART-1: Single Ascending Dose Cohorts
Visit Identifiera
Screening
Periods 1-4b
F/U
Contactc,j
E/T
Days Relative to Day 1
Days
-28 to -2
Day 
-1
Day 1
Day 
2
Day 
3
Day 
4
Day 
5
Day 6
Day 
29-36
Planned Hours Post Dose
0
0.25 0.5
1 1.5 2
4
6
8
12
16 24h 48h 72h 96h
120h
Informed consent
X
Inclusion/exclusion criteria
X
Xd
Demographics (including height & weight)
X
Medical/Medicine history 
X
Xd
SARS-CoV-2 RT-PCRe
X
Xd
Xd
COVID-19 Assessmentr
X
X
X
X
X
X
Xh
CRU Confinementf
X






X
Xh
Physical examg
X
X
X
Vital signs (temperature, respiratory rate, 
pulse rate, blood pressure)
X
X
X
X
X
X
X
X
X
X
X
12-Lead ECG (triplicate)
X
X
X
X
X
X
X
X
X
X
X
Continuous cardiac telemetry monitoringi
X

X
Contraception check
X
Xd
Xj
X
X
Serious and nonserious AE monitoring 
X









X
X
Study intervention administration
PF-07321332 or Placeboq
X
Ritonavir (if used)
Xk
X
X


PF-07321332
Protocol C4671001
Final Protocol Amendment 3, 24 June 2021
PFIZER CONFIDENTIAL
Page 20
Table 1.
PART-1: Single Ascending Dose Cohorts
Visit Identifiera
Screening
Periods 1-4b
F/U
Contactc,j
E/T
Days Relative to Day 1
Days
-28 to -2
Day 
-1
Day 1
Day 
2
Day 
3
Day 
4
Day 
5
Day 6
Day 
29-36
Planned Hours Post Dose
0
0.25 0.5
1 1.5 2
4
6
8
12
16 24h 48h 72h 96h
120h
Blood Samples for:
Pregnancy test (WOCBP only)
X
Xd
Xj
X
Safety laboratory (4h fasting except 6h
sample)
X
X
X
X
X
X
X
HIV, HBsAg, HBsAb,l HBcAb and 
HCVAb 
X
Serum FSH (post-menopausal females 
only) 
X
Plasma Pharmacokinetics (PF-07321332) 
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
19F-NMR measurements and metabolite 
profilingp
X
X
X
X
X
Urine Samples for:
Drug screen testing
X
Xd
Urinalysis
X
X
X
X
X
X
X
19F-NMR Measurement and metabolic 
profilingn,p
X
X
→
→→→→→→→→
→
X
X
X
X
X
Feces Collection for:
19F-NMR Measurement and metabolic 
profilingo,p
X
X
→
→→→→→→→→
→
X
X
X
X
X
a.
Visit Identifier: Day relative to start of study treatment (Day 1).
b.
Period 1 to Period 4: Washout duration of at least 5 days between dosing. May be adjusted based on emerging data. Period 3 and 4 are optional.
c.
F/U Contact: Follow-up phone call may occur via telephone 28-35 days after the last dose of investigational product in the final period.
d.
Period 1 only. If participants are discharged and readmitted, follow all Period 1 activities except I/E criteria, medical history update 
 
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Protocol C4671001
Final Protocol Amendment 3, 24 June 2021
PFIZER CONFIDENTIAL
Page 21
e.
SARS-CoV-2 RT-PCR: Screening, admission (Day -1), 4 days following admission (Day 4), ad hoc test based on symptoms, and for ambulatory on-site 
visits.
f.
CRU Confinement: Participants will be required to stay at CRU from Day -1 in Period 1 until completing Day 4 (72h) activities in the final period.
g.
Physical Examination: Complete physical examination will be conducted at Screening or upon admission (Day -1) in Period 1. Brief physical examination 
may be performed at other times, as appropriate, for findings during previous examination or new/open AEs, at investigator’s discretion.
h.
COVID-19 assessment and PCRU confinement: Not done in the last period.
i.
Continuous cardiac telemetry monitoring: Baseline telemetry to be recorded for at least 2 hours between admission and prior to dosing in Period 1 only 
while awake. Post dose telemetry will continue for 8 hours after the start of dosing for each period.
j.
Last Period only, unless discharged at the discretion of the investigator.
k.
Ritonavir: To be administered approximately 12 hours before PF-07321332 administration on Day 1.
l.
HBsAb: Can be done either automatically or only if HBcAb or HBsAg is positive, as per local practices.
 
n.
Urine Sample Collection: “Blank” pre-dose urine sample to be collected within 24h prior to dosing and at each subsequent 24h interval until dosing in next 
period or up to 120 h, whichever is earlier. Forced void into the collection container at the end of each collection period.
o.
Feces Sample Collection: “Blank” fecal sample to be collected at baseline from at least one bowel movement during the 48h predose interval. Fecal 
samples will also be collected at intervals of 0-24 h post oral dose, and at each subsequent 24h interval until dosing in next period or up to 120 h, whichever 
is earlier.
p.
Metabolite profiling and quantitative F-NMR: conducted for Cohort 1, Period 2 only.
q.
Study Drug Administration: The study drug should be administered after approximately at least 10h of fast in the morning dose (0h). For dosing in fed 
condition, please refer Section 5.3.1.
r.
COVID-19 Assessment: Temperature check as per local requirement. Questionnaire before admission.
C
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Protocol C4671001
Final Protocol Amendment 3, 24 June 2021
PFIZER CONFIDENTIAL
Page 22
Table 2.
PART-2: Multiple Ascending Dose Cohorts (Including Optional Japanese Cohort)
Visit Identifiera
Screening
F/U
Contactb
ET
Days Relative to Day 1
Days
-28 to -2
Day 
-1
Day 
1k
Day 2 Day 3 Day 4 Day 
5k
Day 6 Day 7 Day 8 Day 9 Day 
10k
Day 11 Day 
12
Day 38-45
Informed consent
X
Inclusion/exclusion criteria
X
X
Demographics (including height & weight)
X
Medical/Medicine history
X
X
SARS-CoV-2 RT-PCRc
X
X
X
COVID-19 Assessmentm
X
X
X
X
X
X
X
X
X
X
X
X
X
X
CRU Confinementd
X
→
→
→
→
→
→
→
→
→
→
→
X
Physical exame
X
X
X
Supine Vital signs (temperature, respiratory 
rate, pulse rate, blood pressure)f
X
X
X
X
X
X
X
X
12-Lead ECG (triplicate)f
X
X
X
X
X
X
X
X
Contraception check
X
X
X
X
X
Serious and nonserious AE monitoring
X
→
→
→
→
→
→
→
→
→
→
→
→
X
X
X
Study intervention administration
PF-07321332 or Placebo (BID or TID)g
X
X
X
X
X
X
X
X
X
X
Ritonavir BID (if used)l
X
X
X
X
X
X
X
X
X
X
Blood samples for:
Pregnancy test (WOCBP only)
X
X
X
X
Safety laboratory (4h fasting)o
X
X
X
X
X
X
X
X
X
TSH and Free T4
Xq
Xq
X
HIV, HBsAg, HBsAbn, HBcAb and HCVAb 
X
Serum FSH (post-menopausal females only)
X
Plasma Pharmacokinetics (PF-07321332)
X
Xj
Xj
X
Xj
Xj
X
Xj
Xj
X
Metabolite profiling
X
X
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PF-07321332
Protocol C4671001
Final Protocol Amendment 3, 24 June 2021
PFIZER CONFIDENTIAL
Page 23
Table 2.
PART-2: Multiple Ascending Dose Cohorts (Including Optional Japanese Cohort)
Visit Identifiera
Screening
F/U
Contactb
ET
Days Relative to Day 1
Days
-28 to -2
Day 
-1
Day 
1k
Day 2 Day 3 Day 4 Day 
5k
Day 6 Day 7 Day 8 Day 9 Day 
10k
Day 11 Day 
12
Day 38-45
Optional Microsampling Pharmacokinetics 
(PF-07321332)p
Xj
Xj
Urine samples for:
Drug screen testing
X
X
Urinalysiso
X
X
X
X
X
X
X
X
X
Pharmacokinetics
X
X
a.
Visit Identifier: Day relative to start of study treatment (Day 1).
b.
F/U Contact: Follow-up contact may occur via telephone and must occur 28 to 35 days after the last dose of investigational product.
c.
SARS-CoV-2 RT-PCR: Screening, admission (Day -1), 4 days following admission (Day 4), ad hoc test based on symptoms, and for ambulatory on-site 
visits.
d.
CRU Confinement: Participants will be required to stay at CRU from Day-1 until completing Day 12 activities.
e.
Physical Examination: Complete physical examination will be conducted at Screening or upon admission (Day -1). Brief physical examination may be 
performed at other times, as appropriate, for findings during previous examination or new/open AEs, at investigator’s discretion.
f.
Vital signs and 12-lead ECG: Except on D1, D5 and D10, all vital signs and ECGs are to be collected pre-dose. on D12, collected 48h after last dose of 
PF-07321332/placebo.
g.
Study drug administration: From Day 1 – Day 9 at approximately 0, 8 and 16 h for TID regimen (ie, every 8 h) of PF-07321332/placebo alone and at 
0 and 12h for BID regimen (ie, every 12h). On Day 10, at approximately 0h for TID or BID regimen of PF-07321332/placebo. The study drug should be 
administered after approximately at least 7h of fast in the morning dose (0h) and at least 2 hours of fast for afternoon and/or evening doses. For dosing in fed 
condition, please refer Section 5.3.1.
 
 
j.
Plasma PK sample and optional microsampling PK sample collections: To be collected prior to morning dosing, except D11 and 12 which is at 24h and 
48 h after last dose of PF-07321332/placebo, respectively.
k.
Day 1; 5 and 10: Refer to Table 3.
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PF-07321332
Protocol C4671001
Final Protocol Amendment 3, 24 June 2021
PFIZER CONFIDENTIAL
Page 24
l.
Ritonavir dosing: To be used with BID dosing of PF-07321332/placebo only. On Day 10 12h Ritonavir will be administered without PF-07321332/placebo.
m. COVID-19 Assessment: Temperature check as per local requirement. Questionnaire before admission.
n.
HBsAb: Can be done either automatically or only if HBcAb or HBsAg is positive, as per local practices.
o.
Safety labs and urinalysis: should be taken pre-dose only, except on Day 5 (refer to Table 3).
p.
Optional Microsampling exploratory PK sample: To be collected only at NH CRU.
q.
TSH and Free T4: Must be collected at least once before dosing. PI may choose to either collect at screening or Day -1 or both.  


PF-07321332
Protocol C4671001
Final Protocol Amendment 3, 24 June 2021
PFIZER CONFIDENTIAL
Page 25
Table 3.
PART-2: PK Days (Day 1, Day 5, Day 10) in MAD Cohorts
Visit Identifiera
Treatment Period on PK Days
Days Relative to Day 1
Day 1
Day 5
Day 10
Planned Hours Post 1st Dose on that day 
0b 0.5 1 1.5 2
4
6
8 12 16 0b 0.5 1 1.5 2
4
6
8 12 16 0b 0.5 1 1.5 2 4
6 8 12 16
COVID-19 assessmentc
X
X
X
X
X
X
Supine Vital signs (temperature, pulse rate, 
respiratory rate, blood pressure)
X
X
X
X
X
X
X
12-Lead ECG (Triplicate)
X
X
X
X
X
X
X
Study intervention administration
PF-07321332 or Placebo (TID dosing)d
X
X
X
X
X
X
X
PF-07321332 or Placebo (BID dosing)d
X
X
X
X
X
Ritonavir BID (if used)h
X
X
X
X
X
X
Blood samples for:
Safety laboratory (4h fasting except 6h sample on 
Day 5)
X
X
X
TSH and Free T4
X
Plasma Pharmacokinetics (PF-07321332) if TID 
dosing 
X
X
X
X
X X
X X
X
X
X
X
X
X
X X
X
X
X
X X X X X X X
Plasma Pharmacokinetics (PF-07321332) if BID 
dosing
X
X
X
X
X X
X X X
X
X
X
X
X
X
X X X
X
X
X
X X X X X X X
Metabolite Profiling
X
X
X
X
X X
Urine samples for:
Urinalysis
X
X
X
Pharmacokinetics and metabolic profiling (TID 
dosing)
Xe
X
→→→→→→X
Pharmacokinetics and metabolic profiling (BID 
dosing)
Xe
X
→→→→→→→X
a.
Visit Identifier: Day relative to start of study treatment (Day 1).
b.
Day 1-0H, Day 5-0H and Day 10-0H: Predose sample collection/procedure, except for study intervention administration.
c.
COVID-19 assessment: Temperature check as per local requirement. Questionnaire before admission.
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Final Protocol Amendment 3, 24 June 2021
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d.
PF-07321332 or placebo administration: Morning dose (0h) to be administered after at least 7h of fast. Afternoon dose (8h) and/or evening doses (12h or 
16h) require at least 2h fast before dosing. For dosing in the fed condition, please refer Section 5.3.1.
e.
Urine sample for PK and metabolic profiling: A single aliquot of blank urine to be collected before dosing.
 
 
h.
Ritonavir dosing: To be used with BID dosing of PF-07321332/placebo only. On Day 10, 12h Ritonavir will be administered without 
PF-07321332/placebo.
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Protocol C4671001
Final Protocol Amendment 3, 24 June 2021
PFIZER CONFIDENTIAL
Page 27
Table 4.
PART-3: Relative Bioavailability/Food Effect Cohort
Visit Identifiera
Screening
Periods 1-3b
F/U
Contactc
E/T
Days Relative to Day 1
Days
-28 to -2
Day -1d
Day 1
Day 2 Day 3i
Day 
29-36
Planned Hours Post Dose
0
0.5
1
1.5
2
4
8
12
16
24h
48h
Informed consent
X
Inclusion/exclusion criteria
X
X
Demographics (including height & weight)
X
Medical/Medicine history
X
X
SARS-CoV-2 RT-PCRe
X
X
COVID-19 Assessmentn
X
X
X
X
X
X
CRU Confinementf
X
→
→
→→→→
→
→
→
→
X
Physical examg
X
X
X
Supine Vital signsh (temperature, respiratory rate, 
pulse rate, blood pressure)
X
X
X
X
12-Lead ECG (single)h
X
X
X
X
Contraception check
X
X
X
X
X
Serious and nonserious AE monitoring 
X
→
→
→
→→→→
→
→
→
→
X
X
X
Study intervention administration
PF-07321332m
X
Blood Samples for:
Pregnancy test (WOCBP only)
X
X
X
X
Safety laboratory (4h fasting)
X
X
X
X
HIV, HBsAg, HBsAb,j HBcAb and HCVAb 
X
Serum FSH (post-menopausal females only) 
X
Plasma Pharmacokinetics (PF-07321332)
X
X
X
X X
X
X
X
X
X
X
X
Urine samples for:
Urine drug screen testing
X
X
Urinalysis
X
X
X
X
Other Assessments
CCI
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Final Protocol Amendment 3, 24 June 2021
PFIZER CONFIDENTIAL
Page 28
a.
Visit Identifier: Day relative to start of study treatment (Day 1).
b.
Period 1 to Period 3: Washout duration of at least 2 days between dosing. May be adjusted based on emerging data.
c.
F/U Contact: Follow-up phone call may occur via telephone approximately 28 to 35 days after the last dose of investigational product in the final period.
e.
SARS-CoV-2 RT-PCR: Screening, admission (Day -1), 4 days following admission in Period 1, ad hoc test based on symptoms, and for ambulatory on-site 
visits.
f.
CRU Confinement: Participants will be required to stay at CRU from Day-1 until completing Day 3 (48h) activities in the final period.
g.
Physical Examination: Complete physical examination will be conducted at Screening or upon admission (Day -1) in Period 1. Brief physical examination 
may be performed at other times, as appropriate, for findings during previous examination or new/open AEs, at investigator’s discretion.
h.
12-lead ECG and Vitals: Single ECG. Based on emerging safety data, additional ECGs (including triplicate ECG) and/or vital measurements may be 
added.
i.
Last Period only.
j.
HBsAb: Can be done either automatically or only if HBcAb or HBsAg is positive, as per local practices.
 
m. Study Drug Administration: The study drug should be administered after approximately at least 10h of fast. For dosing in fed condition, please refer 
Section 5.3.1. 
n.
COVID-19 Assessment: Temperature check as per local requirement. Questionnaire before admission.
C
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C
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PF-07321332
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Table 5.
PART-4: Metabolism and Excretion Cohort
Visit Identifiera
Screening
F/U
Contactb
E/T
Days Relative to Day 1
Days
-28 to -2
Day 
-1
Day 1
Day 
2
Day 
3
Day 
4
Day 5-
10
Day 11
Day 
29-36
Planned Hours Post Dose
0
0.25 0.5
1 1.5 2
4
6
8
12
16 24h 48h 72h 96h-
216h
240h
Informed consent
X
Inclusion/exclusion criteria
X
X
Demographics (including height & weight)
X
Medical/Medicine history 
X
X
SARS-CoV-2 RT-PCRc
X
X
X
COVID-19 Assessmentk
X
X
X
X
X
X
X
X
CRU Confinement
Xl
→
→
→→→→→→→→
→
→
→
X
X
X
Physical examd
X
X
X
Vital signs (pulse rate, blood pressure)
X
X
X
X
12-Lead ECG (Single)
X
X
X
X
Contraception check
X
X
X
X
X
Serious and nonserious AE monitoring 
X
→
→
→
→→→→→→→→
→
→
→
→
→
→
X
X
Study intervention administration
PF-07321332j
X
Ritonavir 
Xe
X
X
X
Blood Samples for:
Safety laboratory (4h fasting)
X
X
X
X
TSH and Free T4
Xm
Xm
X
HIV, HBsAg, HBsAb,f HBcAb and 
HCVAb 
X
Plasma Pharmacokinetics (PF-07321332) 
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Drug-related material measurement and 
metabolite profiling
X
X
X
X
X
X
X
Urine Samples for:
Drug screen testing
X
X
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Table 5.
PART-4: Metabolism and Excretion Cohort
Visit Identifiera
Screening
F/U
Contactb
E/T
Days Relative to Day 1
Days
-28 to -2
Day 
-1
Day 1
Day 
2
Day 
3
Day 
4
Day 5-
10
Day 11
Day 
29-36
Planned Hours Post Dose
0
0.25 0.5
1 1.5 2
4
6
8
12
16 24h 48h 72h 96h-
216h
240h
Urinalysis
X
X
X
X
Drug related material measurement and 
metabolic profilingh
X
X
→
→→→→→→→→
→
X
X
X
X
X
Feces Collection for:
Drug related material measurement and 
metabolic profilingi
X
X
→
→→→→→→→→
→
X
X
X
X
X
a.
Visit Identifier: Day relative to start of study treatment (Day 1).
b.
F/U Contact: Follow-up phone call may occur via telephone 28-35 days after the last dose of investigational product.
c.
SARS-CoV-2 RT-PCR: Screening, admission, 4 days following admission, ad hoc test based on symptoms.
d.
Physical Examination: Complete physical examination will be conducted at Screening or upon admission (Day -1). Brief physical examination may be 
performed at other times, as appropriate, for findings during previous examination or new/open AEs, at investigator’s discretion.
e.
Ritonavir: To be administered approximately 12 hours before PF-07321332 administration on Day 1.
f.
HBsAb: Can be done either automatically or only if HBcAb or HBsAg is positive, as per local practices.
 
h.
Urine Sample Collection: A “Blank” pre-dose urine sample to be collected within 24h prior to dosing. Post-dose urine samples need to be collected at 
intervals of 0-24h post oral dose, and at each subsequent 24h intervals until discharge. Forced void into the collection container at the end of each collection 
period.
i.
Feces Sample Collection: A “Blank” fecal sample to be collected at baseline from at least 1 bowel movement during the 48h predose interval. Post-dose 
fecal samples will also be collected at intervals of 0-24h post oral dose, and at each subsequent 24h interval until discharge.
j.
Study Drug Administration: The study drug should be administered after approximately at least 10h of fast in the morning dose (0h). 
k.
COVID-19 Assessment: Temperature check as per local requirement. Questionnaire before admission.
l.
CRU Confinement: May be admitted earlier to facilitate pre-dose fecal collection. At the discretion of the investigator, one or more Day -1 assessments 
may be conducted at admission if admitted earlier.
m. TSH and Free T4: Must be collected at least once before dosing. PI may choose to either collect at screening or Day -1 or both.
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Table 6. PART-5: Supratherapeutic Exposure (NH CRU only)
Visit Identifiera
Screening
Periods 1-4b
F/U
Contactc,i E/T
Days Relative to Day 1
Days
-28 to -2
Day 
-1
Day 1
Day 2 Day 3 Day 4 Day 5
Day 
29-36
Planned Hours Post Dose
0
1
2
3 3.5 4 4.5 5 5.5
6
8
12
24h
48h
72h
96h
Informed consent
X
Inclusion/exclusion criteria
X
Xd
Demographics (including height & 
weight)
X
Medical/Medicine history 
X
Xd
SARS-CoV-2 RT-PCRe
X
Xd
Xd
COVID-19 Assessmentn
X
X
X
X
X
X
X
CRU Confinementf
X






X
X
Physical examg
X
Xd
X
Vital signs (temperature, respiratory 
rate, pulse rate, blood pressure)
X
X
X X
X
X
X
X
X
X
X
X
X
X
12-Lead ECG (triplicate)r
X
X
X X
X
X
X
X
X
X
X
X
X
X
X
X
X
Continuous cardiac telemetry 
monitoringh
X 


X
Contraception check
X
Xd
Xi
X
X
Serious and nonserious AE 
monitoring 
X









X
X
Standardized mealq

X
X
X
X
X
X
X
Study intervention administration
PF-07321332 or Placebom
X
X
X
Ritonavir
Xj
X
X
Blood Samples for:
Pregnancy test (WOCBP only)
X
Xd
Xi
X
Safety laboratory (fasted for 4 h)
X
X
X
Xi
X
HIV, HBsAg, HBsAb,k HBcAb and 
HCVAb 
X


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Table 6. PART-5: Supratherapeutic Exposure (NH CRU only)
Visit Identifiera
Screening
Periods 1-4b
F/U
Contactc,i E/T
Days Relative to Day 1
Days
-28 to -2
Day 
-1
Day 1
Day 2 Day 3 Day 4 Day 5
Day 
29-36
Planned Hours Post Dose
0
1
2
3 3.5 4 4.5 5 5.5
6
8
12
24h
48h
72h
96h
Serum FSH (post-menopausal 
females only) 
X
Plasma Pharmacokinetics 
(PF-07321332) 
Xp X X X
X
X
X
X
X
X
X
X
X
X
X
X
X
TSH and free T4
Xo
Xo
Xi
Urine Samples for:
Drug screen testing
X
Xd
Urinalysis
X
Xd
X
Xi
X
a.
Visit Identifier: Day relative to start of study treatment (Day 1).
b.
Period 1 to Period 4: Washout duration of at least 5 days between 1st dosing in each period. Periods 3 and 4 are optional.
c.
F/U Contact: Follow-up phone call may occur via telephone 28 to 35 days after the last dose of investigational product in the final period.
d.
Period 1 only. If participants are discharged and readmitted, follow all Period 1 activities except I/E criteria, medical history update 
 
e.
SARS-CoV-2 RT-PCR: Screening, admission (Day -1), 4 days following admission (Day 4), ad hoc test based on symptoms, and for ambulatory on-site 
visits.
f.
CRU Confinement: Participants will be required to stay at CRU from Day -1 in Period 1 until completing Day 5 (96h) activities in the final period.
g.
Physical Examination: Complete physical examination will be conducted at Screening or upon admission (Day -1) in Period 1. Brief physical examination 
may be performed at other times, as appropriate, for findings during previous examination or new/open AEs, at investigator’s discretion.
h.
Continuous cardiac telemetry monitoring: Baseline telemetry to be recorded for at least 2 hours between admission and prior to dosing while awake. Post 
dose telemetry will continue for 12 hours after the start of dosing for each period.
i.
Last Period only, unless discharged at the discretion of the investigator.
j.
Ritonavir: To be administered approximately 12 hours before PF-07321332 administration on Day 1.
k.
HBsAb: Can be done either automatically or only if HBcAb or HBsAg is positive, as per local practices.
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m. Study Drug Administration: The first split dosing of study drug should be at approximately 2h after the breakfast.
n.
COVID-19 Assessment: Temperature check as per local requirement. Questionnaire before admission.
o.
TSH and Free T4: Must be collected at least once before dosing in each period. PI may choose to either collect at screening or Period 1 Day -1 or both.
p.
Pre-dose sample.
q.
Standardized meal: On Day 1, the breakfast to be provided after collection of vitals, ECGs 
and approximately 2h before the administration 
of study intervention at 0h and lunch to be provided at approximately 4h after the last administration of PF-07321332/placebo.
r.
ECG (triplicate): To be collected in fasted state (>3h after the previous meal).
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2. INTRODUCTION
PF-07321332 is a potent and selective inhibitor of the SARS-CoV-2 3CL protease, that is 
being developed as an oral treatment in patients with COVID-19.
2.1. Study Rationale 
The current study is the first in human (FIH) study of PF-07321332 in healthy adult 
participants. It is a 5-part study combining PART-1: SAD, PART-2: MAD, PART-3: relative 
bioavailability/food effect, PART-4: metabolism and excretion and PART-5: 
supratherapeutic exposure (SE). PART-1 and 2 are a randomized, double-blind, 
sponsor-open, placebo-controlled trial to evaluate safety, tolerability and PK of single and 
multiple escalating oral doses of PF-07321332 in healthy adult participants and PART-3 is a 
randomized open label study to evaluate relative bioavailability and food effect of an oral 
tablet formulation. PART-2 of the study may also evaluate the safety, tolerability and PK in 
Japanese participants. PART-4 is an open-label, non-randomized, single period to evaluate 
the metabolism and excretion of PF-07321332. PART-5 is a double-blind, sponsor-open, 
randomized, cross-over cohort to evaluate safety and tolerability at supratherapeutic 
exposures.
2.2. Background 
Disease Overview
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
COVID-19 manifests as a wide range of illnesses, from asymptomatic infection to severe 
pneumonia, ARDS and death. While the majority of cases (approximately 80%) are 
asymptomatic or mild,2 patients who are hospitalized with COVID-19 may have significant 
morbidity and mortality,3,4 and are at increased risk of developing complications such as 
severe inflammation associated with elevations in pro-inflammatory cytokines, ARDS, acute 
cardiac injury, thromboembolic events, hypercoagulability, and/or kidney injury.5-9
Current Treatment Options
As of the date of issuance of this protocol, only 1 anti-viral drug with activity against 
SARS-CoV-2, Remdesivir, an RNA polymerase inhibitor, has received approval in 
hospitalized patients with COVID-19.10
Antibody cocktails (containing casirivimab and imdevimab) and bamlanivimab received 
emergency use authorization for recently diagnosed patients with mild to moderate 
COVID-19 in high risk patients. Both these options are administered intravenously and 
require administration by healthcare professionals. As of the date of issuance of the protocol, 
no orally administered therapeutic intervention has been approved or received emergency use 
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Despite these advances, there remains an urgent need for additional safe and more effective 
therapeutic interventions that shorten time to clinical recovery and prevent the progression of 
infection to more severe disease and death. The direct reduction of viral replication, through 
inhibition of other critical viral enzymes, offers an important mechanism as monotherapy or 
in combination, to achieve greater patient benefit.
Rationale for Development of PF-07321332
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).11 Mutagenesis experiments with other coronaviruses and 
picornaviruses that are related to SARS-CoV-2 (picornavirus-like supercluster) have 
demonstrated that the activity of the 3CL protein (or the corresponding picornaviral 
3C enzyme) is essential for viral replication. No close human analogs of coronavirus
3CL enzymes are known, suggesting that appropriate 3CL inhibitors may function as 
selective inhibitors of SARS-CoV-2 and other coronaviruses as therapeutic agents.
Inhibition of the SARS-CoV-2 3CL protease is a mechanism of action distinct from that of 
Remdesivir, which is a prodrug of an adenosine nucleoside analogue that interferes with 
SARS-CoV-2 RNA-dependent RNA polymerase. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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2.3. Benefit/Risk Assessment
PF-07321332 is not expected to provide any clinical benefit to healthy participants. This 
study is designed primarily to generate safety, tolerability, and pharmacokinetic data for 
further clinical development.
More detailed information about the known and expected benefits and risks and reasonably 
expected AEs of PF-07321332 may be found in the IB, which is the SRSD for this study. The 
SRSD for the Ritonavir19 is the US FDA approved label and SmPC.
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2.3.2. Benefit Assessment
For healthy participants in this study, no clinical benefit is expected. 
2.3.3. Overall Benefit/Risk Conclusion
PF-07321332 is not expected to provide any clinical benefit to healthy participants in this 
study. Taking into account the measures taken to minimize risk to participants of this study, 
the potential risks identified in association with administration of PF-07321332 is clinically 
acceptable.
3. OBJECTIVES AND ENDPOINTS
PART-1: SAD
Objectives
Endpoints
Primary: 
Primary: 

To assess the safety and tolerability 
following a single dose of PF-07321332 
alone or in combination with a PK 
boosting agent (ritonavir).

Frequency, severity, and causal relationship of TEAEs 
and withdrawals due to TEAEs.

Frequency and magnitude of abnormal laboratory 
findings.

Changes from baseline in vital sign measurements and
12-lead ECG parameters.
Secondary: 
Secondary: 

To assess the plasma PK profile of 
PF-07321332 following single ascending 
doses of PF-07321332 alone or in 
combination with a PK boosting agent 
(ritonavir).

Plasma PK parameters of PF-07321332: 

Cmax, Tmax, AUClast, Cmax(dn), AUClast(dn).

If data permit, AUCinf, AUCinf(dn), t½, Vz/F, and 
CL/F.
Tertiary/Exploratory: 
Tertiary/Exploratory: 

To explore metabolites in plasma, urine, 
and feces, if data permit.

Qualitative characterization of metabolites of 
PF‑07321332 in pooled plasma, urine, and feces if data 
permit.

Quantitative excretion of drug-related 
material using 19F-NMR spectroscopy, if 
data permit.

Total excretion of drug-related material in urine and 
feces separately, and both routes combined, expressed 
as a percent of total dose administered, if data permit.

To determine the oral bioavailability of a 
tablet formulation of PF-07321332 
relative to suspension, if evaluated 
(Optional).

The ratio of AUClast, AUCinf and Cmax of tablet 
formulation and suspension.

To evaluate the effect of food (high fat 
meal) on the exposure of PF-07321332 
following a single oral dose of 
PF-07321332 tablet formulation, if 
evaluated (Optional).

The ratio of AUClast, AUCinf and Cmax under fed 
condition and fasted condition.


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PART-2: MAD (including optional Japanese cohort)
Objectives
Endpoints
Primary: 
Primary: 

To assess the safety and tolerability 
following multiple ascending doses of 
PF-07321332 alone or in combination 
with a PK boosting agent (ritonavir).

Frequency, severity, and causal relationship of TEAEs 
and withdrawals due to TEAEs.

Frequency and magnitude of abnormal laboratory 
findings.

Changes from baseline in vital sign measurements and 
12-lead ECG parameters.
Secondary: 
Secondary: 

To assess the plasma PK profile of 
PF-07321332 on Days 1, 5 and 10 
following multiple ascending doses of 
PF-07321332 alone or in combination 
with a PK boosting agent (ritonavir).

Plasma PK parameters of PF-07321332: 

Cmax, Tmax, AUCtau (where tau=8 hours for TID 
dosing or 12 hours for BID dosing), Cmin, Cmax(dn), 
AUCtau(dn), Cav, Rac, Rac,Cmax, PTR,CL/F and Vz/F.

If data permit, t½.

To assess the urinary PK profile of 
PF-07321332 on Day 10 following 
multiple ascending doses of 
PF-07321332 alone or in combination 
with a PK boosting agent (ritonavir).

PF-07321332 urinary PK parameters: 

Aetau and Aetau%, CLr.
Tertiary/Exploratory: 
Tertiary/Exploratory: 

To explore metabolites in plasma if data 
permit.

Qualitative characterization of metabolites of 
PF‑07321332 in pooled plasma if data permit.

To explore PK by microsampling 
technique(s), if evaluated (Optional).

Concentration of PF-07321332, if evaluated.
PART-3: Relative Bioavailability/Food Effect Cohort
Objectives
Endpoints
Primary: 
Primary: 

To determine the oral bioavailability of a 
tablet formulation of PF-07321332 relative 
to suspension.

The ratio of AUClast, AUCinf and Cmax of tablet 
formulation and suspension.
Secondary: 
Secondary: 

To evaluate the effect of food (high-fat
high-calorie meal) on the exposure of 
PF-07321332 following a single oral dose 
of PF-07321332 tablet formulation.

The ratio of AUClast, AUCinf and Cmax of tablet 
formulation under fed condition and fasted condition.

To determine the pharmacokinetics of 
PF-07321332 following oral 
administration of tablet and suspension of 
PF-07321332.

Plasma PK parameters of PF-07321332: Tmax, Cmax,
AUClast, Cmax(dn), AUClast(dn), if data permit AUCinf, 
AUCinf(dn), t½, CL/F, Vz/F.


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•
To determine the safety and tolerability of 
PF-07321332 following oral 
administration of tablet and suspension of 
PF-07321332.
•
Frequency, severity, and causal relationship of TEAEs 
and withdrawals due to TEAEs.
•
Frequency and magnitude of abnormal laboratory 
findings.
•
Changes from baseline in vital sign measurements and 
12-lead ECG parameters.
 
 
 
 
 
PART-4: Metabolism and Excretion 
Objectives
Endpoints
Primary: 
Primary: 
•
To determine the extent of excretion of 
drug related material in urine and feces 
after a single oral administration of
PF-07321332 with PK boosting agent 
ritonavir.
•
Total recovery of drug related material in urine and 
feces separately, and both routes combined, expressed 
as a percent of total dose administered.
Secondary: 
Secondary: 
•
To determine the pharmacokinetics of 
PF-07321332 following oral 
administration of PF-07321332 with PK 
boosting agent ritonavir.
•
Plasma PK parameters of PF-07321332: Tmax, Cmax,
AUClast, if data permit AUCinf, t½, CL/F, Vz/F.
•
To determine the safety and tolerability of 
PF-07321332 after a single oral 
administration of PF-07321332 with PK 
boosting agent ritonavir.
•
Frequency, severity, and causal relationship of TEAEs 
and withdrawals due to TEAEs.
•
Frequency and magnitude of abnormal laboratory 
findings.
•
Changes from baseline in vital sign measurements and 
12-lead ECG parameters.
Tertiary/Exploratory: 
Tertiary/Exploratory: 
•
To characterize the metabolic profile and 
identify circulating and excreted 
metabolites following administration of a 
single oral dose of PF-07321332 with PK 
boosting agent ritonavir, if possible.
•
Metabolic profiling/identification and determination 
of relative abundance of PF-07321332 and the 
metabolites of PF-07321332 in plasma, urine, and 
feces, if possible.
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PART-5: Supratherapeutic Exposure (NH CRU only)
Objectives
Endpoints
Primary: 
Primary: 

To assess the safety and tolerability of a 
supratherapeutic exposure of PF-07321332 
with a PK boosting agent (ritonavir)
administered as split dosing.

Frequency, severity, and causal relationship of 
TEAEs and withdrawals due to TEAEs.

Frequency and magnitude of abnormal laboratory 
findings.

Changes from baseline in vital sign measurements 
and 12-lead ECG parameters.
Secondary: 
Secondary: 

To assess the plasma PK of PF-07321332 at a 
supratherapeutic exposure of PF-07321332 
with a PK boosting agent (ritonavir)
administered as split dosing.

Plasma PK parameters of PF-07321332: 

Cmax, Tmax, AUClast

If data permit, AUCinf, t½.
4. STUDY DESIGN
4.1. Overall Design
This study may be conducted at 1-3 sites in the USA and/or European Union. 
This Phase 1 first-in-human (FIH) study will evaluate safety, tolerability, and PK of 
PF-07321332 in healthy participants. This 5-part study will combine PART-1: single 
ascending dose (SAD), PART-2: multiple ascending dose (MAD, including optional 
Japanese cohort), PART-3: relative bioavailability and food effect cohort, PART-4: 
metabolism and excretion cohort and PART-5: supratherapeutic exposure cohort. PART-1 
and 2 are randomized, double-blind (participant and investigator blinded and sponsor open) 
and PART-3 is open label. PART-4 is an open-label, non-randomized, single period to 
evaluate the metabolism and excretion of PF-07321332. PART-5 is a double-blind, 
sponsor-open, randomized, cross-over cohort to evaluate safety and tolerability at 
supratherapeutic exposures to be conducted at NH CRU only.
In all 5 parts, participants will be screened within 28 days of their first dose of investigational 
product. Participants will be admitted to the CRU on Day -1 or earlier and may be discharged 
at investigator discretion following completion of assessments per SoA. In PART-4, 
participants may be admitted earlier to facilitate collection of pre-dose fecal sample. If a 
participant has any clinically significant, study related abnormalities at the conclusion of a 
scheduled inpatient portion of the study, the Pfizer medical monitor (or designated 
representative) should be notified and the participant may be asked to remain in the CRU 
until such abnormalities are deemed not clinically significant, or it is safe for outpatient 
follow-up. 
Participants who discontinue for non-safety related reasons prior to completion of the study 
may be replaced, at the discretion of the PI and sponsor. The replacement participant(s) may 
or may not be required to complete all periods of the cohort in which they are participating at 
the discretion of the PI and sponsor.


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Study schema is shown in Section 1.2. In PART-1 and 2, treatment sequences, actual doses, 
dose increments and dosing regimen may be adjusted, and intermediate or alternative dose 
levels may be substituted during the study based on emerging safety, tolerability, and PK 
data.
PART-1: SAD
SAD will include 2 interleaving cohorts with a total of approximately 12 participants planned 
(approximately 6 participants in each cohort), with 4-period cross-over in each cohort. 
Period 3 and 4 are optional periods which may be used to further explore PK at additional 
doses or PK in combination with ritonavir or relative bioavailability of a new formulation or 
food effect (high-fat high-calorie meal), etc, based on emerging safety, tolerability and PK 
assessments. For each period, approximately 4 participants will receive a single oral dose of 
PF-07321332, and approximately 2 participants will receive placebo after at least 10 hours of 
fasting. In order to improve gastrointestinal tolerability, if required based on emerging safety 
data, PF-07321332 may also be dosed with standard meal (Section 5.3.1). If required to be 
dosed in fed state, the participants will be required to eat a meal before drug administration 
as specified in Sections 5.3.1 and 6.1. Each participant may receive either a single dose of 
PF-07321332 or a placebo during each period. In each period, participants on active 
treatment in Cohort 1 will receive D1, D3, D5 and D7 dose levels and Cohort 2 will receive 
D2, D4, D6 and D8 dose levels in dose escalation format as specified in Table 9
(Section 4.3). Provisional dosing scheme in PART-1 is provided in Table 6. In SAD cohorts 
requiring co-administration of PF-07321332/placebo with ritonavir, all participants (active 
and placebo) will receive 3 doses of 100 mg of ritonavir as specified in the SoA. Except D1 
of Cohort 1 in SAD, all other dose levels and/or meal condition may be changed based on 
emerging PK and safety data. Dose escalation to subsequent dose levels in SAD cohorts will
be based on all available (a minimum of 48 hours post-dose) safety data and PK over 
approximately ≥6 hours in a minimum of 4 participants (3 active and 1 placebo) at previous 
dose levels.
Table 6.
Provisional Dosing Scheme in Part-1:SAD
Period 1
Period 2
Period 3a
Period 4a
Cohort 1
N=2
Placebo (PL)
D3
D5
D3 (Tablet)b
N=2
D1
PL
D5
PL
N=2
D1
D3
PL
D3 (Tablet)b
Cohort 2
N=2
PL
D4
D6
PL+Food
N=2
D2
PL
D6
D2+Foodb
N=2
D2
D4
PL
D2+Foodb
Dose levels D1 to D6 are specified in Table 9.
a.
Period 3 and 4 are optional. These periods may be used for evaluation of additional dose levels or 
combination with ritonavir or relative bioavailability of tablet formulation or food effect etc.
b.
Period and dose levels for relative bioavailability of tablet or administration with food may be changed 
based on emerging PK data. If relative bioavailability and food effect conducted in Period 3 or 4, the 
active/Placebo allocation will be the same as equivalent dose used in period 1 or 2.


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There will be a washout interval of ≥5 days between dosing to a given participant. 
Participants will be required to stay at the CRU for the duration of the washout interval. 
However, they may be released at the discretion of the investigator. The washout interval 
may be adjusted based on data emerging from previous cohorts/periods. 
Optional Period 3 or 4 of Cohort 1 or 2 may be used to explore food effect (high-fat 
high-calorie meal) and/or relative bioavailability. If conducted, the active/Placebo allocation 
will be the same as equivalent dose used in Period 1 or 2.
At dose level of D3 (Cohort-1, Period 2), the urine and feces will be collected for 5 days as 
specified in SoA for 19F-NMR spectroscopy and metabolite profiling. Based on the emerging 
PK data, the dose level for urine and feces collection may be changed. If needed, the feces 
and urine may also be collected at an additional dose level. 
PART-2: MAD 
The first MAD cohort may start after a total daily dose, which provides comparable or higher
total daily exposure (24h) in SAD to the projected total daily steady-state exposure (over 
24h) at the starting dose in MAD, is found safe and well tolerated in the PART-1 of the 
study. The proposed MAD study design will be parallel cohorts, with 10 days of dosing. 
PART-2 will consist of approximately 2 to 5 cohorts including up to 3 optional cohorts 
(Cohort 5, 6 and 7) with approximately 6 participants in each cohort. Cohort 7 is an optional 
Japanese participants cohort. In each cohort, approximately 4 participants will receive one of 
the escalating doses of PF-07321332 as specified in Table 10 (Section 4.3) and 
approximately 2 participants will receive matching placebo after at least 7h of fast for the 
morning dose and 2h of fast for the next dose(s). From Day 1 – Day 9, PF-07321332/placebo
will be administered every 8h (ie, TID) when administered alone and every 12h (ie, BID)
when co-administered with ritonavir; however, PF-07321332/placebo alone may also be 
administered every 12h, if needed, based on emerging PK data. On Day 10, 
PF-07321332/placebo will be administered at approximately 0h for TID or BID regimen. In 
MAD cohorts requiring co-administration of PF-07321332/placebo with ritonavir, all 
participants (active and placebo) will receive 100 mg of ritonavir as specified in the SoA. If 
required to be dosed in fed state, the participants will be required to eat a meal before drug 
administration (as specified in Sections 5.3.1 and 6.1). Dose escalation to subsequent dose 
levels in MAD cohorts will be based on a minimum of 6 days safety data and PK over 
approximately ≥6 hours on Day 5 in a minimum of 4 participants (3 active and 1 placebo) at 
previous dose levels. 
Safety, tolerability and PK may be evaluated in participants of Japanese descent (defined as 
having 4 biological Japanese grandparents who were born in Japan) after multiple oral 
administration of PF-07321332 in PART-2. If conducted, this cohort will have all evaluations 
as specified in SoA for MAD cohorts and the dose level in this cohort will be equal or lower 
than the highest dose level already evaluated in healthy western participants. Frequency of 
administration and meal condition will be based on safety, tolerability and PK data from 
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If possible, microsampling PK and/or metabolite profiling may also be done.
PART-3: RBA and Food effect
If conducted, this cohort will be an open label, randomized, 3-period, 3-sequence cross-over 
single dose cohort evaluating the relative bioavailability of PF-07321332 tablet compared to 
PF-07321332 oral suspension and to evaluate the effect of food on the bioavailability of the 
PF-07321332 tablet in healthy adult participants (Table 7).
 
 
Number of participants required in this part of the study will be 
determined based on the variability observed in PK data emerging from SAD cohorts. A 
maximum of 18 participants may be enrolled in PART-3 of the study with approximately
equal number of participants randomized to each sequence. The dose level to be evaluated in 
PART-3 will be determined based on emerging PK and safety data from SAD and MAD 
cohorts. The selected dose will be equal or lower than the highest tolerated dose already 
evaluated in PART-1. In this part, there will be a washout interval of at least 2 days between 
dosing to a given participant in each period. Participants will be required to stay at the CRU 
until the discharge in the last period. The washout interval may be adjusted based on data 
emerging from SAD and MAD cohorts. 
Table 7.
Randomization Sequence in Relative Bioavailability/Food Effect Cohort
Sequence 
Period 1
Period 2
Period 3
1 
A
B
C
2 
B
C
A
3
C
A
B
A: PF-07321332 oral suspension in fasted state.
B: PF-07321332 tablet formulation in fasted state.
C: PF-07321332 tablet formulation in fed (high-fat high-calorie meal) state.
PART-4: Metabolism and Excretion
This part will include a single cohort of approximately 6 male participants. All participants
will receive 4 doses of 100 mg ritonavir as specified in the SoA. Each participant will receive 
a single dose of 300 mg of PF-07321332 on Day 1 0 hr along with 100 mg of ritonavir after 
at least 10 hr of fasting. The plasma for PK and metabolic profiling will be collected as 
specified in the SoA. The urine and feces will be collected for 10 days as specified in SoA to
determine excretion routes and metabolite profiling. A fecal sample is required prior to 
dosing on Day 1. Dietary fiber supplementation anduse of laxative (Section 5.3.1.1) should 
be considered with the goal to facilitate at least once daily bowel movement. The use of the 
laxative should be recorded. The participants will be discharged on Day 11. 
PART-5: SE (NH CRU only)
This cohort will include up to 12 participants in a 4-period (Periods 3 and 4 are optional), 
double-blind, sponsor-open, 2-sequence, cross-over design to explore safety, tolerability and 
PK at supratherpeutic exposure. For each period, participants will receive split dosing 
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administration (3 doses) of PF-07321332 or placebo at short intervals (approximately 2 h of 
the previous dose) after at least 2 hours after breakfast on Day 1. The first 2 periods will be a 
cross-over where participants will be given PF-07321332 at 0, 2 and 4 hrs at the dose of 
750 mg (or placebo). Periods 3 and 4 (if conducted) will only be conducted if 
supratherapeutic concentrations are not reached in Period 1. In Periods 3 and 4 (if conducted) 
doses may be given up to 4 times for a total daily dose not exceeding 3000 mg, with or 
without food. The timing of the food, ECGs, PK collection in Periods 3 and 4 may be 
modified based on the data from Period 1 but the total number of these assessments will 
remain the same. 
In each period, participants will receive 3 doses of 100 mg ritonavir as specified in SoA.
Provisional dosing scheme in PART-5 is provided in Table 8.
Table 8.
Provisional Dosing Scheme in Part-5:Supratherpeutic Exposure
Sequence
Period 1
Period 2
Period 3a
Period 4a
1
Placebo (PL)
Treatment P
PL
Treatment Q
2
Treatment P
PL
Treatment Q
PL
a.
Periods 3 and 4 are optional. 
Treatment P=750 mg of PF-07321332 to be administered at 0, 2 and 4h and PK enhancer (ritonavir)
administered at -12, 0 and 12h. Treatment Q = To be determined
There will be a washout interval of ≥5 days between dosing of PF-07321332/placebo to a 
given participant. Participants will be required to stay at the CRU for the duration of the 
washout interval. However, they may be released at the discretion of the investigator.
Dose escalation, if required, to subsequent dose levels (Treatment Q) in Periods 3 and 4 will 
be based on all available (a minimum of 48 hours post-dose) safety data and PK data over 
approximately ≥6 hours (after the first dose on Day 1) in Period 1.
The dose escalation stopping criteria are specified in Section 6.6.1. The total daily dose in 
this part will not exceed 3000 mg.
In PART-1 and PART-2 of the study, the dose levels, frequency of administration and/or 
meal condition may be changed based on emerging PK and safety data. During the SAD and 
MAD the dose increments and planned doses may be adjusted, as the study progresses 
dependent upon emerging PK, safety, and tolerability data. Other intermediate doses or lower 
doses may be administered instead of the planned doses, or changes in dosing frequency or 
titration schemes may be proposed for MAD cohorts if safety/tolerability or PK issues 
become apparent, if evidence of nonlinear PK dictates the need to escalate more slowly, or if 
subsequent doses are predicted to result in exposures that exceed the target limits. Any 
potential altered dose scheme will be equal to or less than a 3.3-fold increase in exposure 
from the previous highest dose if a higher dose is warranted to achieve exposure. If 
gastrointestinal tolerability issue becomes dose-limiting in PART-1 or 2, dosing with food 
(standard meal) or pre-dosing with anti-emetics may be considered. The projected average 
exposure of the altered dose scheme will not exceed the exposure limit specified in 
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In all cohorts (all parts of the study), participants can be released after completing activities 
specified in SoA. A telephone follow-up contact will occur between 28 to 35 days after the 
day of last administration of study intervention. At the discretion of the investigator, 
telephone follow-up contact may be substituted with an on-site visit in case of additional 
follow-up of open AEs or clinically significant laboratory findings.
The total planned duration of participation, from Screening visit to the Follow-up phone call, 
may be approximately 12 weeks for PART-1 and PART-5, 10 weeks for PART-2 and 
PART-3 and 8 weeks for PART-4.
Participants who discontinue from the study (due to non-safety reasons) may be replaced at 
the Sponsor’s discretion.
4.2. Scientific Rationale for Study Design
Given the current study is the first to dose PF-07321332 to healthy participants, an escalating 
single dose design with careful assessment and ongoing review of safety and PK data of 
PF-07321332 is planned. The 5-part combined SAD, MAD, RBA/FE, M&E and SE design 
was selected because it provides the opportunity to shorten the drug development timeline, 
without compromising the safety of the participants.
Male and female of 18-60 years of age was selected to better represent COVID-19 patient 
population. PF-07321332 is a non-genotoxic but its effect on embryo-fetal development is 
currently not known. Therefore, male and female are required to follow contraception 
requirements as specified in Section 5.3.4 and Appendix 4. 
In addition to the standard safety assessments, fibrinogen, PT and aPTT will also be 
monitored 
 
PART-1: SAD
The crossover design will permit both a within and between participant assessment of safety, 
tolerability, and PK. Furthermore, 2 interleaving cohorts will permit assessment of safety and 
PK over a wider dose range within a given participant compared to a sequential cohort 
design. To permit an unbiased assessment of safety, the administration of active versus 
placebo in each period will be double blinded to site staff (except those involved in 
preparation of doses) as well as the study participants. 
For a given participant, dosing will be separated by ≥5 days. This planned dosing interval is 
deemed sufficient to permit washout of previous treatment. Based on the projected 
PF-07321332 effective t½ of ~2 hours (see Section 2.2.1.4), almost complete PK washout is 
expected within 24 hours of dosing.
In SAD period, the urine and feces may be collected to calculate total excretion of 
drug-related material using 19F-NMR technique and understand metabolic profile as 
described in previous publications.15
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If a reasonable dose of PF-07321332 is not able to achieve desired concentrations in the 
efficacious range, ritonavir may be used as PK boosting agent. If required, 3 doses of 100 mg 
ritonavir at -12h, 0h (co-administered with PF-07321332) and 12h may be used as boosting 
agent to increase the exposure of PF-07321332 because the primary route of elimination of 
PF-07321332 is expected to be via CYP3A4 mediated metabolism. This dose of ritonavir is a 
subtherapeutic dose and provides maximum CYP3A4 inhibition. In SAD, participants will 
begin receiving ritonavir dose approximately 12 hours before the PF-07321332 dose to 
maximize the PK boosting potential of ritonavir. Although ritonavir is generally 
recommended to be dosed under fed condition for better gastrointestinal tolerability, lower 
dose of ritonavir (100 mg) is expected to provide acceptable gastrointestinal tolerability 
based on the fact that lopinavir/ritonavir combination are recommended to be dosed with or 
without food.
PART-2: MAD
The safety and tolerability will be collected up to 12 days to evaluate the impact of 
PF-07321332 on relatively longer dosing; however, the dose escalation decision will be 
based on Day 5 PK. PBPK simulations (including time dependent induction and inhibition 
potential) showed that the PK concentration after 5 days of dosing is expected to be very 
close to the steady state. Therefore, the Day 5 PK and all available safety will be used to dose 
escalate to the next cohort in order to rapidly collect the PK and safety data to initiate the 
study in COVID-19 patients. By Day 10, the PK of PF-07321332 is expected to achieve 
steady-state and therefore, the steady-state plasma and urine PK will be determined on 
Day 10.
Exploratory microsampling PK sample may be collected to evaluate the microsampling 
techniques which may be employed in future clinical trials. 
In order to understand the qualitative metabolic profile of PF-07321332 at steady-state, 
exploratory plasma samples may be collected on Day 10.  
PART-3: RBA and FE
This part of the study will evaluate bioavailability of a tablet formulation relative to the 
formulation used in PART-1 and/or PART-2 of the study and explore the food effect on the 
PK of a new formulation in healthy participants. 
Based on the projected half-life of 2h, the 48h washing interval should be sufficient to 
provide the concentration <5% of Cmax in the subsequent period.
 
 
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PART-4: Metabolism and Excretion
This part is an open-label, non-randomized, single period cohort to evaluate the metabolism 
and excretion of PF-07321332 in healthy male participants. Only males will be included in 
this study given the desire to enroll a homogeneous population due to the small sample size.
A single dose of PF-07321332 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.
The urine and feces samples collected will only be analyzed at the end of the study to 
determine the amount of drug related material excreted. Considering the half-life and 
variability in gastrointestinal transit time, feces and urine will be collected up to 10 days after 
dosing to allow near complete collection of the drug or drug related materials.
PART-5: Supratherapeutic exposure (NH CRU only)
This part is a double-blind, sponsor-open, randomized, 2-sequence, cross-over cohort to 
evaluate safety, tolerability and PK at supratherapeutic exposures. The dose currently being 
evaluated in Phase 2/3 studies is PF-07321332/ritonavir 300/100 mg BID which is expected 
to achieve a geometric mean Cmax of approximately 
 and it is desirable to 
establish safety and tolerability at least 2 fold exposure margins to cover the impact of DDI 
or organ impairment. In SAD and MAD, the increase in exposure of PF-07321332 was less 
than dose proportional and therefore the supratherapeutic exposure was not achieved. In this 
cohort, PF-07321332 will be administered into split doses at time around expected Tmax to 
achieve higher Cmax of PF-07321332. The projected exposures at the dosing regimen used in 
this part will not exceed PK stopping limits as defined in Section 6.6.1.
Extensive PK and triplicate ECGs are collected to enable potential exposure-response 
modeling with PF-07321332 concentration and ECG parameters. The cross-over, randomized
design provides an intrasubject comparison of placebo for exposure-response analysis using 
PF-07321332 concentration and ECG parameters. The timing of the food was selected to 
avoid the effect of food on QTc ie, ≥4h before and after Tmax, while avoiding very long 
fasting requirements for the participants.
Considering half-life and inter-individual variability in PART-1 of this study, a wash out of 
≥5 days was deemed sufficient. 
 
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4.3. Justification for Dose
4.3.1. Justification of Dose for PART-1, PART-2 and PART-3 (Original Protocol, 
28 January 2021)
The approach for dose selection for this study includes consideration of all relevant 
information obtained in non-clinical pharmacology and toxicity studies with PF-07321332. 
Similar to other antiviral therapies,  PF-07321332 is expected to exhibit therapeutic 
anti-SARS-CoV-2 activity in patients when the free plasma exposure is maintained at or 
above the in vitro EC90 values.16-18 The primary dNHBE cell assay is considered the most 
relevant for translation and has an EC90 value 
 
This potency is also consistent with the SARS-CoV-2 VeroE6 monkey kidney cell line assay 
EC90 
in the presence of a P-gp inhibitor. Since 
high levels of P-gp expression are not expected in lung cells, the primary site of viral 
replication during SARS-CoV-2 infection, the potency in the presence of the P-gp inhibitor is 
considered most relevant. Based on this antiviral data the target Ceff was defined 
 
 
The human PK of PF-07321332 after single and multiple dose administration (with and 
without ritonavir) was predicted using physiology based pharmacokinetic (PBPK) modeling 
by scaling in vitro hepatic clearance obtained from human liver microsomes (HLM) and 
CLbile from human hepatocytes under sandwich-cultured conditions in SimCyp® ADME 
simulator Version 19 release 1 (Certara, NJ, USA). The predicted plasma CL and Vss of 
PF-07321332 are 
 and 1 L/kg, respectively, providing 
 
. In addition, inhibition (reversible and time dependent inhibition of 
CYP3A), induction potential and transporter interaction potential of PF-07321332 were also 
included in the PBPK model. For ritonavir, in-built PBPK model in SimCyp simulator was 
used. 
 
 
 
 
 
 
 
The planned starting dose of PF-07321332 as a single dose is 150 mg. Being an anti-viral 
agent, the target (3CL-protease) is not expressed in healthy participants hence primary 
pharmacology related effect is not expected in healthy participants. The projected average 
free concentration (Caverage,free) of approximately 
at 150 mg is more than 
1000 times lower than the observed IC50 (IC50 >100 μM) in off-target pharmacology 
screening panel. The projected total Cmax and the AUCinf of PF-07321332 at the proposed 
starting dose of 150 mg is
 and 
, which provides approximately
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 safety margins (based on free concentrations), respectively. The maximum 
recommended starting dose based on human equivalent dose (HED) approach with safety 
factor of 
. Given the absence of target from healthy participants, absence of 
off-target pharmacology and high safety margin based on pre-clinical toxicology study, the 
proposed starting dose of 150 mg is expected to be safe.
Dose escalation is aimed to occur in incremental increases of ≤½ log (ie, up to approximately 
3.3-fold) based on predicted exposures. The margins for the highest proposed single dose 
(3000 mg) established on the free exposures in rats are projected to be approximately 
 
for Cmax and 
 for AUCinf which are well within the NOAEL exposure. In the presence 
of ritonavir, the projected exposure is lower than the projected exposures at the highest 
proposed dose of 3000 mg. 
The nominal doses, projected PK exposure parameters and safety margins of PF-07321332 
relative to PK stopping limits at the planned doses in SAD are listed in Table 9. Doses 
presented are projected based on nonclinical data and may be modified based on emerging 
safety, tolerability, and PK data. The projected exposures (adjusted based on observed PK) at 
the modified doses will not exceed the PK stopping limits (Section 6.6.1). 
 
 
 
 
 
 
 
 
 
 
The starting dose in MAD cohort is planned at 500 mg TID; however, the starting dose in 
MAD may be adjusted based on available PK and safety data from the SAD cohorts. Based 
on the current human PK predictions, a dose of approximately 500 mg TID would provide 
the Cmin consistently above Ceff. Since the target is not expressed in healthy participants, a 
dose that is expected to be efficacious is proposed as a starting dose in MAD in order to 
minimize the exposure of healthy participants at subtherapeutic dose levels. 
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Based on the predicted steady state exposures (Cmax,ss and AUC24,ss), 500 mg TID is expected 
to provide margins of approximately
 for Cmax,ss and 
for AUC24,ss relative to the 
free exposure in rats on Day 14 at the NOAEL. All dose levels listed are nominal since doses 
will be driven by exposure. Dose escalation is aimed to occur in incremental increases of
≤½ log (ie, up to approximately 3.3-fold) based on predicted exposures.
Due to the uncertainties in the in vitro potencies and PK parameters scaling and anticipated 
interpatient variability, the current intent of the development program is to explore dosing 
regimens resulting in a multiple of this Cmin target. Highest daily dose of PF-07321332 is 
expected to be 3000 mg/day (ie, 1000 mg TID), which is expected to provide margins of 
approximately 
for Cmax,ss and 
 for AUC24,ss relative to the free exposure in rats
on Day 14 at the NOAEL.
The nominal dosing regimen, projected PK exposure parameters and safety margins of 
PF-07321332 relative to PK stopping limits at the planned doses in MAD are listed in
Table 10.
 
 
 
 
 
 
All the doses in SAD or MAD cohorts except starting dose of 150 mg in SAD cohort are 
nominal and may be adjusted, as the study progresses depending upon emerging PK, PD, 
safety, and tolerability data. Other intermediate doses or lower doses or repeat doses may be 
administered instead of the planned doses, or changes in dosing frequency or titration 
schemes may be proposed for MAD cohorts if safety/tolerability issues become apparent, if 
evidence of nonlinear PK dictates the need to escalate more slowly, or if subsequent doses 
are predicted to result in exposures that exceed the target limits. However, the projected 
exposure for the modified doses or additional cohorts following either single dose or multiple 
dose administration will not exceed PK stopping limit.
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The dosing regimen to be evaluated in optional Japanese cohort will be equal to or lower than 
the safe and tolerated dosing regimen in western healthy adult participants in MAD cohorts. 
Similarly, the dose to be evaluated in relative bioavailability cohort will be the dose which 
will be projected to provide the exposure (in fed condition) equal to or lower than the 
exposure already observed in SAD or MAD cohorts at safe and tolerated doses.
4.3.2. Justification of Dose for PART-4:Metabolism and Excretion (Protocol 
Amendment 2, 2 June 2021)
In PART-4: Metabolism and Excretion cohort, a single oral dose of 300 mg PF-07321332, 
pharmacokinetically enhanced with ritonavir (4 doses of 100 mg at -12, 0, 12, and 24 hours 
relative to PF-07321332), is planned. This dose is anticipated to be a clinically effective dose 
and currently planned to be evaluated in Phase 2/3 studies. 
 
 
 
 
 
 
The dose of ritonavir to be used in this study is 100 mg. This dose is the typical dose of 
ritonavir when dosed as a PK enhancer. 
 
 
4.3.3. Justification of Dose for PART-5: Supratherapeutic Exposure (Protocol 
Amendment 3, 24 June 2021)
In PART-5, the total dose planned for PF-07321332 is 2250 mg administered as 3 split doses
of 750 mg at 0, 2h and 4h, pharmacokinetically enhanced with ritonavir (3 doses of 100 mg 
at -12, 0 and 12 hours relative to PF-07321332). Based on the simulations using preliminary 
population PK model, this dose is anticipated to provide a supratherapeutic exposure 
 
. 
 
 
 
 
 
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The dose of ritonavir to be used in this study is 100 mg. This dose is the typical dose of 
ritonavir as a PK enhancer. 
The projected exposure for the proposed dose / regimen of PF-07321332 was based on a 
preliminary population PK model. The model for PF-07321332 750 mg (administered at 0h, 
2h and 4h) with PK enhancement predicts the total AUC24 and Cmax to be 
μg•hr/mL 
and 
μg/mL, which is less than 
 higher than the observed exposure at PF-07321332 
750 mg (with ritonavir), and approximately 
 and 
 lower, respectively, in terms of 
unbound concentration than the observed NOAEL 
 
 in rats in the 14-day toxicity study.
Using the same preliminary population PK model, the projected AUC24 and Cmax at the 
maximum allowed dose in this protocol (3000 mg total daily dose administered as 4 split 
doses of 750 mg at every 2 hour intervals) are approximately 
μg•hr/mL and 
, which is approximately 
 and 
 below the PK stopping limit.
At this dosing regimen, the supratherapeutic exposure is expected to be achieved while being 
safe. 
4.4. End of Study Definition
A participant is considered to have completed the study if he/she has completed all phases of 
the study, including the last visit.
The end of the study is defined as the date of the last visit of the last participant in the trial 
globally.
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 
taken into consideration when deciding whether a particular participant is suitable for this 
protocol.
Prospective approval of protocol deviations to recruitment and enrollment criteria, also 
known as protocol waivers or exemptions, is not permitted.
5.1. Inclusion Criteria
Participants are eligible to be included in the study only if all of the following criteria apply:
Age and Sex:
1. Male and female participants must be 18 to 60 years of age, inclusive, at the time of 
signing the ICD. Only Male participants will be included in PART-4.
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
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 overtly healthy as determined by medical evaluation including 
medical history, physical examination, laboratory tests, and vital signs and standard 
12-lead ECGs.
3. Participants who are willing and able to comply with all scheduled visits, treatment 
plan, laboratory tests, lifestyle considerations, and other study procedures.
4. For optional Japanese cohort only: Japanese participants who have 4 Japanese 
biologic grandparents who were born in Japan.
Weight: 
5. BMI of 17.5 to 30.5 kg/m2; and a total body weight >50 kg (110 lb).
Informed Consent:
6. Capable of giving signed informed consent as described in Appendix 1, which 
includes compliance with the requirements and restrictions listed in the ICD and in 
this protocol.
5.2. Exclusion Criteria
Participants are excluded from the study if any of the following criteria apply:
Medical Conditions:
1. 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, gastrectomy, cholecystectomy, 
intestinal resection).  
3. Positive test result for SARS-CoV-2 infection at the time of screening or Day-1.
4. History of HIV infection, hepatitis B, or hepatitis C; positive testing at screening for 
HIV, HBsAg, HBcAb, or HCVAb. As an exception a positive HBsAb test due to 
Hepatitis B vaccination is allowed.
5. Other medical or psychiatric condition including recent (within the past year) or 
active suicidal ideation/behavior or laboratory abnormality that may increase the risk 
of study participation or, in the investigator’s judgment, make the participant 
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Prior/Concomitant Therapy:
6. 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 6.5 for additional details).
7. Participants who have received a COVID-19 vaccine within 7 days before screening 
or admission, or who are to be vaccinated with a COVID-19 vaccine at any time 
during the study confinement period
Prior/Concurrent Clinical Study Experience:
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 study intervention
used in this study (whichever is longer). 
Diagnostic Assessments:
9. A positive urine drug test at screening or admission.
10. Screening supine BP ≥140 mm Hg (systolic) or ≥90 mm Hg (diastolic), following at 
least 5 minutes of supine rest. If BP is ≥140 mm Hg (systolic) or ≥90 mm Hg 
(diastolic), the BP should be repeated 2 more times and the average of the 3 BP 
values should be used to determine the participant’s eligibility.
11. Baseline 12-lead ECG that demonstrates clinically relevant abnormalities that may
affect participant safety or interpretation of study results (eg, baseline QTcF interval
>450 msec, complete LBBB, signs of an acute or indeterminate-age myocardial
infarction, ST-T interval changes suggestive of myocardial ischemia, second- or 
third-degree AV block, or serious bradyarrhythmias or tachyarrhythmias). If the 
baseline uncorrected QT interval is >450 msec, this interval should be rate-corrected 
using the Fridericia method and the resulting QTcF should be used for decision 
making and reporting.  Computer-interpreted ECGs should be overread by a 
physician experienced in reading ECGs before excluding participants. In PARTs-1,
2 and 5, the average of triplicate measurement should be used for eligibility 
determination. 
In PART-3 and PART-4 only: If QTcF exceeds 450 msec, or QRS exceeds 
120 msec, the ECG should be repeated 2 more times and the average of the 3 QTcF or 
QRS values should be used to determine the participant’s eligibility.  


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12. Participants with ANY of the following abnormalities in clinical laboratory tests at 
screening, as assessed by the study-specific laboratory and confirmed by a single 
repeat test, if deemed necessary: 
•
AST or ALT level ≥1.5 × ULN;
•
Total bilirubin level ≥1.5 × ULN; participants with a history of Gilbert's 
syndrome may have direct bilirubin measured and would be eligible for this study 
provided the direct bilirubin level is ≤ULN.
Other Exclusions:
13. 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).
14. Blood donation (excluding plasma donations) of approximately 1 pint (500 mL) or 
more within 60 days prior to dosing.  
15. Unwilling or unable to comply with the criteria in the Lifestyle Considerations
section of this protocol.
16. Use of tobacco or nicotine containing products in excess of the equivalents of 
5 cigarettes per day or 2 chews of tobacco per day.
17. 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.
18. Pregnant or breastfeeding women.
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 safety laboratory evaluations (except 6h post dose on Day 1 in PART-1 and Day 5 
in PART-2) and at least 10 hours in PART-1, PART-3 and PART-4 and at least 
7 hours before morning doses in PART-2.
•
PART-5: On Day 1, the breakfast to be provided after collection of vitals, ECGs 
 
 and approximately 2h before the administration of study intervention at 0h 
and lunch to be provided at approximately 4h after the last administration of 
PF-07321332/placebo.
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•
PART-1, PART-3, PART-4 and on PK days in PART-2 (if dosed under fasted 
condition):
•
Water is permitted until 1 hour prior to study intervention administration at 0h on 
PK days. Water may be consumed without restriction beginning 1 hour after
dosing at 0h on PK days. Water consumption is not restricted on afternoon and/or 
evening dose(s) on PK days and on all doses of non-PK days.
•
No food will be allowed for approximately 4 hours post-dose in PART-1, 
PART-3 and after the morning dose on PK days (Days 1, 5, 10) in PART-2. For 
all other doses in PART-2, no food will be allowed approximately 2 hours before 
and after dosing. 
•
Noncaffeinated drinks (except grapefruit or grapefruit-related citrus fruit juices (see 
below) may be consumed with meals and the evening snack.
•
Lunch will be provided approximately 4 hours after morning dosing.
•
Dinner will be provided approximately 9 to 10 hours after morning dosing.
•
An evening snack may be permitted.
•
Participants will refrain from consuming red wine, grapefruit, or grapefruit-related 
citrus fruits (eg, Seville oranges, pomelos, fruit juices) from 7 days prior to the first 
dose of study intervention until collection of the final PK blood sample.  
•
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.
PART-5 only:
•
On Day 1 in all periods, following an overnight fast of at least 10 hours and collection 
of ECGs, vitals
, participants should finish a standard breakfast 
approximately 2 hours prior to the administration of the investigational product. 
Participants will be encouraged to eat the full standard meal. If participants are unable 
to complete the entire meal, the approximate portion of the meal consumed will be 
documented.
•
Water is restricted for 30 minutes prior and 1 hour after dosing (1st, 2nd and 3rd split 
dose). Ambient temperature water may be consumed without restriction 1 hour after 
3rd split dose.
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
Participants will be restricted to consuming ambient temperature or warm drinks form 
Day 1 (prior to baseline ECG measurements) until final ECG measurements have 
been collected in each study period. Hot or cold drinks are prohibited during this time 
frame.

Non-caffeinated drinks (except grapefruit or grapefruit-related citrus fruit juices) may 
be consumed with meals and evening snacks.

Participants will not be allowed to eat or drink grapefruit or grapefruit-related citrus 
fruits (eg, Seville oranges, pomelos) from 7 days prior to the first dose of 
investigational product until collection of the final PK blood sample in the last period.

On Day 1 in Periods 1 and 2, lunch will be provided approximately 4 hours after last 
dosing (ie, following the scheduled 8 hour ECG and PK assessments).

On Day 1 in all Periods, dinner will be provided approximately 8 hours after last split
dosing (ie, after collection of the ECG and PK measurements scheduled at 12 hours 
postdose).

The timing of meals should be standardized between period 1 and 2 and between 
period 3 and 4. The timing of the meals and snacks must be recorded. It should be 
noted if subject fails to consume the majority of a meal.

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.
If dosed under standard meal condition in PART-1 or PART-3:
Following an overnight fast of at least 10 hours, participants should start a standard breakfast 
approximately 30 minutes prior to the administration of the investigational product. The 
breakfast will be consumed over approximately 20 minutes with investigational product 
administered within approximately 10 minutes after completion of the meal. Participants will 
be encouraged to eat the full standard meal. If participants are unable to complete the entire 
meal, the approximate portion of the meal consumed will be documented. No food will be 
allowed for at least 2 hours post-dose.

Water can be allowed as desired except for 1 hour after investigational product 
administration. There are no water restrictions prior to dosing for participants dosed 
under fed conditions. 
If dosed under high fat meal condition in PART-1 or PART-3:

Following an overnight fast of at least 10 hours, participants should start a 
high-fat/high-calorie breakfast approximately 30 minutes prior to administration of 
the investigational product. The breakfast will be consumed over approximately 


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20 minutes with investigational product administered within approximately 
10 minutes after completion of the meal. Participants will be encouraged to eat the 
full meal. If participants are unable to complete the entire meal, the approximate 
portion of the meal consumed will be documented. No food will be allowed for at 
least 2 hours post-dose.

The breakfast will be a high-calorie/high-fat test meal. The test meal should 
derive approximately 150, 250 and 500-600 calories from protein, carbohydrate 
and fat, respectively. The following breakfast as a representative example of a 
high-fat, high-calorie meal: 2 eggs fried in butter, 2 strips of bacon, 2 slices of 
toast with butter, 4 ounces of hash brown potatoes, 8 fluid ounces (240 mL) of 
whole milk.

Water can be allowed as desired except for 1 hour after investigational product 
administration. There are no water restrictions prior to dosing for participants
dosed under fed conditions. 
If dosed under standard meal condition in PART-2:
Morning dosing condition:
Following an overnight fast of at least 7 hours, participants should start a standard breakfast 
approximately 30 minutes prior to the morning administration of the investigational product. 
The breakfast will be consumed over approximately 20 minutes with investigational product 
administered within approximately 10 minutes after completion of the meal. Participants will 
be encouraged to eat the full standard breakfast. If participants are unable to complete the 
entire breakfast on PK profile assessment days (Days 1, 5 and 10), the approximate portion 
of the breakfast consumed will be documented. On non-PK days, it is not required to 
document the approximate portion of food consumed. No food will be allowed for at least 
2 hours post-dose.
Water can be allowed as desired except for 1 hour after investigational product 
administration on PK days. There are no water restrictions on non-PK days neither prior to 
dosing for participants dosed under fed conditions.
Afternoon and/or evening dosing condition:
A snack consisting of at least 400 kcal will be provided approximately 20 minutes before 
dosing in the afternoon and/or evening. The snacks will be consumed over approximately 
10 minutes with investigational product administered within approximately 10 minutes after 
completion of the snack. Participants will be encouraged to eat the full snack. There is no 
food restrictions on afternoon and/or evening dose(s).
There are no water restrictions on afternoon and/or evening dose(s) on PK days and on 
non-PK days.


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5.3.1.1. Dietary Fiber Supplementation (PART-4 and PART-5 only)
To help assure regularity in bowel movements, nutritional composition should include high
fiber content. This may include consumption of fiber capsules, at a frequency dictated by
investigator, starting with the evening meal (ie, approximately 8 or 9 hours post dose) on 
Day 1, for duration of inpatient stay to ensure at least 1 bowel movement per day.
If an individual participant has not experienced a bowel movement in the first 24 hours after
dosing water intake should be increased and prune juice should be offered on Day 2.
Despite these measures, if bowel movement does not occur regularly (ie, at least once daily 
bowel movement), consideration should be given to administration of mild laxative/stool 
softener (eg, milk of magnesia or docusate), at investigator’s discretion.
5.3.2. Caffeine, Alcohol, and Tobacco

Participants will abstain from caffeine containing products for 24 hours prior to the 
start of dosing of PF-07321332/placebo until collection of the final PK sample of 
each study period. 

Participants will abstain from alcohol for 24 hours prior (or as specified above for red 
wine) to admission to the CRU and continue abstaining from alcohol until collection 
of the final PK sample of each study period. Participants may undergo an alcohol 
breath test or blood alcohol test at the discretion of the investigator.

Participants will abstain from the use of tobacco or nicotine containing products for 
24 hours prior to dosing of PF-07321332/placebo and during confinement in the 
CRU. 
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.

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, 
respiratory rate and ECG measurements) for first 4 hours after morning dose, and 
may be required to follow meals and dietary restrictions as specified in Section 5.3.1.

PART-1 and PART-5 only: Participants will be confined to the procedure room for 
the first 4 hours after last PF-07321332/placebo dosing on Day 1 during continuous 
cardiac monitoring, except to use the bathroom. After this, if the equipment setup 
allows, participants may be ambulatory during the ECG monitoring period, but 
should not engage in strenuous activities. If equipment does not allow ambulation, 
appropriate accommodations will be made by the investigator site to facilitate 
continuous monitoring (eg, bedside urinals should be provided to accommodate 
participants’ excretory needs). 


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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 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). 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 randomly assigned to study intervention/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. 
6. STUDY INTERVENTION
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 all of the following:

PF-07321332;

Placebo for PF-07321332;

Ritonavir.
6.1. Study Intervention(s) Administered
PF-07321332 and placebo will be provided by Pfizer as bulk powders for extemporaneous 
preparation of oral suspensions at the CRU. 
PF-07321332 or placebo will be presented to the participants in individual dosing containers.
In addition, PF-07321332 and matching placebo may also be supplied as tablets. If provided, 
tablets will be supplied to the CRU in bulk along with individual dosing containers for unit 
dosing.


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Ritonavir 100 mg tablets will be supplied locally by the CRU.
6.1.1. Administration
Dosing of PF-07321332/placebo (placebo for PART-1 only) and ritonavir (if used) in 
PART-1 and PART-3
If dosed under fasted condition, participants will receive PF-07321332/placebo (placebo for 
PART-1 only) at approximately 08:00 hours (±2 hours) per the SoA following an overnight 
fast of at least 10h. In PART-1, if required, 3 doses of 100 mg ritonavir may be administered 
as a PK boosting agent as per SoA. At a time point when PF-07321332/placebo (placebo for 
PART-1 only) will be dosed with ritonavir (ie, at 0h), both PF-07321332/placebo (placebo 
for PART-1 only) and ritonavir will be dosed simultaneously (within no more than 5 minutes 
of each other). Participants will swallow ritonavir and PF-07321332/placebo (placebo for 
PART-1 only) tablets whole (if administered as tablet) and will not chew prior to 
swallowing. 
Investigator site personnel will administer with ambient temperature water to a total volume 
of approximately 240 mL. Study intervention will be administered according to the EDR.
If dosed under fed condition (standard meal or high-fat high-calorie meal), the 
PF-07321332/placebo (placebo for PART-1 only) should be administered approximately 
10 minutes after finishing the meal/snack (refer Section 5.3.1 for further details).
Dosing of PF-07321332/placebo and ritonavir (if used) in PART-2 
If dosed under fasted condition, participants will receive PF-07321332/placebo at 
approximately 08:00 hours (plus or minus 2 hours) per the SoA following an overnight fast 
of at least 7 hours. At least 2h of fast is required for afternoon and/or evening dosing for BID 
and TID dosing regimen. When dosed with ritonavir, both PF-07321332/placebo and 
ritonavir will be dosed simultaneously (within no more than 5 minutes of each other). 
Participants will swallow ritonavir and PF-07321332/placebo tablets whole (if administered 
as tablet) and will not chew prior to swallowing.
Investigator site personnel will administer with ambient temperature water to a total volume 
of approximately 240 mL. Study intervention will be administered according to the EDR.
If dosed under fed condition (meal/snack), the PF-07321332/placebo should be administered 
approximately 10 minutes after finishing the meal/snack (refer Section 5.3.1 for further 
details).
Dosing of PF-07321332 and ritonavir in PART-4
Participants will receive PF-07321332 and ritonavir at approximately 08:00 hours (±2 hours) 
per the SoA following an overnight fast of at least 10h. Participants will receive 4 doses of 
100 mg ritonavir as a PK boosting agent as per SoA. At a time point when PF-07321332 will 
be dosed with ritonavir (ie, at 0h), both PF-07321332 and ritonavir will be dosed


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simultaneously (within no more than 5 minutes of each other) in fasted state. Except when 
dosed with PF-07321332, ritonavir may be administered with or without food. Participants 
will swallow ritonavir tablets whole and will not chew prior to swallowing. 
Investigator site personnel will administer PF-07321332 oral suspension and ritonavir tablets 
with ambient temperature water to a total volume of approximately 240 mL. PF-07321332
oral suspension will be administered according to the EDR. 
Dosing of PF-07321332/placebo and ritonavir in PART-5
In this part, for each period, participants will receive split administrations (3 doses) of 
PF-07321332 or placebo at short intervals (within 2 h of the previous dose).
Participants will receive first split dose of PF-07321332/placebo oral suspension at 
approximately 08:00 hours (±2 hours) at least 2h after the morning breakfast per the SoA.
The second and third split doses will be administered at approximately 2h and 4h after the 
first dose, respectively. A total of 3 doses of 100 mg ritonavir tablet will be administered as a 
PK boosting agent as per SoA. At a time point when PF-07321332/placebo will be dosed 
with ritonavir (ie, at 0h), both PF-07321332/placebo and ritonavir will be dosed
simultaneously (within no more than 5 minutes of each other). Participants will swallow 
ritonavir tablets whole and will not chew prior to swallowing. 
Investigator site personnel will administer with ambient temperature water to a total volume 
of approximately 240 mL. PF-07321332/placebo will be administered according to the EDR. 


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Intervention Name
PF-07321332
Placebo
Ritonavir (if used)
ARM Name
(group of patients 
receiving a specific 
treatment (or no 
treatment)
PF-07321332 
Placebo 
NA
Type
Drug
Placebo
Boosting agent
Dose Formulation
Suspension or Tablet
Suspension or Tablet
Tablet
Unit Dose Strength(s)
Planned nominal unit 
doses strength for 
tablets: 25 mg, 100 mg, 
and 250 mg
0 mg
100 mg
Dosage Level(s)
Planned nominal unit
doses strength for 
tablets: 25 mg, 100 mg, 
and 250 mg
0 mg
100 mg
Route of 
Administration
Oral
Oral
Oral
Use
Experimental
Placebo
PK Boosting agent
IMP or NIMP
IMP
IMP
NIMP
Sourcing
Provided centrally by 
the sponsor
Provided centrally by 
the sponsor
Provided locally by the 
trial site, subsidiary, or 
designee
Packaging and Labeling
Materials (API and 
components) for 
extemporaneous prep of 
oral suspensions will be 
provided in bulk.
Tablets will be provided 
in bulk. PCRU staff will 
prepare individual doses 
for administration. 
Individual dose 
containers will be 
labeled by site staff per 
country requirement
Materials for 
extemporaneous prep of 
oral suspensions will be 
provided in bulk.
Tablets will be provided 
in bulk. PCRU staff will 
prepare individual doses 
for administration. 
Individual dose 
containers will be 
labeled by site staff per 
country requirement
PCRU will procure 
commercially labeled 
materials
Current/Former 
Name(s) or Alias(es)
PF-07321332
Placebo
Norvir® or other local 
commercialized product
6.2. Preparation/Handling/Storage/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 


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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 PCRU site procedures.
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.
6. See the EDR for storage conditions of the study intervention once prepared.
7. 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.
8. Further guidance and information for the final disposition of unused study 
interventions are provided in the PCRU’s site procedures. All destruction must be 
adequately documented. If destruction is authorized to take place at the investigator 
site, the investigator must ensure that the materials are destroyed in compliance with 
applicable environmental regulations, institutional policy, and any special instructions 
provided by Pfizer.
Upon identification of a product complaint, notify the sponsor within 1 business day of 
discovery.
6.2.1. Preparation and Dispensing
Within this protocol, preparation refers to the investigator site activities performed to make 
the study intervention ready for administration or dispensing to the participant by qualified 
staff. Dispensing is defined as the provision of study intervention, concomitant treatments, 
and accompanying information by qualified staff member(s) to a healthcare provider, 
participant in accordance with this protocol. Local health authority regulations or investigator 
site guidelines may use alternative terms for these activities.


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PF-07321332 and placebo oral dosing suspensions will be prepared in the CRU by 
2 operators, 1 of whom is a pharmacist. Details of dose preparation will be given in a 
separate EDR. Prepared doses will be provided in unit dose containers and labeled in 
accordance with Pfizer regulations and the investigator site’s labeling requirements.
PF-07321332 and placebo tablets, if used, will be dispensed 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 in unit dose 
containers and labeled in accordance with Pfizer regulations and the clinical site’s labeling 
requirements.
Ritonavir will be administered to the participant in an unblinded (open-label) fashion. 
Ritonavir tablets will be dispensed 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 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 will assign participant numbers to the participants as they are screened for 
the study. Pfizer will provide a randomization schedule to the investigator and, in accordance 
with the randomization numbers, the participant will receive the study treatment regimen 
assigned to the corresponding randomization number.
Investigators and participants will remain blinded to each participant’s assigned study 
intervention throughout the course of the study. In order to maintain this blind, an otherwise 
uninvolved third party (for example, pharmacist) will be responsible for the preparation and 
dispensing of all study intervention according to the randomization schedule and assigned 
treatment for the individual participant.
This third party will instruct the participant to avoid discussing the taste, or packaging of the 
study intervention with the investigator.
Blinding procedures do not apply to PART-3 and PART-4 of this study because it will be 
conducted as open-label. Where the design is open-label, 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.


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6.3.2. Breaking the Blind 
The method for breaking the blind in this study will be manual. In case of an emergency, the 
investigator has the sole responsibility for determining if unblinding of a participant’s 
treatment assignment is warranted. Participant safety must always be the first consideration 
in making such a determination. If the investigator decides that unblinding is warranted, the 
investigator should make every effort to contact the sponsor prior to unblinding a 
participant’s treatment assignment unless this could delay further management of the 
participant. If a participant’s treatment assignment is unblinded, the sponsor must be notified 
within 24 hours after breaking the blind. When the blinding code is broken, the reason must 
be fully documented in a CRF.
Blood specimens will be obtained from all participants for PK analysis to maintain the study 
blind at the investigator site. Only the investigator site staff and blinded study monitor, if 
assigned, will be blinded to study treatment. A limited number of Pfizer study team personnel 
will be unblinded to participant treatments in order to permit real-time interpretation of the 
safety and PK data; and provide information necessary to potentially alter the dose escalation 
sequence. The blinded study monitor, if assigned, will remain blinded to treatment until all 
monitoring for the study has been completed. Specimens from participants randomized to 
placebo will not be routinely analyzed. To minimize the potential for bias, treatment 
randomization information will be kept confidential by Pfizer unblinded personnel and will 
not be released to the blinded investigator or blinded investigator site personnel until the 
study database has been locked or the investigator requests unblinding for safety reasons.
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. 
Study site personnel will examine each participant’s mouth to ensure that the study 
intervention was ingested.
6.5. 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.
Females using hormonal contraceptives or taking hormone replacement therapy may be 
eligible to participate in this study if they are willing to discontinue therapy at least 28 days 
prior to the first dose of study treatment and remain off hormonal therapy for the duration of 
the study. Depo-Provera® must be discontinued at least 6 months prior to the first dose of 
study treatment. Hormonal contraceptives that meet the requirements of this study are 
allowed to be used in participants who are WOCBP (See Appendix 4).


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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.
6.5.1. Rescue Medicine 
There is no rescue therapy to reverse the AEs observed with study intervention; standard 
medical supportive care must be provided to manage the AEs. 
6.6. Dose Modification
Progression to the next dose in PART-1 will occur if the last dose was well tolerated and 
after satisfactory review of the available safety and PK data. Each dose escalation will be 
based on review of the safety data up to a minimum of 48-hours post dose plus PK 
assessments up to 6-hours post dose, in at least 3 actively treated participants and at least 
1 placebo-treated participant dosed in the previous dose-level. 
Progression to the next dose in PART-2 will occur if the last dose was well tolerated and 
after satisfactory review of the available safety and PK data. Each dose escalation will be 
based on review of the safety data up to a minimum of 6-days plus PK assessments up to 
6-hours post dose on Day 5, in at least 3 actively treated participants and at least 
1 placebo-treated participant dosed in the previous dose-level.
6.6.1. Dose Escalation and Stopping Rules 
Dose escalation stopping rules will be used to determine whether the maximal tolerated dose 
has been attained. Dose escalation may be stopped if it is determined that the limits of safety 
and/or tolerability have been reached. This decision will be made after a discussion takes 
place between the sponsor study team and the investigator. The sponsor study team may not 
overrule the investigator’s decision to stop dose escalation. If dose escalation is stopped 
because of any of these criteria, additional cohorts may receive the same or lower doses of 
the study intervention.
The dose escalation will be terminated based on the following criteria:

If 50% or more of the participants receiving active drug at a given dose level (but not 
participants receiving placebo) develop similar clinically significant laboratory, ECG, 
or vital sign abnormalities, in the same organ class, indicating dose-limiting 
intolerance.

Severe nonserious AEs, considered as, at least, possibly related to study intervention
administration, in 2 participants at a given dose level (but not participants receiving 
placebo), independent of within or not within the same system organ class, indicating 
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•
Dosing will be paused for any SAE that occurs in a participant receiving active 
treatment until causality is fully assessed by the PI and sponsor. Dosing may resume 
if the SAE is determined to be not drug-related by the PI and sponsor. If the SAE is 
determined to be either drug-related or unknown, either dosing will cease or the SAE 
will be evaluated by the sponsor’s protocol review committee (or similar review 
group), which is independent of the study team and investigators. If the protocol 
review committee determines that dosing may resume, a plan that mitigates risks to 
participants with the resumption of dosing will be implemented. Such a plan could 
include a revision of inclusion/exclusion criteria, repeating or reducing the dose, or 
adding appropriate safety monitoring.
•
It is determined that the limit of safety and/or tolerability has been reached. This 
decision will be made following discussions between the study team and the 
investigator.
•
Other findings that, at the discretion of the study team and investigator, indicate that 
dose escalation should be halted.
•
If, at any dose level, the average exposure reaches or exceeds the PK stopping limits, 
total plasma AUC (AUCinf in PART-1 and PART-5 and AUCtau in PART-2) and Cmax
of 
μg•h/mL and 
μg/mL.  
•
If, based on the observed data, the group mean Cmax or AUC (based on total plasma 
concentration) of the next planned dose is projected to exceed the escalation limits, 
that dose will not be explored. Modified doses may be explored if they are not 
expected to exceed PK stopping criteria.
Progression to the next dose will occur if the last dose was well tolerated and after 
satisfactory review of the available safety and PK data.
6.7. Intervention After the End of the Study
No intervention will be provided to study participants at the end of the study.
7. DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL
7.1. Discontinuation of Study Intervention
In rare instances, it may be necessary for a participant to permanently discontinue study 
intervention (definitive discontinuation). Reasons for definitive discontinuation of study 
intervention include the following 
•
AE requiring discontinuation in investigator’s view;
•
Pregnancy;
CCI
CCI


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
Positive COVID-19 test.
If study intervention is definitively discontinued, the participant will not remain in the study 
for further evaluation. See the SoA for data to be collected at the time of discontinuation of 
study intervention.
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.
ECG Changes 
A participant who meets either bulleted criteria based on the average of triplicate ECG 
readings will be withdrawn from the study intervention. 

QTc, QTcB, QTcF >500 msec.

Change from baseline: QTc >60 msec.
If a clinically significant finding is identified (including, but not limited to, changes from 
baseline in QTcF after enrollment), the investigator or qualified designee will determine if 
the participant can continue in the study and if any change in participant management is 
needed. This review of the ECG printed at the time of collection must be documented. Any 
new clinically relevant finding should be reported as an AE.
Potential Cases of Acute Kidney Injury
Abnormal values in SCr concurrent with presence or absence of increase in BUN that meet 
the criteria below, in the absence of other causes of kidney injury, are considered potential 
cases of acute kidney injury and should be considered important medical events. 
An increase of ≥0.3 mg/dL (or ≥26.5 µmol/L) in SCr level relative to the participant’s own 
baseline measurement should trigger another assessment of SCr as soon as practically 
feasible, preferably within 48 hours from awareness.
If the second assessment (after the first observations of ≥0.3 mg/dL [or ≥26.5 µmol/L] in SCr
relative to the participant’s own baseline measurement) is ≥0.4 mg/dL (or ≥35.4 µmol/L), the 
participant should be discontinued from the study and adequate, immediate, supportive 
measures taken to correct apparent acute kidney injury.
Participants should return to the investigator site and be evaluated as soon as possible, 
preferably within 48 hours from awareness of the second assessment confirming abnormal 
SCr result. This evaluation should include laboratory tests, detailed history, and physical 
assessment. In addition to repeating SCr, laboratory tests should include serum BUN, serum 
creatine kinase, and serum electrolytes (including at a minimum potassium, sodium, 


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phosphate/phosphorus, and calcium), in addition to urinary dipstick, urine microscopic 
examination, and urinary indices. All cases confirmed on repeat testing as meeting the 
laboratory criteria for acute kidney injury, with no other cause(s) of laboratory abnormalities 
identified, should be considered potential cases of drug-induced kidney injury irrespective of 
availability of all the results of the investigations performed to determine etiology of the 
abnormal SCr. If ≥2 healthy participants in a given period in PART-1 and 3 and in a 
treatment arm in PART-2 are noted to have 2 consecutive SCr results of ≥0.3 mg/dL (or 
≥26.5 µmol/L), an assessment of whether the finding may be considered an adverse drug 
reaction should be undertaken.
7.2. 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 follow-up;

Lost to follow-up;

Death;

Study terminated by sponsor;

Investigator’s decision;

Pregnancy.
At the time of discontinuing from the study, if possible, an early discontinuation visit should 
be conducted. See the SoA for assessments to be collected at the time of study 
discontinuation and follow-up and for any further evaluations that need to be completed. 
The early discontinuation visit applies only to participants who are enrolled/randomized and 
then are prematurely withdrawn from the study. Participants should be questioned regarding 
their reason for withdrawal. 
The participant will be permanently discontinued both from the study intervention and from 
the study at that time.
If a participant withdraws from the study, he/she may request destruction of any remaining 
samples taken and not tested, and the investigator must document any such requests in the 
site study records and notify the sponsor accordingly.
If the participant withdraws from the study and also withdraws consent (see Section 7.2.1) 
for disclosure of future information, no further evaluations should be performed and no 
additional data should be collected. The sponsor may retain and continue to use any data 
collected before such withdrawal of consent.


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Lack of completion of all or any of the withdrawal/early termination procedures will not be 
viewed as protocol deviations so long as the participant’s safety was preserved.
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 and counsel the participant on the importance of maintaining the 
assigned visit schedule and ascertain whether or not 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. 
Study procedures and their timing are summarized in the SoA. Protocol waivers or 
exemptions are not allowed.


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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.
A participant who qualified for this protocol but did not enroll from an earlier cohort/group 
may be used in a subsequent cohort/group without rescreening, provided laboratory results 
obtained prior to the first dose administration meet eligibility criteria for this study. In 
addition, other clinical assessments or specimen collections, eg, banked biospecimens, may 
be used without repeat collection, as appropriate.
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 may be up to
approximately 480 mL, 290 mL, 160 mL, 205 mL and 485 mL in PART-1, PART-2,
PART-3, PART-4 and PART-5, respectively. 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.


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To prepare for study participation, participants will be instructed on the information in the 
Lifestyle Considerations and Concomitant Therapy sections of the protocol.
8.1. Efficacy Assessments
No efficacy assessment is planned in this study.
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. 
8.2.2. Vital Signs
Supine 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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8.2.2.1. Respiratory Rate
Respiratory rate will be measured after approximately 5 minutes of rest in a supine position 
by observing and counting the respirations of the participant for 30 seconds and multiplying
by 2. When BP is to be taken at the same time, respiration measurement will be done during
the 5 minutes of rest and before BP measurement.
8.2.2.2. Temperature
Temperature will be measured orally.  No eating, drinking, or smoking is allowed for 
15 minutes prior to the measurement.
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) is not 
recommended 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 10 minutes in a supine position. 
In PART-1 and PART-5, triplicate 12-lead ECGs will be obtained approximately 2 to 
4 minutes apart; the average of the triplicate ECG measurements collected before dose 
administration on Day 1 of each period will serve as each participant’s baseline QTc value. 
In PART-2, triplicate 12-lead ECGs will be obtained approximately 2 to 4 minutes apart; the 
average of the triplicate ECG measurements collected at each nominal time point on Day 1 in 
MAD cohorts will serve as each participant’s time-controlled baseline QTc value. 
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) the mean 
value from the triplicate measurements for any postdose QTcF interval is increased by 
≥60 msec from the baseline and is >450 msec; or b) an absolute QTcF value is ≥500 msec 
for any scheduled ECG. If either of these conditions occurs, then a single ECG measurement 
must be repeated at least hourly until QTcF values from 2 successive ECGs fall below the 
threshold value that triggered the repeat measurement.
For PART-3 and PART-4 only (when Single ECGs are conducted): 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 QTc interval 
is increased by ≥60 msec from the baseline and is >450 msec; or b) an absolute QTc 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.


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If a) a postdose QTc interval remains ≥60 msec from the baseline and is >450 msec; or b) an 
absolute QTc value is ≥500 msec for any scheduled ECG for greater than 4 hours (or sooner, 
at the discretion of the investigator); or c) QTc intervals get progressively longer, the 
participant should undergo continuous ECG monitoring. A cardiologist should be consulted 
if QTc intervals do not return to less than the criterion 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 QTc values are in the 
acceptable range.
ECG values of potential clinical concern are listed in Appendix 7.
8.2.3.1. Continuous Cardiac Monitoring by Telemetry (PART-1 and PART-5 only)
All abnormal rhythms will be recorded and reviewed by the study physician for the presence 
of rhythms of potential clinical concern. The time, duration, and description of the clinically 
significant event will be recorded in the CRF. In addition, a printed record of the tracing(s) of 
the clinically significant rhythm(s) will be made and retained with other source documents.
Telemetry should be collected using a centralized system that also allows for the storage and 
advanced analysis of all recorded data in order to preserve important events for future 
evaluations. Holter monitoring should not be used in parallel with continuous telemetry, 
unless it is the only means of data storage available at the investigator site, or verifiable 
arrhythmia quantification is required. To establish a baseline, telemetry should be recorded 
for at least 2 hours before dosing in Period 1. This may be done immediately prior to dosing 
or at some 2-hour continuous interval in the 24 hours prior to dosing, as long as the recording 
is performed when the participant is awake. Telemetry may be stopped within a reasonably 
short period of time prior to dosing, in order to avoid interference with study operations 
conducted immediately before dosing. However, it is expected that the telemetry leads will 
be in place and the system connected prior to dosing.
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. 
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 


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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 48h 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.
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. 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 treatment. 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 discharge. Pregnancy tests may also be repeated if 
requested by IRBs/ECs or if required by local regulations.
8.3. Adverse Events and Serious Adverse Events
The definitions of an AE and an SAE can be found in Appendix 3.
AEs will be reported by the participant (or, when appropriate, by a caregiver, surrogate, or 
the participant's legally authorized representative).
The investigator and any qualified designees are responsible for detecting, documenting, and 
recording events that meet the definition of an AE or SAE and remain responsible to pursue 
and obtain adequate information both to determine the outcome and to assess whether the 
event meets the criteria for classification as an SAE or caused the participant to discontinue 
the study intervention (see Section 7.1). 
Each participant will be questioned about the occurrence of AEs in a nonleading manner.
In addition, the investigator may be requested by Pfizer Safety to obtain specific follow-up 
information in an expedited fashion.


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8.3.1. 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 and Pfizer concurs with that assessment.
For participants who are screen failures, the active collection period ends when screen failure 
status is determined.
If the participant withdraws from the study and also withdraws consent for the collection of 
future information, the active collection period ends when consent is withdrawn.
If a participant definitively discontinues or temporarily discontinues study intervention 
because of an AE or SAE, the AE or SAE must be recorded on the CRF and the SAE 
reported using the CT SAE Report Form.
Investigators are not obligated to actively seek AE or SAE 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.
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.


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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/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 towards the safety of participants and the safety of a 
study intervention under clinical investigation are met.
The sponsor has a legal responsibility to notify both the local regulatory authority and other 
regulatory agencies about the safety of a study intervention under clinical investigation. The 
sponsor will comply with country-specific regulatory requirements relating to safety 
reporting to the regulatory authority, IRBs/ECs, and investigators.
Investigator safety reports must be prepared for SUSARs according to local regulatory 
requirements and sponsor policy and forwarded to investigators as necessary.
An investigator who receives SUSARs or other specific safety information (eg, summary or 
listing of SAEs) from the sponsor will review and then file it along with the SRSD(s) for the 
study and will notify the IRB/EC, if appropriate according to local requirements.
8.3.5. Exposure During Pregnancy or Breastfeeding, and Occupational Exposure
Exposure to the study intervention under study during pregnancy or breastfeeding and 
occupational exposure are reportable to Pfizer Safety within 24 hours of investigator 
awareness.


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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 exposure during pregnancy: 

A female family member or healthcare provider reports that she is pregnant after 
having been exposed to the study intervention by ingestion, inhalation, or skin 
contact.

A male family member or healthcare provider who has been exposed to the study 
intervention by ingestion, inhalation, or skin contact then 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 
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).


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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.
8.3.5.2. Exposure During Breastfeeding
An exposure during breastfeeding occurs if: 

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, inhalation or skin contact. 
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.


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8.3.5.3. Occupational Exposure
An occupational exposure occurs when a person receives unplanned direct contact with the 
study intervention, which may or may not lead to the occurrence of an AE. Such persons may 
include healthcare providers, family members, and other roles that are involved in the trial 
participant’s care.
The investigator must report occupational exposure to Pfizer Safety within 24 hours of the 
investigator’s awareness regardless of whether there is an associated SAE. The information 
must be reported using the CT SAE Report Form. Since the information 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 is 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
All AESIs must be reported as an AE or SAE following the procedures described in 
Section 8.3.1 through Section 8.3.4. An AESI is to be recorded as an AE or SAE on the CRF. 
In addition, an AESI that is also an SAE must be reported using the CT SAE Report Form.
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.


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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. Treatment of Overdose
For this study, any dose of PF-07321332 greater than 3000 mg within a 24-hour [-2 hour]
time period will be considered an overdose.
Sponsor does not recommend 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 study intervention 
(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 Safety only when associated with an SAE.


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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). 
Decisions regarding dose interruptions or modifications will be made by the investigator in 
consultation with the medical monitor based on the clinical evaluation of the participant.
8.5. Pharmacokinetics 
8.5.1. Plasma for Analysis of PF-07321332 PK, 19F-NMR measurement and Metabolic 
Profiling
Blood samples of approximately 4 mL, to provide approximately 1.5 mL of plasma, will be 
collected for measurement of plasma concentrations of PF-07321332 as specified in the SoA. 
In PART-2 MAD portion of the study conducted at NH CRU only, exploratory 
microsampling PK blood samples for the measurement of PF-07321332 concentrations may 
be collected in order to evaluate one or more approach(es). Total blood volume for 
exploratory microsampling PK will not exceed 0.4 mL at each time point specified in the 
SoA. In Cohort 1, Period 2 in PART-1 and PART-2 of the study, blood samples of 
approximately 6 mL, to provide a minimum of 2 mL of plasma, may be collected for 
19F-NMR measurement of drug related materials and/or metabolic profiling as specified in 
the SoA. In PART-4, 10 mL blood samples will be collected for metabolite identification as 
specified in the SoA. Instructions for the collection and handling of biological samples will 
be provided in the laboratory manual or by the sponsor. The actual date and time (24-hour 
clock time) of each sample will be recorded.
The actual times may change, but the number of samples will remain the same. All efforts 
will be made to obtain the samples at the exact nominal time relative to dosing. Collection of 
samples up to and including 10 hours after dose administration that are obtained within 
10% of the nominal time relative to dosing (eg, within 6 minutes of a 60-minute sample) will 
not be captured as a protocol deviation, as long as the exact time of the collection is noted on 
the source document and the CRF. Collection of samples more than 10 hours after dose
administration that are obtained ≤1 hour away from the nominal time relative to dosing will 
not be captured as a protocol deviation, as long as the exact time of the collection is noted on 
the source document and the CRF.
Samples collected for analyses of PF-07321332 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, or for the measurement of 
ritonavir or for other internal exploratory purposes.
Genetic analyses will not be performed on these plasma samples unless consent for this was 
included in the informed consent. Participant confidentiality will be maintained.
Samples collected for measurement of plasma concentrations of PF-07321332 will be 
analyzed using a validated analytical method in compliance with applicable SOPs. Samples 
collected for exploratory PK may be analyzed with either validated or qualified methods. 


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This exploratory data will not be included in the clinical study report. 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.
Drug concentration information that would unblind the study will not be reported to 
investigator sites or blinded personnel until the respective cohort of study has been 
unblinded.
Any changes in the timing or addition of time points for any planned study assessments must 
be documented and approved by the relevant study team member and then archived in the 
sponsor and site study files, but will not constitute a protocol amendment. The IRB/EC will 
be informed of any safety issues that require alteration of the safety monitoring scheme or 
amendment of the ICD.
8.5.2. Urine Pharmacokinetics (PART-2 only)
Urine samples will be collected for an interval as specified in the SoA and mixed thoroughly 
and the total volume will be measured and recorded on the CRF. An aliquot of 5 mL will be 
collected for the measurement of urine concentrations of PF-07321332. 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 start and end of each collection 
interval will be recorded.
The urine blank (approximately 5 mL) for PK will be obtained prior to dosing.
Samples collected for measurement of urine 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.
Drug concentration information that would unblind the study will not be reported to 
investigator sites or blinded personnel until the respective cohort of the study has been 
unblinded.


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Any changes in the timing or addition of time points for any planned study assessments must 
be documented and approved by the relevant study team member and then archived in the 
sponsor and site study files, but will not constitute a protocol amendment. The IRB/EC will 
be informed of any safety issues that require alteration of the safety monitoring scheme or 
amendment of the ICD.
As part of understanding the pharmacokinetics of the study drug, samples may be used for 
metabolite identification and/or evaluation of the bioanalytical method. These data will be 
used for internal exploratory purposes and will not be included in the CSR. 
8.5.3. Urine and Feces for Measurement of Drug-Related Material by 19F-NMR and 
Metabolic Profiling (PART-1: Cohort-1, Period 2 only)
Urine will be collected in Cohort 1, Period 2 of PART-1 for determination of total drug 
related material by 19F-NMR spectroscopy and metabolite profiling as specified in the SoA. 
The participants will force void before oral dosing. Prior to dosing on Day 1 (within 
24 hours), each participant must empty his urinary bladder; an aliquot from this urine will 
serve as the “urine blank”. The details regarding the collection, processing, storage and 
shipping of the urine samples will be provided in the lab manual and supporting 
documentation. 
Feces will be collected for determination of total drug related material by 19F-NMR 
spectroscopy and metabolite profiling as specified in the SoA. If possible, a pre-dose fecal 
sample within 48 hours prior to dosing should be collected.
Details of the collection of aliquots, volume, processing, storage and shipping of the urine 
and feces samples will be provided in the lab manual and supporting documentation. The 
actual date and time (24-hour clock time) of each sample will be recorded.
At the discretion of the Sponsor, one or more assessments on urine and feces may not be 
conducted if deemed unnecessary by the Sponsor.  
8.5.4. Urine and Feces for Measurement of Drug-Related Material and Metabolic 
Profiling (PART-4 only)
Urine will be collected in PART-4 for determination of total drug-related material and 
metabolite profiling as specified in the SoA. The participants will force void before oral 
dosing. Prior to dosing on Day 1 (within 24 hours), each participant must empty his urinary 
bladder; an aliquot from this urine will serve as the “urine blank”. The details regarding the 
collection, processing, storage and shipping of the urine samples will be provided in the lab 
manual and supporting documentation. 
Feces will be collected for determination of total drug-related material and metabolite 
profiling as specified in the SoA. A pre-dose fecal sample within 48 hours prior to 
PF-07321332 dosing is required before dosing drug.


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Details of the collection of aliquots, volume, processing, storage and shipping of the urine 
and feces samples will be provided in the lab manual and supporting documentation. The 
actual date and time (24-hour clock time) of each sample will be recorded.
At the discretion of the Sponsor, one or more assessments on urine and feces may not be 
conducted if deemed unnecessary by the Sponsor.  
8.6. Pharmacodynamics
Pharmacodynamic parameters are not evaluated in this study.
 
 
 
 
 
 
 
 
 
 
 
CCI
CCI


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8.9. Immunogenicity Assessments
Immunogenicity assessments are not included in this study.
8.10. 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
There are no statistical hypotheses for this study.
9.2. Sample Size Determination
A total of up to 78 participants (12 in PART-1: SAD, up to 30 [with 2 cohorts and 3 optional 
cohorts] in PART-2: MAD, a maximum of 18 in PART-3: Relative Bioavailability/Food 
Effect cohort,6 in PART-4: metabolism and excretion and up to 12 in PART-5: 
Supratherapeutic Exposure) are planned to be randomized in this study. Participants who 
discontinue for reasons other than safety during the study may be replaced at the discretion of 
the sponsor and Investigator.
9.2.1. PART-1: SAD
A sample size of 6 participants per cohort for this single, dose-escalating, 4-period 
cross-over, with placebo substitution study (4 active, 2 placebo per dose level) has been 
chosen based on the need to minimize first exposure of healthy participants to a new 
chemical entity and the requirement to provide adequate safety and toleration information
and PK information at each dose level.
CCI


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9.2.2. PART-2: MAD
A sample size of 6 participants per cohort, with 4 participants randomized to PF-07321332 
plus 2 participants to placebo per cohort, has been selected as a compromise between the 
need to minimize exposure to PF-07321332 and the need to have sufficient participants 
randomized to provide adequate safety and toleration information and PK. 
This sample size has been judged sufficient to obtain a preliminary evaluation of safety, 
tolerability, and PK data in these populations.
9.2.3. PART-3: Relative Bioavailability/Food Effect
A sample size of up to 18 participants will provide adequate precision to compare the relative 
bioavailability of a tablet formulation of PF-07321332 relative to oral suspension. This 
sample size assumes that the within-participant SD for log-transformed PK parameters would 
not increase beyond approximately 0.3. The expected widths of the 90% CIs with 
80% coverage probability for the comparison of tablet formulation of PF-07321332 relative 
to oral suspension are shown in Table 11 for a range of possible effects. The sample size 
ultimately decided for Relative Bioavailability, by the sponsor, will depend on observed 
variability in plasma PK observed in PART-1: SAD.
Table 11.
Probable 90% CI with 80% coverage probability for Varying SDs, Effect 
Sizes and Sample Sizes – in PART-3: Relative Bioavailability
Effect Size
SD = 0.2
SD = 0.3
N = 12
N = 18
N = 12
N = 18
0.75
0.64 – 0.88
0.66 – 0.85
0.59 – 0.95
0.62 – 0.90
1.0
0.85 – 1.17
0.88 – 1.13
0.79 – 1.27
0.83 – 1.20
1.25
1.07 – 1.46
1.10 – 1.41
0.99 – 1.58
1.04 – 1.51
9.2.4. PART-4: Metabolism and Excretion
A sample size of approximately 6 participants (with at least 4 completers) is chosen based on 
the industry standard sample size for metabolism and excretion studies. This sample size was 
not justified by any empirical data or hypothesis testing criteria.
9.2.5. PART-5: Supratherapeutic Exposures
A sample size of up to 12 participants (with at least 10 completers) is chosen based on the 
need to provide adequate safety, tolerability and PK information at each dose level and/or 
administration schedule. At the discretion of the sponsor and investigator, participant who 
were enrolled in PART-2 may be enrolled in PART-5.  


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9.3. Analysis Sets
For purposes of analysis, the following analysis sets are defined:
Participant Analysis Set
Description
Enrolled/Randomly 
assigned to study 
intervention
"Enrolled" means a participant's, agreement to participate in a 
clinical study following completion of the informed consent 
process. 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.
Evaluable
All participants randomly assigned to study intervention and 
who take at least 1 dose of study intervention for the given 
part of the study.
Safety
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.
PK Concentration Set
All participants randomly assigned to study intervention and 
who take at least 1 dose of study intervention and in whom at 
least 1 concentration value is reported for the given part of the 
study.
PK Parameter Set
All participants randomly assigned to study intervention and 
who take at least 1 dose of study intervention and in whom at 
least 1 of the PK parameters of interest are reported for the 
given part of the study.
Excretion analysis set
In PART-4, excretion analysis population will be defined by 
evaluable participants who have received 1 dose of 
PF-07321332 and who have completed drug related material
concentration (urinary and fecal) data and who had no 
protocol deviations that may have affected the mass balance 
analysis.
9.4. Statistical Analyses
The SAP will be developed and finalized before any analyses are performed and will 
describe the analyses and procedures for accounting for missing, unused, and spurious data. 
This section is a summary of the planned statistical analyses of the primary and secondary 
endpoints.
9.4.1. General Considerations
The data from each part of the study will be analyzed and reported separately in a single CSR 
issued at the end of this study. 


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9.4.2. Primary Endpoint(s)
The primary endpoints in PART-1,PART-2 and PART-5 are related to safety/tolerability 
with analyses as described in Section 9.4.5. 
The primary endpoints in PART-3 are the plasma PK endpoints whose analyses are described 
in Sections 9.4.3.1 and 9.4.3.2.
The primary endpoints in PART-4 are percent recovery and cumulative recovery of 
drug-related material in urine, feces determined based on total administered dose. Percent 
recovery of drug-related material in urine and feces will be determined based on total 
administered dose. The total recovery of drug-related material in urine and feces and their 
combination will be listed and summarized. 
9.4.3. Secondary Endpoint(s)
The secondary endpoints in PART-1,  PART-2 and PART-5 as well as the primary endpoints 
in PART-3 related to PK are described herein. 
9.4.3.1. PK Analysis
9.4.3.1.1. Derivation of PK Parameters
Plasma PK parameters for PF‑0732332 will be derived (if data permit) from the 
concentration-time data using standard noncompartmental methods following a single oral 
dose (Table 12) and multiple oral doses (Table 13). Urine PF‑07321332 PK parameters are 
described in Table 13. 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 12.
Plasma PF‑07321332 PK Parameters For PART-1: Single Ascending 
Doses, PART-3: Relative Bioavailability/Food Effect, PART-4: 
Metabolism and Excretion and PART-5: Supratherapeutic Exposure
Parameter
Part of The 
Study
Definition
Method of Determination
AUClastb
1, 3, 5
Area under the concentration-time 
curve from time zero to the time of the 
last quantifiable concentration (Clast)
Linear/Log trapezoidal method
AUCinfa
1, 3, 5
Area under the concentration-time 
curve from time zero extrapolated to 
infinity
AUClast + (Clast*/kel),
where Clast* is the predicted 
plasma concentration at the last 
quantifiable time point from the 
log-linear regression analysis
Cmax
1, 3, 5
Maximum plasma concentration
Observed directly from data
Tmax
1, 3, 5
Time for Cmax
Observed directly from data as 
time of first occurrence
t½a
1, 3, 5
Terminal half-life
Loge(2)/kel, 


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where kel is the terminal phase 
rate constant calculated by a 
linear regression of the log-linear 
concentration-time curve. Only 
those data points judged to 
describe the terminal log-linear 
decline are used in the regression.
CL/Fa
1, 3
Apparent clearance
Dose/AUCinf
Vz/Fa
1, 3
Apparent volume of distribution
Dose/(AUCinf • kel)
AUClast(dn)
1, 3
Dose normalized AUClast
AUClast/Dose
AUCinf(dn)a
1, 3
Dose normalized AUCinf
AUCinf/Dose
Cmax(dn)
1, 3
Dose normalized Cmax
Cmax/Dose
a.
If data permit.
b.
In PART-3, pre-dose (0h) sample from Periods 2 and 3 will also be considered as 48h PK sample for 
Periods 1 and 2, respectively. 
dn=dose normalized to a 1 mg dose.


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Table 13.
Plasma and Urine PF‑07321332 PK Parameters for PART-2: Multiple 
Ascending Doses
Parameter
Day(s)
Definition
Method of Determination
Plasma
AUCτ
1, 5, 10
Area under the plasma concentration-
time profile from time zero to time tau 
(τ), the dosing interval, where τ = 8 for 
TID dosing or 12 hours for BID dosing
Linear/Log trapezoidal method
Cmax
1, 5, 10
Maximum plasma concentration during 
the dosing interval
Observed directly from data
Tmax
1, 5, 10
Time for Cmax
Observed directly from data as time of 
first occurrence
Cmin
5, 10
Minimum observed concentration 
during the dosing interval
Observed directly from data
PTR
5, 10
Peak-to-trough ratio
Cmax/Cmin
Rac
5, 10
Observed accumulation ratio for AUCτ
Day 5 or Day 10 AUCτ/Day 1 AUCτ
Rac,Cmax
5, 10
Observed accumulation ratio for Cmax
Day 5 or Day 10 Cmax/Day 1 Cmax
CL/F
5, 10
Apparent clearance
Dose/AUCτ
t½a
10
Terminal half-life
Loge(2)/kel, 
where kel is the terminal phase rate 
constant calculated by a linear 
regression of the log-linear 
concentration-time curve. Only those 
data points judged to describe the 
terminal log-linear decline are used in 
the regression
Vz/Fa
10
Apparent volume of distribution
Dose/(AUCτ • kel)
AUCτ(dn)
1, 5, 10
Dose normalized AUCτ
AUCτ/Dose
Cmax(dn)
1, 5, 10
Dose normalized Cmax
Cmax/Dose
Urine
Aeτ
10
Amount excreted in urine as unchanged 
drug over the dosing interval τ
Sum of (urine volume × urine 
concentration) for each collection over 
the dosing interval 
Aeτ%
10
Percent of dose excreted in urine as 
unchanged drug over the dosing interval 
τ
100 * Aeτ/Dose
CLr
10
Renal clearance
Aeτ/AUCτ
a.
If data permit.
dn=dose normalized to a 1 mg dose.
9.4.3.2. Statistical Methods for PK Data
No formal inferential statistics will be applied to the plasma PK data apart from the 
comparisons of formulation and food effect in either Part 1 or Part 3.


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For all parts of the study, plasma concentrations will be listed and summarized descriptively 
by PK sampling time and treatment. Individual participant and median profiles of the 
concentration-time data will be plotted by treatment. For summary statistics and median 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 for plasma samples. Median profiles will 
be presented on both linear-linear and log-linear scales.
The plasma PK parameters listed in Table 12 and Table 13 will be summarized descriptively 
by dose.
For PART-1,PART-2 and PART-5, dose normalized (to 1 mg) AUCinf or AUCtau and Cmax of 
PF-07321332 will be plotted against dose (using a logarithmic scale) and will include 
individual participant values as well as the geometric means for each dose. These plots may
be used to help understand the relationship between the PK parameters and dose. 
For PART-2, urine amounts as listed in Table 13 of PF-07321332 will be listed and 
summarized descriptively, if data permit.
For PART-3, natural log transformed AUClast, Cmax, and AUCinf (if data permit) for 
PF-07321332 will be analyzed using a mixed effect model with sequence, period, and 
treatment included as fixed effects and participant nested within sequence as a random effect.
Estimates of the adjusted mean differences (Test-Reference) and corresponding 90% CIs will 
be obtained from the model. The adjusted mean differences and 90% CIs for the differences 
will be exponentiated to provide estimates of the ratio of adjusted geometric means
(Test/Reference) and 90% CIs for the ratios.
The following comparisons will be made:
Comparison
Test
Reference
Formulation
PF-07321332 tablet formulation in fasted 
state (B)
PF-07321332 oral suspension in fasted state (A)
Food Effect
PF-07321332 tablet formulation in fed 
(high fat meal) state (C)
PF-07321332 tablet formulation in fasted state (B)
Additional specifications about the tables, listings, and figures will be outlined in the SAP.
9.4.4. Tertiary/Exploratory Endpoint(s)
Exploratory endpoints may not be reported in the CSR and may be reported separately.  
9.4.5. Safety Analyses
9.4.5.1. Standard Safety Analyses
In this study, assessment of safety and tolerability following single- and multiple-ascending 
doses forms the primary objective for PART-1,PART-2 and PART-5. In all 5 parts of the 
study, all safety analyses will be performed on the Safety Analysis Set.


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All AEs, ECGs, BP, pulse rate, continuous cardiac monitoring, 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 PE and neurological examination information, as applicable, collected 
during the course of the study will be considered source data and will not be required to be 
reported, unless otherwise noted. However, any untoward findings identified on physical 
and/or neurological examinations conducted during the active collection period will be 
captured as AEs, if those findings meet the definition of an AE. Data collected at screening 
that are used for inclusion/exclusion criteria, such as laboratory data, ECGs, and vital signs, 
will be considered source data, and will not be required to be reported, unless otherwise 
noted. Demographic data collected at screening will be reported.
9.4.5.2. Electrocardiogram Analyses
Changes from baseline for the ECG parameters QT interval, heart rate, QTcF interval, PR 
interval, and QRS complex will be summarized by treatment and time.
The number (%) of participants with maximum post dose QTcF values and maximum 
increases from baseline in the categories outlined in Table 14 will be tabulated by treatment.
Table 14.
Safety QTcF Assessment
Degree of Prolongation
Mild (msec)
Moderate (msec)
Severe (msec)
Absolute value
>450-480
>480-500
>500
Increase from baseline
30-60
>60
 
 
 
 
 
 
 
 
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9.5. Interim Analyses
No formal interim analysis will be conducted for this study. As this is a sponsor-open study, 
the sponsor will conduct unblinded reviews of the data during the course of the study for the 
purpose of safety assessment, facilitating dose escalation decisions, facilitating PK modeling, 
and/or supporting clinical development. Unblinded results will be reviewed by a designated 
limited number of sponsor colleagues within the study team.
9.6. Data Monitoring Committee or Other Independent Oversight Committee
This study will not use a DMC.


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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 and 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.
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 guidelines, the IRB/EC, European regulation 536/2014 
for clinical studies (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.  
In addition, the investigator will inform Pfizer immediately of any urgent safety measures 
taken by the investigator to protect the study participants against any immediate hazard, and 
of any serious breaches of this protocol or of ICH GCP that the investigator becomes aware 
of.


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10.1.2. Informed Consent Process
The investigator or his/her representative will explain the nature of the study 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, HIPAA 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 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.
A copy of the ICD(s) must be provided to the participant.
A participant who is rescreened is not required to sign another ICD if the rescreening occurs 
within 10 days from the previous ICD signature date.
For NH CRU only: unless prohibited by local requirements or IRB/EC decision, the ICD
will contain a separate section that addresses the use of samples for optional additional
research. The optional additional research does not require the collection of any further 
samples. The investigator or authorized designee will explain to each participant the 
objectives of the additional research. Participants will be told that they are free to refuse to 
participate and may withdraw their consent at any time and for any reason during the storage 


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period. A separate signature will be required to document a participant's agreement to allow 
specimens to be used for additional research. Participants who decline to participate in this 
optional additional research will not provide this separate signature.
10.1.3. Data Protection
All parties will comply with all applicable laws, including laws regarding the implementation 
of organizational and technical measures to ensure protection of participant data.
Participants’ personal data will be stored at the study site in encrypted electronic and/or paper 
form and will be password protected or secured in a locked room to ensure that only 
authorized study staff have access. The study site will implement appropriate technical and 
organizational measures to ensure that the personal data can be recovered in the event of 
disaster. In the event of a potential personal data breach, the study site will be responsible for 
determining whether a personal data breach has in fact occurred and, if so, providing breach 
notifications as required by law.
To protect the rights and freedoms of participants with regard to the processing of personal 
data, participants will be assigned a single, participant-specific numerical code. Any 
participant records or data sets that are transferred to the sponsor will contain the numerical 
code; participant names will not be transferred. All other identifiable data transferred to the 
sponsor will be identified by this single, participant-specific code. The study site will 
maintain a confidential list of participants who participated in the study, linking each 
participant’s numerical code to his or her actual identity and medical record identification. 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.
10.1.4. 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, 
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.


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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 available data from these trials 
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.
10.1.5. 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.
The investigator must maintain accurate documentation (source data) that supports the 
information entered in the CRF.


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The investigator must ensure that the CRFs are securely stored at the study site in encrypted 
electronic and/or paper form and are password protected or secured in a locked room to 
prevent access by unauthorized third parties.
The investigator must permit study-related monitoring, audits, IRB/EC review, and 
regulatory agency inspections and provide direct access to source data documents. This 
verification may also occur after study completion. It is important that the investigator(s) and 
their relevant personnel are available during the monitoring visits and possible audits or 
inspections and that sufficient time is devoted to the process.
Monitoring details describing strategy (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, remote, or on-site monitoring), are provided in the IQMP.
The sponsor or designee is responsible for the data management of this study, including 
quality checking of the data.
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, and all applicable regulatory requirements.
Records and documents, including signed ICDs, pertaining to the conduct of this study must 
be retained by the investigator for 15 years after study completion unless local regulations or 
institutional policies require a longer retention period. No records may be destroyed during 
the retention period without the written approval of the sponsor. No records may be 
transferred to another location or party without written notification to the sponsor. The 
investigator must ensure that the records continue to be stored securely for as long as they are 
maintained.
When participant data are to be deleted, the investigator will ensure that all copies of such 
data are promptly and irrevocably deleted from all systems.
The investigator(s) will notify the sponsor or its agents immediately of any regulatory 
inspection notification in relation to the study. Furthermore, the investigator will cooperate 
with the sponsor or its agents to prepare the investigator site for the inspection and will allow 
the sponsor or its agent, whenever feasible, to be present during the inspection. The 
investigator site and investigator will promptly resolve any discrepancies that are identified 
between the study data and the participant's medical records. The investigator will promptly 
provide copies of the inspection findings to the sponsor or its agent. Before response 
submission to the regulatory authorities, the investigator will provide the sponsor or its 
agents with an opportunity to review and comment on responses to any such findings.


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10.1.6. Source Documents
Source documents provide evidence for the existence of the participant and substantiate the 
integrity of the data collected. Source documents are filed at the investigator site.
Data reported on the CRF or entered in the eCRF that are from source documents must be 
consistent with the source documents or the discrepancies must be explained. The 
investigator may need to request previous medical records or transfer records, depending on 
the study. Also, current medical records must be available.
Definition of what constitutes source data can be found in source document locator.
Description of the use of computerized system is documented in source document locator.
10.1.7. 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 if 
requested to do so by the responsible IRB/EC or if such termination is required to protect the 
health of study participants.
Reasons for the early closure of a study site by the sponsor may include but are not limited 
to:

Failure of the investigator to comply with the protocol, the requirements of the 
IRB/EC or local health authorities, the sponsor's procedures, or 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.


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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.
10.1.8. 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. 
If publication is addressed in the clinical study agreement, the publication policy set out in 
this section will not apply.
10.1.9. 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 CTMS. 
To facilitate access to appropriately qualified medical personnel on study-related medical 
questions or problems, participants are provided with a contact card at the time of informed 
consent. The contact card contains, at a minimum, protocol and study intervention identifiers, 
participant numbers, contact information for the investigator site, and contact details for a 
contact center in the event that the investigator site staff cannot be reached to provide advice 
on a medical question or problem originating from another healthcare professional not 
involved in the participant’s participation in the study. The contact number can also be used 
by investigator staff if they are seeking advice on medical questions or problems; however, it 


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should be used only in the event that the established communication pathways between the 
investigator site and the study team are not available. It is therefore intended to augment, but 
not replace, the established communication pathways between the investigator site and the 
study team for advice on medical questions or problems that may arise during the study. For 
sites other than a Pfizer CRU, the contact number is not intended for use by the participant
directly, and if a participant calls that number, 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 15.
Protocol -Required Safety Laboratory Assessments
Hematology
Chemistry
Urinalysis
Other
Hemoglobin
Hematocrit
RBC count
MCV
MCH
MCHC
Platelet count
WBC count
Total neutrophils (Abs)
Eosinophils (Abs)
Monocytes (Abs)
Basophils (Abs)
Lymphocytes (Abs)
BUN and creatinine
Glucose (fasting)
Calcium
Sodium
Potassium
Chloride
Total CO2 (bicarbonate)
AST, ALT
Total bilirubin
Alkaline phosphatase
Uric acid
Albumin
Total protein
pH
Glucose (qual)
Protein (qual)
Blood (qual)
Ketones
Nitrites
Leukocyte esterase
Urobilinogen
Urine bilirubin
Microscopya
•
Urine drug screeningc
•
SARS-CoV-2 RT-PCR
•
eGFR [CKD EPI]
•
Pregnancy test (β-hCG)d
•
aPTT
•
PT-INR
•
Fibrinogen
•
TSH
•
Free T4
At screening only:
•
FSHb
•
Hepatitis B surface 
antigen
•
Hepatitis B surface 
antibodye
•
Hepatitis B core antibody
•
Hepatitis C antibody
•
Human 
immunodeficiency virus
a.
Only if urine dipstick is positive for blood, protein, nitrites, or leukocyte esterase.
b.
For confirmation of postmenopausal status only, at screening only.
c.
The minimum requirement for drug screening includes cocaine, THC, opiates/opioids, benzodiazepines, 
and amphetamines (others are site and study specific).
d.
Serum or urine β-hCG for female participants of childbearing potential.
e.
Can be done either automatically or only if HBcAb or HBsAg is positive, as per local practices.
Investigators must document their review of each laboratory safety report.
Any remaining serum/plasma from samples collected for clinical safety laboratory 
measurements at baseline and at all times after dose administration may be retained and 
stored for the duration of the study.
 
 
CCI


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CCI


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10.3. Appendix 3: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting
10.3.1. Definition of AE
AE Definition

An AE is any untoward medical occurrence in a patient or clinical study 
participant, temporally associated with the use of study intervention, whether or not 
considered related to the study intervention.

NOTE: An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease (new or exacerbated) 
temporally associated with the use of study intervention.
Events Meeting the AE Definition

Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) 
or other safety assessments (eg, ECG, radiological scans, vital sign measurements), 
including those that worsen from baseline, considered clinically significant in the 
medical and scientific judgment of the investigator. Any abnormal laboratory test 
results that meet any of the conditions below must be recorded as an AE:

Is associated with accompanying symptoms;

Requires additional diagnostic testing or medical/surgical intervention;

Leads to a change in study dosing (outside of any protocol-specified dose 
adjustments) or discontinuation from the study, significant additional 
concomitant drug treatment, or other therapy.

Exacerbation of a chronic or intermittent preexisting condition including either an 
increase in frequency and/or intensity of the condition.

New conditions 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/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 which 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 SAE
If an event is not an AE per definition above, then it cannot be an SAE even if serious 
conditions are met (eg, hospitalization for signs/symptoms of the disease under study, death 
due to progression of disease).
An SAE is defined as any untoward medical occurrence that, at any dose:
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 detained (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.


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Hospitalization for elective treatment of a preexisting condition that did not worsen from 
baseline is not considered an AE.
d. Results in persistent 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) which may interfere with or 
prevent everyday life functions but do not constitute a substantial disruption.
e.
Is a congenital anomaly/birth defect
f.
Other situations:

Medical or scientific judgment should be exercised in deciding whether SAE 
reporting is appropriate in other situations such as important medical events that 
may not be immediately life-threatening or result in death or hospitalization but 
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.

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 patient 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.
10.3.3. Recording/Reporting and Follow-up of AEs and/or SAEs
AE and SAE Recording/Reporting
The table below summarizes the requirements for recording adverse events on the CRF 
and for reporting serious adverse events on the CT SAE Report Form to Pfizer Safety. 
These requirements are delineated for 3 types of events: (1) SAEs; (2) nonserious AEs; and 


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(3) exposure to the study intervention under study during pregnancy or breastfeeding, and 
occupational exposure. 
It should be noted that the 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, and 
occupational exposure
All AEs/SAEs associated 
with exposure during 
pregnancy or breastfeeding
Occupational exposure is 
not recorded.
All (and EDP supplemental 
form for EDP)  
Note: Include all SAEs 
associated with exposure 
during pregnancy or 
breastfeeding. Include all 
AEs/SAEs associated with 
occupational exposure.

When an AE/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/SAE information in the CRF.

It is not acceptable for the investigator to send photocopies of the participant’s 
medical records to Pfizer Safety in lieu of completion of the CT SAE Report 
Form/AE/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/SAE.


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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: An event that is easily tolerated by the participant, causing minimal 
discomfort and not interfering with everyday activities.

Moderate: An event that causes sufficient discomfort and interferes with normal 
everyday activities.

Severe: An event that prevents normal everyday activities. An AE that is assessed 
as severe should not be confused with an SAE. Severe is a category utilized for 
rating the intensity of an event; and both AEs and SAEs can be assessed as severe.
An event is defined as “serious” when it meets at least 1 of the predefined outcomes as 
described in the definition of an SAE, NOT when it is rated as severe.
Assessment of Causality

The investigator is obligated to assess the relationship between study intervention 
and each occurrence of each AE/SAE.

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.

The investigator will use clinical judgment to determine the relationship.

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/SAE, the investigator must document in the medical notes that he/she 
has reviewed the AE/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.


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
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.
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 completed CRF.

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) in order to report the event within 24 hours.


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
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.
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 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 a male condom when engaging in any activity that allows for 
passage of ejaculate to another person.

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), with low user dependency, as described below during the 
intervention period and for at least 28 days after the last dose of study intervention,
which corresponds to the time needed to eliminate any reproductive safety risk of the 
study intervention(s). The investigator should evaluate the effectiveness of the 
contraceptive method in relationship to the first dose of study intervention.
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. 


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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. 

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.
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.


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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.
5. Vasectomized partner.

Vasectomized partner is a highly effective contraceptive method provided that the 
partner is the sole sexual partner of the WOCBP and the absence of sperm has 
been confirmed. If not, an additional highly effective method of contraception 
should be used. The spermatogenesis cycle is approximately 90 days.
Highly Effective Methods That Are User Dependent (for WOCBP partners only) 
1. Combined (estrogen and progestogen-containing) hormonal contraception associated 
with inhibition of ovulation.

Oral;

Intravaginal;

Transdermal;
2. Progestogen-only hormone contraception associated with inhibition of ovulation.

Oral;

Injectable.
3. 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.
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;


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
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 an “adaptor” 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).


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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.  
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 cases of 
Hy’s law, 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, 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 and 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).

Ventricular rhythms >30 seconds’ duration, including idioventricular rhythm (heart 
rate <40 bpm), accelerated idioventricular rhythm (HR >40 bpm to <100 bpm), and 


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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: Abbreviations
The following is a list of abbreviations that may be used in the protocol.
Abbreviation
Term
3CLpro
3C-like protein
Abs
absolute
ADE
adverse device effect
AE
adverse event
Aetau/Ae
amount excreted in urine as unchanged drug over the dosing 
interval τ/tau
Aetau%/Ae%
percent of dose excreted in urine as unchanged drug over the 
dosing interval
AESI
adverse events of special interest
ALT
alanine aminotransferase
API
active pharmaceutical ingredient
aPTT
activated partial thromboplastin time
ARDS
acute respiratory distress syndrome
AST
aspartate aminotransferase
AUC
area under the curve
AUC24
area under the plasma concentration-time profile from time zero to 
the time 24 hours
AUC24,ss
area under the plasma concentration-time profile from time zero to 
the time 24 hours at steady state
AUCinf
area under the plasma concentration-time curve from time 0
extrapolated to infinite time
AUCinf(dn)
dose normalized AUCinf
AUClast
area under the plasma concentration time curve from time 0 to the 
time of the last quantifiable concentration
AUClast(dn)
dose normalized AUClast
AUCtau/AUCt
area under the plasma concentration-time profile from time zero to 
time tau (τ), the dosing interval
AV
atrioventricular
BA
bioavailability
BBS
Biospecimen Banking System
BCRP
breast cancer resistance protein
BE
bioequivalence
-hCG
beta-human chorionic gonadotropin
BID
twice daily
BMI
body mass index
BP
blood pressure
bpm
beats per minute
BUN
blood urea nitrogen
Cav
average concentration


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Abbreviation
Term
Cb/Cp ratio
blood to plasma ratio
Ceff
efficacious concentration
CFR
Code of Federal Regulations
CI
confidence interval
CIOMS
Council for International Organizations of Medical Sciences
CK
creatine kinase
CKD EPI
chronic kidney disease epidemiology collaboration
CL
clearance
Clast
last quantifiable concentration
CL/F
apparent clearance
CLr
renal clearance
Cmax
maximum plasma concentration
Cmax(dn) 
dose normalized Cmax
Cmin
minimum plasma concentration
CO2
carbon dioxide (bicarbonate)
COVID-19
Corona Virus Disease 2019
CPP
coronary perfusion pressure
CRF
case report form
CRO
contract research organization
CRU
clinical research unit
CSR
clinical study report
CT
clinical trial
CTCAE
Common Terminology Criteria for Adverse Events
CTMS
clinical trial management system
CYP
cytochrome P450
DDI
drug-drug interaction
DILI
drug-induced liver injury
DMC
Data Monitoring Committee
dHNBE
differentiated normal human bronchial epithelial
dP/dT
rate of rise of left ventricular pressure
DR
dosing regimen
DU
dispensable unit
EC
ethics committee
EC50
half maximal effective concentration
EC90
90% maximal effective concentration
ECG
electrocardiogram
eCRF
electronic case report form
EDP
exposure during pregnancy
EDR
extemporaneous dispensing record
eGFR
estimated glomerular filtration rate
EMA
European Medicines Agency
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Abbreviation
Term
E/T
early termination
EU
European Union
EudraCT
European Clinical Trials Database
FAMHP
Federal Agency for Med
FDA
US Food and Drug Administration
FIH
first-in-human
19F-NMR
fluorine-19 nuclear magnetic resonance
FOB
functional observational battery
FSH
follicle-stimulating hormone
fu
free fraction
F/U
follow-up
GCP
Good Clinical Practice
GGT
gamma-glutamyl transferase
GLP
Good Laboratory Practice
HAE
human airway epithelial
HBcAb
hepatitis B core antibody
HBsAb
hepatitis B surface antibody
HBsAg 
hepatitis B surface antigen
HCV
hepatitis C virus
HCVAb
hepatitis C antibody
HED
human equivalent dose
hERG
human ether-a-go-go related gene
HIPAA
Health Insurance Portability and Accountability Act
HIV
human immunodeficiency virus
HLM
human liver microsome
HPD
hours post first dose
HR
heart rate
HRT
hormone replacement therapy
IB
Investigator’s Brochure
IC50
inhibitory concentration 50%
ICD
informed consent document
ICH
International Council for Harmonisation
ID
identification
I/E
inclusion/exclusion
IMP
investigational medicinal product
IND
Investigational New Drug 
INR
international normalized ratio
IPAL
Investigational Product Accountability Log
IQMP
Integrated Quality Management Plan
IRB
Institutional Review Board
IV
intravenous
kel
rate constant for terminal phase


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Abbreviation
Term
KI
inhibition constant
kinact
rate of enzyme inactivation
LBBB
left bundle branch block
LFT
liver function test
LVP
left ventricular pressure
MAD
multiple ascending dose
MCH
mean corpuscular hemoglobin
MCHC
mean corpuscular hemoglobin concentration
MCV
mean corpuscular volume
MD
multiple dose
MDR1
multidrug resistance mutation 1
M&E
Metabolism and Excretion
msec
millisecond
N/A
not applicable
Nab
neutralizing antibodies
NH
New Haven
NHP
non-human primates
NIMP
non-investigational medicinal product
NMR
nuclear magnetic resonance
NOAEL
no-observed-adverse-effect level
NTCP
human sodium taurocholate co-transporting polypeptide
OATP
organic anion transporting polypeptides
PBPK
physiology based pharmacokinetic
PCRU
Pfizer clinical research unit
PD
pharmacodynamic(s)
PDE
phosphodiesterase
PE
physical examination
P-gp
P-glycoprotein
PI
principal investigator
PK
pharmacokinetic(s)
PL
placebo
PT
prothrombin time
PTR
peak to trough ratio
PVC
premature ventricular contraction/complex
QTc
corrected QT
QTcB
corrected QT (Bazetts method)
QTcF
corrected QT (Fridericia method)
qual
qualitative
Rac
observed accumulation ratio for AUCτ
Rac,Cmax
observed accumulation ratio for Cmax
RBA/FE
relative bioavailability/food effect
RBC
red blood cell


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Abbreviation
Term
RNA
ribonucleic acid
RT-PCR
reverse transcription polymerase chain reaction
RTV
ritonavir
SAD
single ascending dose
SAE
serious adverse event
SAP
Statistical Analysis Plan
SARS-CoV-2
Severe Acute Respiratory Syndrome Coronavirus 2
SCr
serum creatinine
SD
single dose
standard deviation
stable disease (based on content)
SE
supratherapeutic exposure
SmPC
Summary of Product Characteristics
SoA
schedule of activities
SOP
standard operating procedure
SRSD
single-reference safety document
SUSAR
suspected unexpected serious adverse reaction
t½
terminal half-life
T4
thyroxine
TBili
total bilirubin
TEAE
treatment-emergent adverse events
THC
tetrahydrocannabinol
TID
three times daily
Tmax
time for Cmax
TSH
thyroid stimulating hormone
ULN
upper limit of normal
US
United States
Vss
volume at steady-state
Vz/F
apparent volume of distribution
WBC
white blood cell
WHO
World Health Organization
WOCBP
woman 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.
Wu Z, McGoogan JM. Characteristics of and important lessons from the coronavirus 
disease 2019 (COVID-19) outbreak in China: summary of a report of 72,314 cases from 
the Chinese Center for Disease Control and Prevention. JAMA. 2020;323(13):1239-42.
3.
Richardson S, Hirsch JS, Narasimhan M, et al. Presenting characteristics, comorbidities, 
and outcomes among 5700 patients hospitalized with COVID-19 in the New York City 
area. JAMA. 2020;323(20):2052-9.
4.
Docherty AB, Harrison EM, Green CA, et al. Features of 20-133 UK patients in 
hospital with covid-19 using the ISARIC WHO Clinical Characterisation Protocol: 
prospective observational cohort study. BMJ. 2020;369:m1985.
5.
Wang D, Hu B, Hu C, et al. Clinical characteristics of 138 hospitalized patients with 
2019 novel coronavirus-infected pneumonia in Wuhan, China. JAMA.
2020;323(11):1061-9.
6.
Cummings MJ, Baldwin MR, Abrams D, et al. Epidemiology, clinical course, and 
outcomes of critically ill adults with COVID-19 in New York City: a prospective cohort 
study. Lancet. 2020;395(10239):1763-70.
7.
Chen T, Wu D, Chen H, et al. Clinical characteristics of 113 deceased patients with 
coronavirus disease 2019: retrospective study. BMJ. 2020;368:m1091.
8.
Mao L, Jin H, Wang M, et al. Neurologic manifestations of hospitalized patients with 
coronavirus disease 2019 in Wuhan, China. JAMA Neurol. 2020;77(6):683-90.
9.
Mehta P, McAuley DF, Brown M, et al. COVID-19: consider cytokine storm 
syndromes and immunosuppression. Lancet. 2020;395(10229):1033-4.
10.
Beigel JH, Tomashek KM, Dodd LE, et al. Remdesivir for the treatment of 
Covid-19 - preliminary report. N Engl J Med. 2020:1-12.
11.
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.
12.
Maronpot RR, Yoshizawa K, Nyska A, et al. Hepatic enzyme induction: histopathology. 
Toxicol Pathol. 2010;38(5):776-95.
13.
Sia SF, Yan LM, Chin AWH, et al. Pathogenesis and transmission of SARS-CoV-2 in 
golden hamsters. Nature. 2020;583:834-8.


PF-07321332
Protocol C4671001
Final Protocol Amendment 3, 24 June 2021
PFIZER CONFIDENTIAL
Page 140
14.
Day CW, Baric R, Cai SX, et al. A new mouse-adapted strain of SARS-CoV as a lethal 
model for evaluating antiviral agents in vitro and in vivo. Virology. 2009;395:210-22.
15.
Pearson D, Garnier M, Luneau A, et al. 19F-NMR-based determination of the 
absorption, metabolism and excretion of the oral phosphatidylinositol-3-kinase (PI3K) 
delta inhibitor leniolisib (CDZ173) in healthy volunteers. Xenobiotica. 2019;49
(8):953-60.
16.
Dorr P, Westby M, Dobbs S, et al. Maraviroc (UK-427,857), a potent, orally 
bioavailable, and selective small-molecule inhibitor of chemokine receptor CCR5 with 
broad-spectrum anti-human immunodeficiency virus type 1 activity. Antimicrob Agents 
Chemother. 2005;49(11):4721-32.
17.
Reddy MB, Morcos PN, Le Pogam S, et al. Pharmacokinetic/pharmacodynamic 
predictors of clinical potency for hepatitis C virus nonnucleoside polymerase and 
protease inhibitors. Antimicrob Agents Chemother. 2012;56(6):3144-56.
18. Shen L, Peterson S, Sedaghat AR, et al. Dose-response curve slope sets class-specific 
limits on inhibitory potential of anti-HIV drugs. Nat Med. 2008;14(7):762-6.
19. Ritonavir Single Reference Safety Document (SRSD). 
https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/209512lbl.pdf.

SAP_001.pdf: 
Protocol C4671001 (PF-07321332) Statistical Analysis Plan
PFIZER CONFIDENTIAL 
Page 1
Protocol C4671001
A PHASE 1, RANDOMIZED, DOUBLE-BLIND, SPONSOR-
OPEN, PLACEBO CONTROLLED, SINGLE- AND 
MULTIPLE-DOSE ESCALATION STUDY TO EVALUATE 
THE SAFETY, TOLERABILITY AND PHARMACOKINETICS 
OF PF-07321332 IN HEALTHY ADULT PARTICIPANTS
Statistical Analysis Plan 
(SAP)
Version:
2.0
Date:
25 Aug 2021  


Protocol C4671001 (PF-07321332) Statistical Analysis Plan
PFIZER CONFIDENTIAL 
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TABLE OF CONTENTS
LIST OF TABLES.....................................................................................................................3
LIST OF FIGURES ...................................................................................................................4
APPENDICES ...........................................................................................................................4
1. VERSION HISTORY............................................................................................................5
2. INTRODUCTION .................................................................................................................5
2.1. Study Objectives, Endpoints, and Estimands............................................................7
2.2. Study Design ...........................................................................................................11
2.2.1. Overall Design............................................................................................11
2.2.2. PART-1: SAD.............................................................................................11
2.2.3. PART-2: MAD ...........................................................................................12
2.2.4. PART-3: RBA and Food effect ..................................................................12
2.2.5. PART-4: Metabolism and Excretion ..........................................................12
2.2.6. PART-5: Supratherapeutic Exposure (NH CRU only)...............................12
2.2.7. Number of Participants...............................................................................13
3. ENDPOINTS AND BASELINE VARIABLES:  DEFINITIONS AND 
CONVENTIONS ................................................................................................................14
3.1. Primary Endpoint(s) ................................................................................................14
3.2. Secondary Endpoint(s) ............................................................................................14
3.3. Other Endpoint(s)....................................................................................................14
3.3.1. Pharmacokinetic (PK) Endpoints ...............................................................14
3.4. Baseline Variables...................................................................................................16
3.5. Safety Endpoints .....................................................................................................16
3.5.1. Adverse Events...........................................................................................16
3.5.2. Laboratory Data..........................................................................................16
3.5.3. Vital Signs ..................................................................................................16
3.5.4. ECG ............................................................................................................17
4. ANALYSIS SETS (POPULATIONS FOR ANALYSIS)...................................................18
5. GENERAL METHODOLOGY AND CONVENTIONS....................................................19
5.1. Hypotheses and Decision Rules ..............................................................................19
5.2. General Methods .....................................................................................................19
5.2.1. Analyses for Continuous Endpoints ...........................................................19
CCI


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5.2.2. Analyses for Categorical Endpoints ...........................................................19
5.3. Methods to Manage Missing Data ..........................................................................19
6. ANALYSES AND SUMMARIES ......................................................................................20
6.1. Primary Endpoint(s) ................................................................................................20
6.2. Secondary Endpoint(s) ............................................................................................20
6.3. Other Endpoints.......................................................................................................23
6.4. Subset Analyses.......................................................................................................23
6.5. Baseline and Other Summaries and Analyses.........................................................23
6.5.1. Study Conduct and Participant Disposition................................................23
6.5.2. Demographic Data......................................................................................23
6.5.3. Concomitant Medications and Nondrug Treatments..................................23
6.5.4. Other Screening Data..................................................................................23
6.6. Safety Summaries and Analyses .............................................................................23
6.6.1. Adverse Events...........................................................................................23
6.6.2. Laboratory Data..........................................................................................24
6.6.3. Vital Signs ..................................................................................................24
6.6.4. ECG ............................................................................................................24
7. INTERIM ANALYSES.......................................................................................................25
7.1. Introduction .............................................................................................................25
7.2. Interim Analyses and Summaries............................................................................25
8. REFERENCES ....................................................................................................................25
APPENDICES .........................................................................................................................26
LIST OF TABLES
Table 1.
Summary of Changes..............................................................................................5
Table 2.
Noncompartmental PK Parameters for PART-1: Single Ascending Doses,  
PART-3: Relative Bioavailability/Food Effect Cohort, PART-4: 
Metabolism and Excretion Cohort and PART-5: Supratherapeutic Exposure 
Cohort ...................................................................................................................15
Table 3.
Noncompartmental PK Parameters for PART-2: Multiple Ascending Dose .......15
Table 4.
PK Parameters to be Summarized Descriptively..................................................21


Protocol C4671001 (PF-07321332) Statistical Analysis Plan
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LIST OF FIGURES
Figure 1.
C4671001 Study Design.......................................................................................13
APPENDICES
Appendix 1. Categorical Classes for ECG and Vital Signs of Potential Clinical Concern .....26


Protocol C4671001 (PF-07321332) Statistical Analysis Plan
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Page 5
1. VERSION HISTORY
Table 1.
Summary of Changes
Version/
Date
Associated 
Protocol 
Amendment
Rationale
Specific Changes
1.0
19 Feb 2021
Original 
28 Jan 2021
N/A
N/A
2.0
25 Aug 2021
Amendment 2 
02 Jun 2021
Amendment 3 
24 Jun 2021
PACL 
14 Jul 2021
PART-4 was 
added to evaluate 
metabolism and 
excretion and 
other updates to 
be in-line with 
protocol 
amendment
PART-5 was 
added to evaluate 
safety
and tolerability of 
PF-07321332 at
supratherapeutic 
exposure and 
other updates to 
be in-line with 
protocol 
amendment 

Included PART-4 and PART-5 and 
removed the specification of PART-3 
as optional in the description from 
the protocol (Section 2).

Updated Figure 1 to include PART-4
and PART-5.

Defined endpoints and baseline 
variables for PART-4 and PART-5 
(Section 3).

Defined an additional analysis set, 
the Excretion Analysis Set, for 
PART-4 (Section 4).

Specified analysis methods for 
PART-4 and PART-5 (Section 6).

Updated minor changes following 
table review.
2. INTRODUCTION
The current study is the first clinical administration with PF-07321332. It is a 5-part study 
combining PART-1: SAD, PART-2: MAD, PART-3: relative bioavailability/food effect,
PART-4: metabolism and excretion and PART-5 supratherapeutic exposure (SE). PART-1 
and 2 are randomized, double-blind, sponsor-open, placebo-controlled trial to evaluate 
safety, tolerability and PK of single and multiple escalating oral doses of PF-07321332 in 


Protocol C4671001 (PF-07321332) Statistical Analysis Plan
PFIZER CONFIDENTIAL 
Page 6
healthy adult participants and PART-3 is a randomized open label study to evaluate relative 
bioavailability and food effect of an oral tablet formulation. PART-2 of the study may also 
evaluate the safety tolerability and PK in Japanese participants. PART-4 is an open-label, 
non-randomized, single period to evaluate the metabolism and excretion of PF-07321332.
PART-5 is a double-blind, sponsor-open, randomized, cross-over study to evaluate safety 
and tolerability at supratherapeutic exposures.
This statistical analysis plan (SAP) provides the detailed methodology for summary and 
statistical analyses of the data collected in Study C4671001. This document may modify the 
plans outlined in the protocol; however, any major modifications of the primary endpoint 
definition or its analysis will also be reflected in a protocol amendment.


Protocol C4671001 (PF-07321332) Statistical Analysis Plan
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2.1. Study Objectives, Endpoints, and Estimands
There are no estimands for this study.
PART-1: SAD
Objectives
Estimands
Endpoints
Primary: 
Primary:
Primary: 
•
To assess the safety and 
tolerability following a single 
dose of PF-07321332 alone or 
in combination with a PK 
boosting agent (ritonavir).
N/A
•
Frequency, severity, and causal relationship of 
TEAEs and withdrawals due to TEAEs.
•
Frequency and magnitude of abnormal 
laboratory findings.
•
Changes from baseline in vital sign 
measurements and 12-lead ECG parameters.
Secondary: 
Secondary:
Secondary: 
•
To assess the plasma PK profile 
of PF-07321332 following 
single ascending doses of PF-
07321332 alone or in 
combination with a PK boosting 
agent (ritonavir)
N/A
•
Plasma PK parameters of PF-07321332: 
•
Cmax, Tmax, AUClast, Cmax(dn), AUClast(dn).
•
If data permits, AUCinf, AUCinf(dn), t½, 
Vz/F, and CL/F.
Tertiary/Exploratory: 
Tertiary/
Exploratory:
Tertiary/Exploratory: 
•
To explore metabolites in 
plasma, urine, and feces, if data 
permits.
N/A
•
Qualitative characterization of metabolites of 
PF07321332 in pooled plasma, urine, and 
feces as data permits.
•
Quantitative excretion of drug-
related material using 19F-NMR 
spectroscopy, if data permits.
N/A
•
Total excretion of drug-related material in 
urine and feces separately, and both routes 
combined, expressed as a percent of total dose 
administered, if data permits.
•
To determine the oral 
bioavailability of a tablet 
formulation of PF-07321332 
relative to suspension, if 
evaluated (Optional)
N/A
•
The ratio of AUClast, AUCinf and Cmax of tablet 
formulation and suspension.
•
To evaluate the effect of food 
(high fat meal) on the exposure 
of PF-07321332 following a 
single oral dose of PF 
07321332 tablet formulation, if 
evaluated (Optional)
N/A
•
The ratio of AUClast, AUCinf and Cmax of tablet 
formulation under fed condition and fasted 
condition.


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PART-2: MAD (including optional Japanese cohort)
Objectives
Estimand
Endpoints
Primary: 
Primary:
Primary: 

To assess the safety and 
tolerability following multiple 
ascending doses of PF-07321332 
alone or in combination with a 
PK boosting agent (ritonavir).
N/A

Frequency, severity, and causal relationship of 
TEAEs and withdrawals due to TEAEs.

Frequency and magnitude of abnormal 
laboratory findings.

Changes from baseline in vital sign 
measurements and 12-lead ECG parameters.
Secondary: 
Secondary:
Secondary: 

To assess the plasma PK profile 
of PF-07321332 on Days 1, 5 
and 10 following multiple 
ascending doses of PF-07321332 
alone or in combination with a 
PK boosting agent (ritonavir).
N/A

Plasma PK parameters of PF-07321332: 

Cmax, Tmax, AUCtau (where tau=8 hours for 
TID dosing or 12 hours for BID dosing), 
Cmin, Cmax(dn), AUCtau(dn), Cav, Rac, 
Rac,Cmax, PTR,CL/F and Vz/F.

If data permit, t½.

To assess the urinary PK profile 
of PF-07321332 on Day 10 
following multiple ascending 
doses of PF-07321332 alone or 
in combination with a PK 
boosting agent (ritonavir).
N/A

PF-07321332 urinary PK parameters: 

Aetau and Aetau%, CLr
Tertiary/Exploratory: 
Tertiary/
Exploratory:
Tertiary/Exploratory: 

To explore metabolites in plasma 
if data permits.
N/A

Qualitative characterization of metabolites of 
PF-07321332 in pooled plasma if data permits.

To explore PK by microsampling 
technique(s), if evaluated 
(Optional).
N/A

Concentration of PF-07321332, if evaluated.


Protocol C4671001 (PF-07321332) Statistical Analysis Plan
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PART-3: Relative Bioavailability/Food Effect Cohort
Objectives
Estimands
Endpoints
Primary: 
Primary: 
Primary: 

To determine the oral bioavailability 
of a tablet formulation of PF-
07321332 relative to suspension. 
N/A

The ratio of AUClast, AUCinf and Cmax of tablet 
formulation and suspension.
Secondary: 
Secondary:
Secondary: 

To evaluate the effect of food (high-fat 
high-calorie meal) on the exposure of 
PF-07321332 following a single oral 
dose of PF-07321332 tablet 
formulation.
N/A

The ratio of AUClast, AUCinf and Cmax of tablet 
formulation under fed condition and fasted 
condition.

To determine the pharmacokinetics of 
PF-07321332 following oral 
administration of tablet and 
suspension of PF-07321332.
N/A

Plasma PK parameters of PF-07321332: Tmax,
Cmax, AUClast, Cmax(dn), AUClast(dn), if data 
permits AUCinf, AUCinf(dn), t½, CL/F, Vz/F.

To determine the safety and 
tolerability of PF-07321332 following 
oral administration of tablet and 
suspension of PF-07321332.
N/A

Frequency, severity, and causal relationship 
of TEAEs and withdrawals due to TEAEs.

Frequency and magnitude of abnormal 
laboratory findings.

Changes from baseline in vital sign 
measurements and 12-lead ECG parameters.
 
 
 
 
 
 
CCI


Protocol C4671001 (PF-07321332) Statistical Analysis Plan
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PART-4: Metabolism and Excretion 
Objectives
Estimands
Endpoints
Primary: 
Primary: 
Primary: 

To determine the extent of excretion 
of drug related material in urine and 
feces after a single oral 
administration of PF-07321332 with 
PK boosting agent ritonavir. 
N/A

Total recovery of drug related material in 
urine and feces separately, and both routes 
combined, expressed as a percent of total oral 
dose administered.
Secondary: 
Secondary:
Secondary: 

To determine the pharmacokinetics of
PF-07321332 following oral
administration of PF-07321332 with 
PK boosting agent ritonavir.
N/A

Plasma PK parameters of PF-07321332: Tmax, 
Cmax, AUClast, if data permit AUCinf, t½, CL/F, 
Vz/F.

To determine the safety and 
tolerability of PF-07321332 after a 
single oral administration of PF-
07321332 with PK boosting agent 
ritonavir.
N/A

Frequency, severity, and causal relationship 
of TEAEs and withdrawals due to TEAEs.

Frequency and magnitude of abnormal 
laboratory findings.

Changes from baseline in vital signs 
measurements and 12-lead ECG parameters.
Tertiary/Exploratory: 
Tertiary/
Exploratory:
Tertiary/Exploratory: 

To characterize the metabolic profile 
and identify circulating and excreted
metabolites following administration 
of a single oral dose of PF-07321332 
with PK boosting agent ritonavir, if 
possible.
N/A

Metabolic profiling/identification and 
determination of relative abundance of PF-
07321332 and the metabolites of PF-
07321332 in plasma, urine, and feces, if 
possible.


Protocol C4671001 (PF-07321332) Statistical Analysis Plan
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PART-5: Supratherapeutic Exposure (NH CRU only) 
Objectives
Estimands
Endpoints
Primary: 
Primary: 
Primary: 

To assess the safety and tolerability of 
a supratherapeutic exposure of PF-
07321332 with a PK boosting agent 
(ritanovir) administrered as split 
dosing. 
N/A

Frequency, severity, and causal relationship 
of TEAEs and withdrawals due to AEs.

Frequency and magnitude of abnormal 
laboratory findings.

Changes from baseline in vital sign 
measurements and 12-lead ECG parameters
Secondary: 
Secondary:
Secondary: 

To assess the plasma PK of 
PF-07321332 at a supratherapeutic 
exposure of PF-07321332 with a PK 
boosting agent (ritanovir) 
administrered as split dosing.
N/A

Plasma PK parameters of PF-07321332: 

Cmax, Tmax, AUClast

If data permit, AUCinf, t½.
2.2. Study Design
2.2.1. Overall Design
The study will combine PART-1: single ascending dose (SAD), PART-2: multiple ascending 
dose (MAD, including optional Japanese cohort), PART-3: relative bioavailability and food 
effect cohort, PART-4: metabolism and excretion study, and PART-5: supratherapeutic 
exposure cohort. PART-1 and PART-2 are randomized, double-blind (participant and 
investigator blinded), sponsor open, placebo controlled, single and multiple dose escalation 
study. PART-3 is a randomized open label study to evaluate relative bioavailability and food 
effect. PART-4 is an open-label, non-randomized, single period to evaluate the metabolism 
and excretion of  PF-07321332. PART-5 is a double-blind, sponsor open, randomized, cross-
over study to evaluate safety and tolerability at supratherapeutic exposures to be conducted
at NH CRU only.
2.2.2. PART-1: SAD
SAD will include 2 interleaving cohorts with a total of approximately 12 participants 
planned (approximately 6 participants in each cohort), with 4-period cross-over in each 
cohort. Period 3 and 4 are optional periods which may be used to further explore PK at 
additional doses or PK in combination with ritonavir or relative bioavailability of a new 
formulation or food effect (high-fat high-calorie meal), etc, based on emerging safety, 
tolerability and PK assessments.
There will be a washout interval of ≥5 days between dosing to a given participant.
Participants will be required to stay at the CRU for the duration of the washout interval.
However, they may be released at the discretion of the investigator. The washout interval
may be adjusted based on data emerging from previous cohorts/periods.


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2.2.3. PART-2: MAD
The first MAD cohort may start after a same total daily dose, which provides comparable or 
higher total daily exposure (24 h) in SAD than the projected total daily steady-state exposure 
(over 24 h) at the starting dose in MAD, is found safe and well tolerated in PART-1 of the 
study. The proposed MAD study design will be parallel cohorts, with 10 days of dosing. 
PART-2 will consist of approximately 2 to 5 cohorts including up to 3 optional cohorts 
(cohorts 5, 6 and 7) with approximately 6 participants in each cohort. Cohort 7 is an
optional Japanese participants cohort.
2.2.4. PART-3: RBA and Food effect
This cohort will be an open label, randomized, 3-period, 3-sequence cross-over single dose 
cohort evaluating the relative bioavailability of PF-07321332 tablet compared to 
PF-07321332 oral suspension and to evaluate the effect of food on the bioavailability of the 
PF-07321332 tablet in healthy adult participants. A maximum of 18 participants may be 
enrolled in PART-3 of the study with approximately equal number of participants 
randomized to each sequence. There will be a wash-out period of at least 2 days between 
dosing in each period. Participants will be required to stay at the CRU until discharge in the 
last period. The washout interval may be adjusted based on data emerging from SAD and 
MAD cohorts.
2.2.5. PART-4: Metabolism and Excretion
This part will include a single cohort of approximately 6 male participants with at least 4 
completers. All participants will receive 4 doses of 100 mg ritonavir as specified in the SoA. 
Each participant will receive a single dose of 300 mg of PF-07321332 on Day 1 0h along
with 100 mg of ritonavir after at least 10h of fasting. The participants will be discharged on
Day 11.
In PART-1 and PART-2, treatment sequences, actual doses, dose increments and dosing 
regimen may be adjusted, and intermediate or alternative dose levels may be substituted 
during the study based on emerging safety, tolerability, and PK data.
2.2.6. PART-5: Supratherapeutic Exposure (NH CRU only)
This cohort will include up to 12 participants in a 4-period (Periods 3 and 4 are optional),
double-blind, sponsor-open, randomized, 2-sequence, cross-over design to explore safety,
tolerability and PK at supratherpeutic exposure. For each period, participants will receive
split dosing administration (3 doses) of PF-07321332 or placebo at short intervals
(approximately 2 h of the previous dose) after at least 2 hours after the breakfast on Day 1.
Baseline ECGs, vitals and safety labs will be collected before breakfast. The first 2 periods
will be a cross-over where participants will be given PF-07321332 at 0, 2 and 4 hours at the
dose of 750 mg (or placebo) with ritonavir. Periods 3 and 4 (if conducted) will only be
conducted if supratherapeutic concentrations are not reached in Period 1. In periods 3 and 4
(if conducted) doses may be given up to 4 times for a total daily dose not exceeding 3000 mg, 
with or without food.


Protocol C4671001 (PF-07321332) Statistical Analysis Plan
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2.2.7. Number of Participants
A total of up to 78 participants (12 in PART-1: SAD, up to 30 [with 2 cohorts and 3 optional 
cohorts] in PART-2: MAD, a maximum of 18 in PART-3: Relative Bioavailability/Food 
Effect cohort, 6 participants in PART-4: Metabolism and Excretion cohort, and up to 12 
participants in PART-5: Supratherapeutic Exposure) are planned to be randomized in this 
study. At the discretion of the sponsor and investigator, participant who were enrolled in 
PART-2 may be enrolled in PART-5.
Figure 1.
C4671001 Study Design
*Optional dose levels in SAD/MAD may be used to explore higher doses or food effect or relative 
bioavailability or in combination with ritonavir (see more details in Section 4.1 of the protocol). Dosing with 
food may be done in one or more cohorts in SAD/MAD based on the emerging PK/safety data. PART-4: 
Metabolism and Excretion (M&E) is an open-label single dose cohort (see more details in Section 4.1 of the 
protocol). PART-5: supratherapeutic exposure (SE) is a double-blind, sponsor-open, randomized, cross-over 
cohort (see more details in Section 4.1 of the protocol).
SAD dose levels D1 to D8 and MAD dosing regimens DR1 to DR4 are listed in Table 9 and Table 10, 
respectively in Section 4.3 of the protocol.


Protocol C4671001 (PF-07321332) Statistical Analysis Plan
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3. ENDPOINTS AND BASELINE VARIABLES: DEFINITIONS AND 
CONVENTIONS
3.1. Primary Endpoint(s)
As listed in Section 2.1 the primary endpoints in PART-1, PART-2, and PART-5 are related 
to safety/tolerability and are described in Section 3.5. 
The primary endpoints in PART-3 are the plasma PK endpoints which are described in 
Section 3.3.
The primary endpoints in PART-4 are percent recovery and cumulative recovery of drug-
related material in urine, feces determined based on total administered dose. Percent recovery 
of drug-related material in urine and feces will be determined based on total administered 
dose.
3.2. Secondary Endpoint(s)
The secondary endpoints in PART-1, PART-2, PART-4 and PART-5 related to PK are 
described in Section 3.3. The secondary endpoints in PART-3 and PART-4 related to 
safety/tolerability are described in Section 3.5.
3.3. Other Endpoint(s)
3.3.1. Pharmacokinetic (PK) Endpoints
Blood and urine samples for the PK analysis of PF-07321332 will be taken according to the 
SoA given in the protocol. 
The PK parameters of PF-07321332 to be derived (if data permit) from the concentration-
time data using standard noncompartmental methods are defined in Table 2 (single oral dose) 
and Table 3 (multiple oral doses). Urine PF-07321332 PK parameters are described in 
Table 3. 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.


Protocol C4671001 (PF-07321332) Statistical Analysis Plan
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Table 2.
Noncompartmental PK Parameters for PART-1: Single Ascending 
Doses, PART-3: Relative Bioavailability/Food Effect Cohort, PART-4: 
Metabolism and Excretion Cohort and PART-5: Supratherapeutic 
Exposure Cohort
Parameter
Analysis Scale
PF-07321332
AUClast†
ln
D, A
AUCinf*
ln
D, A
Cmax
ln
D, A
Tmax
R
D
t½*
R
D
CL/F*§
ln
D
Vz/F*§
ln
D
AUClast(dn) ‡
ln
D
AUCinf(dn)* ‡
ln
D
Cmax(dn) ‡
ln
D
Key:
D=displayed with descriptive statistics,
ln=natural-log transformed, R=raw (untransformed), A=analysed
*=if data permits, dn = normalized to a 1mg PF-07321332 dose,
†=In PART-3, pre-dose (0h) sample from Periods 2 and 3 will also be considered as 48h PK 
sample for Periods 1 and 2, respectively,
‡=Not PART-4 or PART-5,
§=Not PART-5.
Tlast will also be provided as a support parameter for AUClast. Tlast values will only be listed 
and not summarized.
Table 3.
Noncompartmental PK Parameters for PART-2: Multiple Ascending 
Dose
Parameter
Analysis Scale
PF-07321332
Plasma
AUCτ
ln
D
Cmax
ln
D
Tmax
R
D
Cmin
R
D
Cav
ln
D
Rac
ln
D
Rac,Cmax
ln
D
PTR
ln
D
CL/F
ln
D
t½*
R
D
Vz/F*
ln
D
AUCτ(dn)
ln
D
Cmax(dn)
ln
D
Urine
Aeτ
R
D
Aeτ%
R
D
CLr
R
D
Key:
D=displayed with descriptive statistics,
ln=natural-log transformed, R=raw (untransformed), 
*=if data permits, dn = normalized to a 1mg PF-07321332 dose.


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3.4. Baseline Variables
Baseline variables are those collected on Day 1 prior to dosing or before Day 1. Baseline for 
laboratory data, vital signs and ECG are defined in Sections 3.5.2, 3.5.3 and 3.5.4
respectively.
3.5. Safety Endpoints
3.5.1. Adverse Events
An adverse event is considered a Treatment-Emergent Adverse Event (TEAE) if the event 
started during the effective duration of treatment. All events that start on or after the first 
dosing day and time/start time, if collected, but before the end of the study will be flagged as 
TEAEs. The algorithm will not consider any events that started prior to the first dose date.
A 3-tier approach for summarizing AEs will not be used due to the low number of 
participants planned to be recruited. 
3.5.2. Laboratory Data
Safety laboratory tests will be performed as described in the protocol.
For PART-1, PART-3 and PART-5, baseline will be the last pre-dose measurement prior to 
administration of PF-07321332 in each study period. For PART-2, baseline will be the last 
pre-dose measurement. For PART-4, baseline will be the last pre-dose measurement prior to 
administration of PF-07321332.
For PART-5, the pre-dose (Day -1) sample in Period 2 will also be used as a Day 5 (96h) 
sample.
To determine if there are any clinically significant laboratory abnormalities, the 
hematological, clinical chemistry (serum) and urinalysis safety tests will be assessed against 
the criteria specified in the sponsor reporting standards. The assessment will take into 
account whether each participant’s baseline test result is within or outside the laboratory 
reference range for the particular laboratory parameter.
3.5.3. Vital Signs
Single supine blood pressure, respiratory rate, temperature and pulse measurements will be 
taken at times detailed in the SoA given in the protocol. 
For PART-1, PART-3 and PART-5, baseline will be defined as the last pre-dose 
measurement prior to administration of PF-07321332 in each study period. For PART-2, 
baseline will be the last pre-dose measurement. For PART-4, baseline will be the last pre-
dose measurement prior to administration of PF-07321332.
The following vital signs endpoints will be determined:

Change from baseline in supine systolic and diastolic blood pressure, pulse rate, 
temperature and respiratory rate.


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
The maximum decrease from baseline over all measurements taken post-dose for 
supine systolic and diastolic blood pressures and respiratory rate. 

The maximum increase from baseline over all measurements taken post-dose for 
supine pulse rate and temperature. 
The maximum increase from baseline will be calculated by first subtracting the baseline 
value from each post-dose measurement to give the change from baseline. The maximum of 
these values over the respective period will then be selected, except in the case where a 
participant does not show an increase. In such an instance, the minimum decrease should be 
taken. 
Similarly, the maximum decrease from baseline will be determined by selecting the 
minimum value of the changes from baseline.  In cases where a participant does not show a 
decrease, the minimum increase should be taken.
3.5.4. ECG
A 12-lead ECG will be obtained on all participants at screening. A triplicate measurement 
will be performed in PART-1, PART-2 and PART-5, and a single measurement in PART-3
and PART-4.
12-lead ECGs will be recorded on all participants at times detailed in the SoA given in the 
protocol. Triplicate measurements will be performed in PART-1, PART-2 and PART-5, and 
single measurements in PART-3 and PART-4. The QT, heart rate, QTcF, PR and QRS will 
be recorded at each assessment time.
The average of the triplicate readings collected at each assessment time will be calculated for 
each ECG parameter. For PART-1 and PART-5, baseline will be defined as the average of 
the triplicate measurements prior to administration of PF-07321332 in each study period. For 
PART-2, baseline will be defined as the average of the triplicate measurements prior to 
administration of PF-07321332 on Day 1. For PART-3, baseline will be defined the last 
measurement prior to administration of PF-07321332 in each study period. For PART-4, 
baseline will be defined as the last measurement prior to administration of PF-07321332.
The following ECG endpoints will be determined:

Change from baseline in QT interval, heart rate, QTcF interval, PR interval, and QRS 
complex.

The maximum absolute value (post-dose) will be calculated for QTcF, PR and QRS.

The maximum increase from baseline over all measurements taken post-dose will be 
calculated for QTcF. 
The maximum increase from baseline will be calculated by first subtracting the baseline value 
from each triplicate-average post-dose measurement to give the change from baseline. The 


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maximum of these values over the respective period will then be selected, except in the case 
where a participant does not show an increase. In such an instance, the minimum decrease 
should be taken.
 
 
 
 
4. ANALYSIS SETS (POPULATIONS FOR ANALYSIS)
Data for all participants will be assessed to determine if participants meet the criteria for 
inclusion in each analysis population prior to unblinding and releasing the database and 
classifications will be documented per standard operating procedures.
The study part referred to below can be either PART-1: SAD, PART-2: MAD, PART-3: 
Relative Bioavailability/Food Effect cohort, PART-4: Metabolism and Excretion cohort,
or PART-5: Supratherapeutic Exposure cohort, unless otherwise specified.
Population
Description
Enrolled/Randomly 
assigned to study 
intervention 
"Enrolled" means a participant's agreement to participate in a 
clinical study following completion of the informed consent 
process. 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.
Evaluable
All participants randomly assigned to study intervention and 
who take at least 1 dose of study intervention for the given part 
of the study.
Safety
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.
PK Concentration Set
All participants randomly assigned to study intervention and 
who take at least 1 dose of study intervention and in whom at 
least 1 concentration value is reported for the given part of the 
study.
PK Parameter Set
All participants randomly assigned to study intervention and 
who take at least 1 dose of study intervention and in whom at 
least 1 of the PK parameters of interest are reported for the 
given part of the study.
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Population
Description
Excretion Analysis Set
In PART-4, excretion analysis population will be defined by 
evaluable participants who have received 1 dose of PF-
07321332 and who have completed drug related material 
concentration (urinary and fecal) data and who had no 
protocol deviations that may have affected the mass balance 
analysis.
5. GENERAL METHODOLOGY AND CONVENTIONS
5.1. Hypotheses and Decision Rules
There is no statistical hypothesis testing planned for this study and no statistical decision 
rules will be applied.
5.2. General Methods
Unless otherwise stated, all summaries and plots will be presented by treatment.
5.2.1. Analyses for Continuous Endpoints
Continuous variables will be presented using summary statistics: number of observations, 
arithmetic mean, standard deviation, cv%, median, minimum and maximum values.
Log transformed continuous variables will be presented using summary statistics: number of 
observations, arithmetic mean, median, cv%, standard deviation, minimum, maximum, 
geometric mean and geometric cv%.
5.2.2. Analyses for Categorical Endpoints
Categorical variables will be presented using summary statistics: number of observations and 
percentages.
5.3. Methods to Manage Missing Data
For the analysis of safety endpoints, the sponsor data standard rules for imputation will be 
applied.
In all PK 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 (LLQ).
For PK summary tables and plots of mean/median profiles, statistics will be calculated 
having set concentrations to missing if 1 of the following cases is true:
1. A concentration has been collected as ND (ie not done) or NS (ie no sample),
2. A deviation in sampling time is of sufficient concern or a concentration has been 
flagged anomalous by the pharmacokineticist/statistician.


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If a PK parameter cannot be derived from a participant’s concentration data, the parameter
will be coded as NC (ie not calculated). (Note that NC values will not be generated beyond
the day that a participant discontinues). In summary tables, statistics will be calculated by
setting NC values to missing; and statistics will be presented for a particular dose with ≥3 
evaluable measurements.
If an individual participant has a known biased estimate of a PK parameter (due for example
to an unexpected event such as vomiting before all the compound is adequately absorbed in
the body), this will be footnoted in summary tables and will not be included in the
calculation of summary statistics or statistical analyses.
6. ANALYSES AND SUMMARIES
Separate tables will be produced for PART-1: SAD, PART-2: MAD, PART-3: Relative 
Bioavailability/Food Effect Cohort, PART-4: Metabolism and Excretion Cohort and 
PART-5: Supratherapeutic Exposure Cohort, unless otherwise specified. Placebo and 
Placebo + Ritonavir will be separate treatment groups. In Part-2, Japanese and non-Japanese 
will be separate treatment groups.
6.1. Primary Endpoint(s)
The primary endpoints in PART-1, PART-2 and PART-5 are related to safety/tolerability and 
their analyses are described Section 6.6.
The primary endpoints in PART-3 are the plasma PK endpoints whose analyses are described 
in Section 6.2.
The primary endpoints in PART-4 are percent recovery and cumulative recovery of drug-
related material in urine, feces based on total administered dose. This will be calculated and 
reported separately. 
6.2. Secondary Endpoint(s)
The secondary endpoints in PART-1, PART-2, PART-4 and PART-5, as well as the 
primary endpoints in PART-3, are related to PK and are described herein.
No formal inferential statistics will be applied to the plasma PK data apart from the 
comparisons of formulation and food effect in either PART-1 or PART-3


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The PK parameters detailed in Section 3.3.1 will be listed and summarized for 
participants in the PK Parameter Set (as defined in Section 4). Missing values will be 
handled as detailed in Section 5.3. Each PK parameter will be summarized by matrix 
(plasma or urine), treatment and dose. Each summary will include the set of summary 
statistics as specified in 
Table 4. Summaries will be performed separately for PART-1, PART-2, PART-3,
PART-4 and PART-5.
Table 4.
PK Parameters to be Summarized Descriptively
Parameter
Summary Statistics
AUClast, AUCinf, Cmax, CL/F, 
Vz/F, AUClast(dn), AUCinf 
(dn), Cmax(dn), AUCτ, Cmin, 
Cav, Rac, Rac,Cmax, PTR,
AUCτ (dn), Aeτ, Aeτ%, and 
CLr
N, arithmetic mean, median, cv%, standard deviation, 
minimum, maximum, geometric mean and geometric 
cv%.
Tmax
N, median, minimum, maximum.
t1/2
N, arithmetic mean, median, standard deviation, 
minimum, maximum.
To assess the relationship between the PK parameters and dose, dose normalized Cmax, 
AUClast, and AUCinf  (PART-1) and Cmax and AUCτ (PART-2) of PF-07321332 will be 
plotted against dose (using a logarithmic scale), and will include individual participant values 
and the geometric means for each dose. Geometric means will have a different symbol than 
the individual values. In Part-2, the data from the Japanese subjects will be identified by 
different symbols/colours. The values will be dose normalized (to a 1 mg dose) by dividing 
the individual values and raw geometric means by dose. A footnote will be added to the plots 
to indicate that geometric means are presented. All dose normalized parameters will be listed 
along with other individual PK parameters.
Supporting data from the estimation of t½ will be listed by treatment and dose where 
applicable: 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. These data may be included in the 
CSR.
Presentations for PF-07321332 concentrations will be presented using participants in the PK 
Concentration Set (as defined in Section 4) and will include:

a listing of all concentrations sorted by participant ID, dose, matrix and nominal time 
post-dose.  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 dose and nominal time post-dose, where the set of 
statistics will include n, mean, median, standard deviation, coefficient of variation (cv), 


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minimum, maximum and the number of concentrations above the lower limit of 
quantification.

individual concentration-time plots by dose (on both linear and semi-log scales) against 
actual time post-dose (there will be separate spaghetti plots for each dose per scale).

individual concentration-time plots by participant (on both linear and semi-log scales) 
against actual time post-dose (there will be separate spaghetti plots for each dose per 
scale).

median concentration-time plots (on both linear and semi-log scales) against nominal
time post-dose by dose (all doses on the same plot per scale, based on the summary of 
concentrations by dose and time post-dose).

mean concentration-time plots (on both linear and semi-log scales) against nominal time 
post-dose by dose (all doses on the same plot per scale, based on the summary of 
concentrations by dose and time post-dose).
The scale used for the x-axis (time) of these plots will be decided on review of the data, and 
will depend on how long PF-07321332 concentration is quantifiable in the matrix.
For summary statistics, median and mean plots by sampling time, the nominal PK sampling 
time will be used. For individual participant plots by time, the actual PK sampling time will be 
used.
For PART-2, urine amounts of PF-07321332 as listed in Table 3 will be listed and 
summarized descriptively, if data permit.
To assess any effect of food/formulation in PART-3, natural log transformed AUClast, Cmax, 
and AUCinf (if data permit) for PF-07321332 will be analyzed using a mixed effects model 
with sequence, period and treatment included as a fixed effect and participant nested within 
sequence as a random effect. If performed, to assess any effect of food/formulation in 
PART-1, natural log transformed AUClast, Cmax, and AUCinf (if data permit) for 
PF-07321332 will be analyzed using a mixed effects model with treatment as a fixed effect 
and participant as a random effect using participants with data from both periods only. The 
Kenward-Roger adjustment for the degrees of freedom will be used. 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 these differences will be 
exponentiated to provide estimates of the ratio of adjusted geometric means (Test/Reference)
and 90% CIs for these ratios.
The following comparisons will be made:
Comparison
Test
Reference
Formulation
PF-07321332 tablet formulation in fasted 
state (B)
PF-07321332 oral suspension in fasted state (A)


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Food Effect
PF-07321332 tablet formulation in fed (high 
fat meal) state (C)
PF-07321332 tablet formulation in fasted state (B)
6.3. Other Endpoints
 
 
 
 
 
 
Qualitative characterization of metabolites of PF-07321332, quantitative excretion of drug 
related material using 19F-NMR spectroscopy, metabolic profiling/identification and 
determination of relative abundance of PF-07321332 and its metabolites will be analysed 
separately and maybe included in the CSR in an appendix. Exploring of PK by 
microsampling is an exploratory endpoint and will not be included in the CSR.
6.4. Subset Analyses
No subset analyses will be performed.
6.5. Baseline and Other Summaries and Analyses
6.5.1. Study Conduct and Participant Disposition
Participant evaluation groups will show participant disposition by treatment. Frequency 
counts and percentages will be supplied for participant discontinuation(s) by treatment. Data 
will be reported in accordance with the sponsor reporting standards.
6.5.2. Demographic Data
Demographic data (age, biological sex, race, ethnicity, weight, body mass index and height) 
will be summarised by cohort for PART-1, PART-3 and PART-5, by treatment for PART-2
and PART-4, and overall (if applicable) in accordance with the sponsor reporting standards. 
6.5.3. Concomitant Medications and Nondrug Treatments
All concomitant medication(s) as well as non-drug treatment(s) will be reported according to 
current sponsor reporting standards. 
6.5.4. Other Screening Data
These data will not be recorded in the study database, and therefore will not be listed.
6.6. Safety Summaries and Analyses
In all 5 parts of the study, all safety analyses will be performed on the Safety Analysis Set.
CCI


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6.6.1. Adverse Events
Adverse events will be reported in accordance with the sponsor reporting standards.
6.6.2. Laboratory Data 
Laboratory data will be listed and summarized by treatment in accordance with the sponsor 
reporting standards. Baseline is as defined in Section 3.5.2.
6.6.3. Vital Signs
Absolute values and changes from baseline in supine systolic and diastolic blood pressure, 
pulse rate, temperature and respiratory rate will be summarized by treatment and time post-
dose, according to sponsor reporting standards. Tables will be paged by parameter. Baseline 
is as defined in Section 3.5.3.
Mean changes from baseline for supine systolic and diastolic blood pressure, pulse rate, 
temperature and respiratory rate will be plotted against time post-dose. Each part will have its 
own output with 1 line for each treatment. Placebo will be pooled in the plots for PART-1, 
PART-2 and PART-5, although the Japanese placebo in PART-2 will be treated as a separate 
treatment. Corresponding individual plots of changes from baseline will also be produced for 
each treatment.
Maximum decrease from baseline for supine systolic and diastolic blood pressures and 
respiratory rate and maximum increase from baseline for supine pulse rate and temperature 
will be summarized by treatment, according to sponsor reporting standards.
Minimum and/or maximum absolute values and changes from baseline for supine vital signs 
will also be summarized descriptively by treatment using categories as defined in 
Appendix 1. Numbers and percentages of participants meeting the categorical criteria will be 
provided. All planned and unplanned post-dose time points will be counted in these 
categorical summaries.  
6.6.4. ECG
Absolute values and changes from baseline in QT, heart rate, QTcF, PR and QRS will be 
summarized by treatment and time post-dose using sponsor reporting standards. Tables will 
be paged by parameter. Baseline is as defined in Section 3.5.4.
Mean changes from baseline in QT, heart rate and QTcF will be plotted against time 
postdose. Each part will have its own output with 1 line for each treatment. Placebo will be 
pooled in the plots for PART-1, PART-2 and PART-5, although the Japanese placebo in 
PART-2 will be treated as a separate treatment. Corresponding individual plots of changes 
from baseline will also be produced for each treatment.
Changes from baseline in QTcF will also be plotted separately against drug concentrations of
PF-07321332. This will be a scatter plot for all observations where QTcF and drug 
concentration are recorded. Placebo data will also be included (with drug concentration set to 
zero). Different symbols will be used for each treatment.


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Maximum increase from baseline for QTcF will be summarized by treatment, according to 
sponsor reporting standards. 
ECG endpoints and changes from baseline (QTcF, PR and QRS) will also be summarized 
descriptively by treatment using categories as defined in Appendix 1 (for QTcF these 
correspond to the Pfizer Guidance in Section 8). Numbers and percentages of participants 
meeting the categorical criteria will be provided. All planned and unplanned postdose time
points will be counted in these categorical summaries.  
Listings of participants with any single post-dose value >500msec will also be produced for 
QTcF.
7. INTERIM ANALYSES
7.1. Introduction
No formal interim analysis will be conducted for this study. As this is a sponsor-open study, 
the sponsor will conduct unblinded reviews of the data during the course of the study for the 
purpose of safety assessment, facilitating dose escalation decisions, facilitating PK modeling, 
and/or supporting clinical development. Unblinded results will be reviewed by a designated 
limited number of sponsor colleagues within the study team.
7.2. Interim Analyses and Summaries
N/A
8. REFERENCES
Pfizer Guidance for Evaluation of QT / QTc Interval Prolongation and Proarrhythmic 
Potential for Non-antiarrhythmic Drugs; Members of the Cardiovascular Safety & Advisory 
Council (CVSAC); January 26, 2018


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APPENDICES
Appendix 1. Categorical Classes for ECG and Vital Signs of Potential Clinical Concern
Categories for QTcF
Absolute value of
QTcF (msec)
450 and 480
>480 and 500
>500
Increase from baseline
in QTcF (msec)
30 and 60
>60
Categories for PR and QRS
PR (ms)
max. ≥300
PR (ms) increase 
from baseline
Baseline >200 
and max. 
≥25% increase
Baseline ≤200 and 
max. ≥50% 
increase
QRS (ms)
max. ≥140
QRS (ms) 
increase from 
baseline
≥50% increase
Categories for Vital Signs
Systolic BP (mm Hg)
min. <90
Systolic BP (mm Hg) 
change from baseline
max. decrease ≥30
max. increase ≥30
Diastolic BP (mm Hg)
min. <50
Diastolic BP (mm Hg) 
change from baseline
max. decrease ≥20
max. increase ≥20
Supine pulse rate (bpm)
min. <40
max. >120