Conditions: Healthy Participant
Keywords: Drug-drug interaction Carbamazepine CYP3A4 inducer
Allocation: NON_RANDOMIZED | Intervention model: CROSSOVER
Enrollment: 12
Healthy volunteers: yes

Brief summary:
This is a drug-drug interaction study to assess the effects of a single dose of PF-07321332/ritonavir after multiple dose administrations of carbamazepine. Pharmacokinetic (PK) will be evaluated for PF-07321332 and ritonavir. Carbamazepine is being utilized as a cytochrome P450 3A4 (CYP3A4) inducer.

Detailed description:

Arms:
arm 1: PF-07321332/ritonavir orally as a single dose arm 2: Carbamazepine + PF-07321332/ritonavir orally.

Interventions: intervention 1: PF-07321332/ritonavir intervention 2: Carbamazepine intervention 3: PF 07321332/ritonavir
Intervention descriptions: intervention 1: PF-07321332/ritonavir administered orally as a single dose on Day 1, Period 1 intervention 2: In Period 2, Days 1-3, participants will receive low-dose of carbamazepine twice daily (BID), then a titrated mid-dose of carbamazepine BID on Days 4-7, and finally maintaining carbamazepine at the high-dose on Days 8-15. intervention 3: In Period 2, Day 14, participants will receive a single dose of PF-07321332/ritonavir orally.

Protocol document:
Prot_000.pdf: 
PF-07321332
Protocol C4671014
Amendment 1, 02 Jul 2021
PFIZER CONFIDENTIAL
Page 1
A PHASE 1, OPEN-LABEL, FIXED SEQUENCE, 2-PERIOD CROSSOVER STUDY 
TO ESTIMATE THE EFFECT OF CARBAMAZEPINE ON THE 
PHARMACOKINETICS OF PF-07321332 BOOSTED WITH RITONAVIR IN 
HEALTHY PARTICIPANTS
Study Intervention Number:
PF-07321332
Study Intervention Name:
N/A
US IND Number:
153517
EudraCT Number:
N/A
ClinicalTrials.gov ID:
N/A
Protocol Number:
C4671014
Phase:
1
Brief Title: A Phase 1 Study to Estimate Effects of Carbamazepine on the PK of
PF-07321332/Ritonavir in Healthy Participants
This document and accompanying materials contain confidential information belonging to Pfizer. Except as 
otherwise agreed to in writing, by accepting or reviewing these documents, you agree to hold this 
information in confidence and not copy or disclose it to others (except where required by applicable law) or 
use it for unauthorized purposes. In the event of any actual or suspected breach of this obligation, Pfizer 
must be promptly notified.


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Protocol Amendment Summary of Changes Table
Document
Version Date
Amendment 1
02 July 2021
Original protocol
17 June 2021
This amendment incorporates all revisions to date, including amendments made at the 
request of country health authorities and IRBs/ECs. 
Protocol Amendment Summary of Changes Table
Amendment 1 (02-July-2021)
Overall Rationale for the Amendment: This study is being amended to reflect changes in 
response to comments from FDA. Detailed changes are summarized below in a tabular form.
Section # and Name
Description of Change
Brief Rationale
Rifampin was replaced by
carbamazepine throughout.
Per FDA request, rifampin will 
not be used as the nitrosamine 
impurities are above acceptable 
limits. Recommended CYP3A4 
inducer by FDA is 
carbamazepine.
Section 1.1 Rationale 
and Brief Summary
Updated rationale and information of 
carbamazepine
Provide information to support 
changes
Section 1.2 Schema
Updated for carbamazepine 
administration
New schema required for 
carbamazepine.
Section 1.3 Schedule 
of Activities

Updated for carbamazepine 
administration

Added clarification that “HBsAb”
is a reflext test

Added “HLA-A*3101 and 
HLA-B*1502”

Removed “QuantiFERON TB 
Gold Test”

New SOA required for 
carbamazepine.

Per PCRU suggestion since 
it’s a reflex.

To insert at screen the 
genetic test for Asian 
Americans

The test is not needed at 
Screening


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Section # and Name
Description of Change
Brief Rationale

Updated the schedule of “CRU 
Confinement”

Day 15 labs was moved to 
Day 16

Vital signs, TSH, T4 and PK 
were all modified on the SOA 
table to accommodate the 
change in CYP3A4 pro: PK 
Sampling Schedule (Days 1-3): 
Vital Signs should include 
(BP/PR/RR); Updated TSH & 
free T4 Days 8, 10, and 14 to 
Days 6, 9, 12 and 16; Removal of 
pharmacogenomics sample

Should not be continuous on 
day 16 if discharging

Update made to respond to 
PCRU comment

To accommodate the 
change in CYP3A4 proble
and updates made per 
PACL
Section 2.3.1 Risk 
Assessment
Added “Aplastic anemia and 
agranulocytosis”
Updates made to reflect the 
current design of the study
Section 4.1 Overall 
Design
Added “Titration Scheme of 
Carbamazepine”
Updates made to reflect the 
current design of the study.
Section 5.2 Exclusion 
Criteria
Additional exclusion criteria included
Updates made to relect the 
current design of the study
Section 6.1 Study 
Intervention(s) 
Administered
Update the intervention of 
carbamazepine
Updates made to reflect the 
current design of the study.
Section 6.1.1 
Administration
Removal of EDR
Updates made per PACL
Section 6.2 
Preparation, Handling, 
Storage, and 
Accountability
Removal of IP Manual
Updates made per PACL
Section 6.8 
Concomitant Therapy
Permitted/prohibited concomitant 
treatments updated
Updates made to reflect the 
current design of the study.
Section 8 Study 
Assessments and 
Procedures
Removal of Section 8.5.1 (Specified 
Genetics)
Updates made per PACL
Section 10.2 Appendix 
2
Removed “QuantiFERON test” and 
added “HLA-B*-1502 & HLA-A* 
3101”
To align with the updates in 
SOA


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PFIZER CONFIDENTIAL
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Section # and Name
Description of Change
Brief Rationale
Section 11 Reference

Reference #4-7 added

Removed original reference #4-6 
related to rifampin

To support the use of 
carbamazepine.

Rifampin was no longer
used in this study
Minor editorial changes throughout


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Amendment 1, 02 Jul 2021
PFIZER CONFIDENTIAL
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TABLE OF CONTENTS
LIST OF TABLES...................................................................................................................10
1. PROTOCOL SUMMARY...................................................................................................11
1.1. Synopsis ..................................................................................................................11
1.2. Schema ....................................................................................................................16
1.3. Schedule of Activities .............................................................................................17
2. INTRODUCTION ...............................................................................................................21
2.1. Study Rationale .......................................................................................................21
2.2. Background .............................................................................................................21
2.2.1. Nonclinical Pharmacology..........................................................................22
2.2.2. Nonclinical Pharmacokinetics and Metabolism .........................................22
2.2.3. Nonclinical Safety ......................................................................................22
2.2.4. Clinical Overview.......................................................................................23
2.2.4.1. Safety Overview........................................................................23
2.2.4.2. Summary of PF-07321332 Pharmacokinetics in Human..........24
2.3. Benefit/Risk Assessment.........................................................................................24
2.3.1. Risk Assessment.........................................................................................25
2.3.2. Benefit Assessment.....................................................................................28
2.3.3. Overall Benefit/Risk Conclusion................................................................28
3. OBJECTIVES AND ENDPOINTS.....................................................................................28
4. STUDY DESIGN.................................................................................................................28
4.1. Overall Design.........................................................................................................28
4.2. Scientific Rationale for Study Design.....................................................................30
4.2.1. Choice of Contraception/Barrier Requirements .........................................31
4.2.2. Collection of Retained Research Samples..................................................31
4.3. Justification for Dose ..............................................................................................31
4.4. End of Study Definition ..........................................................................................32
5. STUDY POPULATION......................................................................................................32
5.1. Inclusion Criteria.....................................................................................................32
5.2. Exclusion Criteria....................................................................................................33
5.3. Lifestyle Considerations..........................................................................................36


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5.3.1. Meals and Dietary Restrictions...................................................................36
5.3.2. Caffeine, Alcohol, and Tobacco .................................................................36
5.3.3. Activity .......................................................................................................37
5.3.4. Contraception..............................................................................................37
5.4. Screen Failures ........................................................................................................37
6. STUDY INTERVENTION(S) AND CONCOMITANT THERAPY.................................37
6.1. Study Intervention(s) Administered........................................................................37
6.1.1. Administration............................................................................................38
6.2. Preparation, Handling, Storage, and Accountability...............................................38
6.2.1. Preparation and Dispensing........................................................................39
6.3. Measures to Minimize Bias: Randomization and Blinding.....................................39
6.3.1. Allocation to Study Intervention ................................................................39
6.4. Study Intervention Compliance...............................................................................39
6.5. Dose Modification...................................................................................................40
6.6. Continued Access to Study Intervention After the End of the Study......................40
6.7. Treatment of Overdose............................................................................................40
6.8. Concomitant Therapy..............................................................................................40
6.8.1. Rescue Medicine.........................................................................................41
7. DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL...........................................................................41
7.1. Discontinuation of Study Intervention ....................................................................41
7.1.1. ECG Changes..............................................................................................42
7.1.2. Potential Cases of Acute Kidney Injury .....................................................42
7.2. Participant Discontinuation/Withdrawal From the Study.......................................43
7.2.1. Withdrawal of Consent...............................................................................43
7.3. Lost to Follow-Up ...................................................................................................44
8. STUDY ASSESSMENTS AND PROCEDURES...............................................................44
8.1. Efficacy Assessments..............................................................................................45
8.2. Safety Assessments .................................................................................................45
8.2.1. Physical Examinations................................................................................45
8.2.2. Vital Signs ..................................................................................................46
8.2.2.1. Respiratory Rate........................................................................46


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8.2.2.2. Temperature ..............................................................................46
8.2.3. Electrocardiograms.....................................................................................46
8.2.4. Clinical Safety Laboratory Assessments ....................................................47
8.2.5. COVID-19 Specific Assessments...............................................................48
8.2.6. Pregnancy Testing ......................................................................................48
8.2.7. Suicidal Ideation and Behavior Risk Monitoring.......................................48
8.3. Adverse Events, Serious Adverse Events, and Other Safety Reporting .................49
8.3.1. Time Period and Frequency for Collecting AE and SAE Information.......49
8.3.1.1. Reporting SAEs to Pfizer Safety...............................................50
8.3.1.2. Recording Nonserious AEs and SAEs on the CRF...................50
8.3.2. Method of Detecting AEs and SAEs ..........................................................50
8.3.3. Follow-up of AEs and SAEs.......................................................................51
8.3.4. Regulatory Reporting Requirements for SAEs...........................................51
8.3.5. Environmental Exposure, Exposure During Pregnancy or 
Breastfeeding, and Occupational Exposure.....................................................51
8.3.5.1. Exposure During Pregnancy......................................................52
8.3.5.2. Exposure During Breastfeeding ................................................53
8.3.5.3. Occupational Exposure .............................................................54
8.3.6. Cardiovascular and Death Events...............................................................54
8.3.7. Disease Related- Events and/or Disease Related- Outcomes Not 
Qualifying as AEs or SAEs..............................................................................54
8.3.8. Adverse Events of Special Interest.............................................................54
8.3.8.1. Lack of Efficacy........................................................................54
8.3.9. Medical Device Deficiencies......................................................................54
8.3.10. Medication Errors.....................................................................................54
8.4. Pharmacokinetics ....................................................................................................55
8.4.1. Plasma for Analysis of PF-07321332 and Ritonavir..................................55
8.4.2. Plasma Qualitative Metabolite Profiling ....................................................56
8.6. Biomarkers ..............................................................................................................56
8.6.1. Specified Gene Expression (RNA) Research .............................................56
CCI


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8.6.2. Specified Protein Research.........................................................................56
8.6.3. Specified Metabolomic Research ...............................................................57
8.7. Immunogenicity Assessments.................................................................................57
8.8. Health Economics ...................................................................................................57
9. STATISTICAL CONSIDERATIONS ................................................................................57
9.1. Statistical Hypotheses .............................................................................................57
9.2. Analysis Sets ...........................................................................................................57
9.3. Statistical Analyses .................................................................................................57
9.3.1. Other Safety Analyses ................................................................................58
9.3.2. Statistical Methods for PK Data .................................................................58
9.3.3. Derivation of Pharmacokinetic Parameters Prior to Analysis ....................58
9.4. Interim Analyses .....................................................................................................59
9.5. Sample Size Determination.....................................................................................59
10. SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS..........................................................................................................61
10.1. Appendix 1: Regulatory, Ethical, and Study Oversight Considerations...............61
10.1.1. Regulatory and Ethical Considerations ....................................................61
10.1.1.1. Reporting of Safety Issues and Serious Breaches of the 
Protocol or ICH GCP.........................................................................61
10.1.2. Informed Consent Process ........................................................................62
10.1.3. Data Protection .........................................................................................63
10.1.4. Committees Structure ...............................................................................63
10.1.4.1. Data Monitoring Committee ...................................................63
10.1.5. Dissemination of Clinical Study Data ......................................................63
10.1.6. Data Quality Assurance ............................................................................64
10.1.7. Source Documents....................................................................................66
10.1.8. Study and Site Start and Closure ..............................................................66
10.1.9. Publication Policy.....................................................................................67
10.1.10. Sponsor’s Qualified Medical Personnel .................................................67
10.2. Appendix 2: Clinical Laboratory Tests .................................................................69
10.3. Appendix 3: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting ......................................................................70


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10.3.1. Definition of AE .......................................................................................70
10.3.2. Definition of an SAE ................................................................................71
10.3.3. Recording/Reporting and Follow-up of AEs and/or SAEs During 
the Active Collection Period............................................................................72
10.3.4. Reporting of SAEs....................................................................................76
10.4. Appendix 4: Contraceptive and Barrier Guidance ................................................78
10.4.1. Male Participant Reproductive Inclusion Criteria....................................78
10.4.2. Female Participant Reproductive Inclusion Criteria.................................78
10.4.3. Woman of Childbearing Potential ............................................................79
10.4.4. Contraception Methods.............................................................................80
10.6. Appendix 6: Liver Safety: Suggested Actions and Follow-Up Assessments .......82
10.7. Appendix 7: ECG Findings of Potential Clinical Concern ...................................84
10.8. Appendix 8: Prohibited and Precautionary Concomitant Medications That 
May Result in DDI ....................................................................................................86
10.9. Appendix 9: Abbreviations ...................................................................................89
11. REFERENCES ..................................................................................................................94
CCI


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LIST OF TABLES
Table 1.
Plasma PK Parameters..............................................................................59
Table 2.
Protocol-Required Safety Laboratory Assessments .................................69


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1. PROTOCOL SUMMARY 
1.1. Synopsis 
Brief Title: A Phase 1 Study to Estimate the Effects of Carbamazepine on the PK of 
PF-07321332/Ritonavir in Healthy Participants
Rationale
PF-07321332 is a potent and selective inhibitor of the SARS-CoV-2 3CL protease that is 
currently being developed as an oral treatment of COVID-19. Ritonavir is a strong CYP3A4 
inhibitor being used to inhibit the metabolism of PF-07321332 in order to increase plasma 
concentrations of PF-07321332 to values that are anticipated to be efficacious. 
In vitro and in vivo metabolite profiling suggests that the primary clearance mechanism for 
PF-07321332 is CYP3A4 mediated oxidation. In a reaction phenotyping study using human 
liver microsomes in the presence of selective CYP inhibitors, CYP3A4 was predicted to be 
the major contributor (fm = 0.99) to the in vitro oxidative metabolism of PF-07321332. As 
such, in the FIH study, C4671001, the CYP3A4 inhibitor ritonavir was used to enhance the 
exposure of PF-07321332 in order to achieve plasma levels that are anticipated to be 
efficacious. Preliminary PK data following multiple oral administrations of 
PF‑07321332/ritonavir at doses of 75/100 mg, 250/100 mg, and 500/100 mg q12h suggest 
that the renal pathway may also play a significant role in PF-07321332 excretion when 
co-administered with ritonavir, with approximately 32.5% (PF‑07321332/ritonavir 
500/100 mg) to 64.6% (PF‑07321332/ritonavir 75/100 mg) of the drug excreted unchanged 
in urine across doses at steady-state, and renal clearance ranging between 3.5 to 4.4 L/h 
across doses. Ritonavir is extensively metabolized, primarily by CYP3A4.1 Based on 
available data to date, it is possible that induction of CYP3A4 (ie, carbamazepine) may lead 
to further decreased exposures of PF‑07321332/ritonavir. Therefore, results of this study will 
provide guidance for dosing with inducers of CYP3A4.
The purpose of this study is to estimate the effect of carbamazepine, a strong inducer of 
CYP3A4 on the PK of PF-07321332/ritonavir in healthy participants.


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Objectives and Endpoints
Objectives
Endpoints
Primary:
Primary:

To estimate the effect of carbamazepine on PK
of PF-07321332 after a single dose of 
PF-07321332/ritonavir (reference) compared
to the PK of PF-07321332 after a single dose
of PF-07321332/ritonavir, following multiple
dosing with carbamazepine (test).

Plasma PF-07321332 PK parameters: Cmax,
AUCinf (or AUClast if AUCinf cannot be reliably 
estimated).
Secondary: 
Secondary: 

To estimate the effect of carbamazepine on PK 
of ritonavir after a single dose of 
PF-07321332/ritonavir (reference) compared 
to the PK of ritonavir after a single dose of 
PF-07321332/ritonavir, following multiple
dosing with carbamazepine (test).

To evaluate the safety and tolerability of 
PF-07321332/ritonavir alone and, following 
multiple dosing with carbamazepine.

To characterize additional PK parameters of 
both PF-07321332 and ritonavir after a single 
dose of PF-07321332/ritonavir (reference) 
compared to the PK of both PF-07321332 and 
ritonavir, following multiple dosing with 
carbamazepine. 

Plasma ritonavir PK parameters: Cmax, AUCinf (or 
AUClast if AUCinf cannot be reliably estimated).

Safety: TEAEs, clinical laboratory tests, vital 
signs, PE, and ECGs.

Plasma PF-07321332 and ritonavir PK 
parameters: Tmax, AUClast, CL/F, Vz/F, and t½, as 
data permit.
Overall Design
Brief Summary
This is a Phase 1, fixed sequence, 2-period study to estimate the effect of a strong CYP3A4 
inducer, carbamazepine, on the PK of PF-07321332 and ritonavir in healthy participants.
A total of approximately 12 healthy male and/or female participants will be enrolled into the 
study. The purpose of this study is to characterize the effects of carbamazepine on the single 
dose PK of PF-07321332 300 mg/ritonavir 100 mg. Safety and tolerability will also be 
assessed throughout the duration of the study. This study will consist of 2 periods. Period 1
(P1) will include PF-07321332 300 mg/ritonavir 100 mg as a single oral dose, and Period 2 
(P2) will include a 15-day dosing of carbamazepine administered orally. Carbamazepine will 
start from 100 mg BID on Days 1, 2, and 3, and then, will titrate up to 200 mg BID on 
Days 4, 5, 6, and 7 in P2. Carbamazepine will eventually titrate up to and maintain at 300 mg
BID stably in the rest of P2 from Days 8 to 15. (Section 4.1, Figure 1). On Day 14 in the P2,
a single dose of PF-07321332 300 mg/ritonavir 100 mg will be administered after 


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multiple-dosed carbamazepine. PK sampling will be included in both Periods 1 and 2 to 
determine PK parameters. 
Each participant will be screened to determine eligibility within 28 days prior to study 
treatment. Eligible participants will report to the CRU at least 12 hours prior to Day 1 dosing 
in P1 and will be required to stay in the CRU for 18 days and 17 nights. 
In P1, each enrolled participant will receive a single dose of PF-07321332 300 mg/ritonavir 
100 mgorally. Serial PK samples will be collected up to 48 hours after a single dose 
administration to determine PK parameters. 
P2 will begin on Study Day 3 (referred to as P2 Day 1). In general, P2 will include a 15-day 
dosing of carbamazepine on a titrated schedule. Specifically, carbamazepine will start from 
100 mg BID on Days 1, 2, and 3, and then, will titrate up to 200 mg BID on Days 4, 5, 6, and 
7 in P2. Carbamazepine will eventually titrate up to and maintain at 300 mg BID stably in the 
rest of P2 from Days 8 to 15. On P2 Day 14, a single oral dose of PF-07321332
300 mg/ritonavir 100 mg will be administered. Following administration of PF-07321332
300 mg/ritonavir 100 mg, participants will undergo serial PK sampling up to 48 hours after 
a single dose administration to determine PK parameters for both PF-07321332 and ritonavir. 
Participants will be discharged from the CRU on Day 16 in P2 following completion of all 
assessments. 
Eligible participants will be admitted to the CRU on Day -1 (at least 12 hours prior to Day 1 
dosing of PF-07321332 300 mg/ritonavir 100 mg on Day 1, P1) and will be confined in the 
CRU for 18 days and 17 nights. On the morning of Day 1 (P1), the participants will receive 
a single dose of PF-07321332 300 mg and ritonavir 100 mg after fasting at least 10 hours. 
Serial blood samples at specified intervals will be collected up to 48 hours post-dose for PK 
assessments. Starting in the morning on Day 1 (P2), carbamazepine 100 mg BID will be 
administered orally on Days 1, 2, and 3, and then titrate up to 200 mg BID on Days 4, 5, 6, 
and 7. Carbamazepine will eventually titrate up to and maintain at 300 mg BID stably in the 
rest of P2 from Days 8 to 15. Carbamazepine (Days 1-15 [P2]) can be administered with or 
without food on all study days except on Study Day 14 when dosing will be under fasting 
conditions.. There are no water restrictions for carbamazepine dosing. On Day 14 in P2, 
a single dose of PF-07321332 300 mg/ritonavir 100 mg will be administered after fasting at 
least10 hours. Serial blood samples at specified intervals will be collected up to 48 hours 
post-dose for PK assessments of both PF-07321332 and ritonavir.
Safety assessments will be performed during Screening, on Day -1 prior to dosing, and at 
specified time points. PEs, vital sign measurements, and clinical laboratory tests will be 
conducted, and AEs will be monitored to assess safety. The total participation time (eg, CRU 
confinement time for study procedures) for each participant in this study is approximately 
18 days/17 nights (excluding screening and follow-up contact).
A safety follow-up call will be made to participants 28 to 35 days from administration of the 
dose of study intervention.


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Number of Participants
Approximately 12 participants may be enrolled to study intervention.
Note: "Enrolled" means a participant, or his or her legally authorized representative’s, 
agreement to participate in a clinical study following completion of the informed consent 
process and screening. A participant will be considered enrolled if the informed consent is 
not withdrawn prior to participating in any study activity after screening. Potential 
participants who are screened for the purpose of determining eligibility for the study, but do 
not participate in the study, are not considered enrolled, unless otherwise specified by the 
protocol.
Intervention Groups and Duration
Each participant will be screened to determine eligibility within 28 days prior to study 
treatment. Eligible participants will report to the CRU at least 12 hours prior to Day 1 and 
will be required to stay in the CRU for 18 days and 17 nights. A safety follow-up call will be 
made to participants approximately 28 to 35 days from administration of the final dose of 
study intervention. 
Each enrolled participant will participate in 2 study periods: 

Period 1: PF-07321332 300 mg/ritonavir 100mg administered orally as a single dose.

Period 2: Carbamazepine 100 mg BID will be administered orally on Days 1, 2, and 
3, and then titrate up to 200 mg BID on Days 4, 5, 6, and 7. Carbamazepine will 
eventually titrate up to and maintain at 300 mg BID stably in the rest of P2 from 
Days 8 to 15. On Day 14, participant will receive a single dose of PF-07321332
300 mg/ritonavir 100 mg orally. 
Participants will be discharged on Day 16 in P2 following completion of all assessments. 
The total planned duration of participation, from the Screening visit to the last Follow-up 
phone call, is approximately 11 to 12 weeks.
Data Monitoring Committee or Other Independent Oversight Committee: No
Statistical Methods
A sample size of 12 participants will provide adequate precision to estimate the effects of 
carbamazepine on the PK of PF-07321332. The expected widths of the 90% CIs with 80% 
coverage probability are shown in the following table for a range of possible effects. 


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Parameter
Estimated Effect 
(100*Test/Reference)
90% CI
CI Width
AUCinf
60%
70%
80%
90%
100%
53%, 68%
62%, 79%
71%, 90%
80%, 102%
88%, 113%
15%
17%
20%
22%
25%
Cmax
60%
70%
80%
90%
100%
55%, 65%
65%, 76%
74%, 87%
83%, 97%
92%, 108%
9%
11%
13%
14%
16%
These estimates are based on the assumption that within-participant standard deviations are 
0.14 and 0.091 for lnAUCinf and lnCmax, respectively, as obtained from ongoing clinical 
Study C4671001 in healthy participants.
Participants who withdraw from the study may be replaced at the discretion of the 
investigator upon consultation with the sponsor.
Pharmacokinetics Analysis
The PK concentration population is defined as all participants assigned to investigational 
product and treated who have at least 1 concentration measured.
The PK parameter analysis population is defined as all participants assigned to 
investigational product and treated who have at least 1 of the PK parameters of primary 
interest measured.
Pharmacokinetic parameters for PF-07321332 and ritonavir will be analyzed by standard 
noncompartmental method of analysis. Actual PK sampling times will be used in the 
derivation of PF-07321332 and ritonavir PK parameters. The PF-07321332 and ritonavir 
plasma PK parameters will be summarized descriptively by treatment. Plasma concentrations 
will be listed and summarized descriptively by treatment and nominal PK sampling time. 
Individual participant and summary profiles (mean and median plots) of the plasma 
concentration time data will be plotted using actual and nominal times, respectively. For 
AUCinf and Cmax, box and whisker plots of these parameters will be plotted by treatment. 
Drug-Drug Interaction
Natural log transformed AUCinf, AUClast and Cmax of PF-07321332 and ritonavir will be 
analyzed using a mixed effect model with treatment as fixed effect and participant as 
a random effect. Estimates of the adjusted mean differences (Test-Reference) and 
corresponding 90% CIs will be obtained from the model. The adjusted mean differences and 
90% CIs for the differences will be exponentiated to provide estimates of the ratio of 
adjusted geometric means (Test/Reference) and 90% CI for the ratios. PF-07321332 and 
ritonavir administered alone will be the Reference treatment and PF-07321332 and ritonavir 
coadministered with carbamazepine will be the Test treatment.


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Safety Analysis 
AEs, ECGs, BP, pulse rate, 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.
1.2. Schema
The following schematic represents the study design.
Screening
Days -28 to -2
Period 1 (P1)
(Days 1 and 2)*
Period 2 (P2)
(Days 1-16)
Follow-up
Days 28-35
(Reference)
PF-07321332 300 mg/ritonavir 
100 mg single dose
(Test)
Carbamazepine+: 100 mg BID on 
Days 1-3, 200 mg BID on Days 4-
7, and 300 mg BID on Days 8-15
in P2
+
PF-07321332 300 mg/ritonavir 
100 mg single dose
on Day 14 in P2
PK sampling
0-48 hrs
PK sampling
0-48 hrs
*P1 includes Day -1.
+.Carbamazepine will start from 100 mg BID on Days 1, 2, and 3, and then, will titrate up to 200 mg BID on 
Days 4, 5, 6, and 7 in P2. Carbamazepine will eventually titrate up to and maintain at 300 mg BID stably in 
the rest of P2 from Days 8 to 15.  


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1.3. Schedule of Activities
P1 (PF-07321332/ritonavir alone): Screening - Day 2
The SoA table provides an overview of the protocol visits and procedures. Refer to the STUDY ASSESSMENTS AND 
PROCEDURES section of the protocol for detailed information on each procedure and assessment required for compliance with the 
protocol. 
The investigator may schedule visits (unplanned visits) in addition to those listed in the SoA table, in order to conduct evaluations or 
assessments required to protect the well-being of the participant. 
Visit Identifier
Abbreviations used in this table may be found in Appendix 9.
Screeninga
Schedule for Period 1
Days Relative to Day 1
-28 to -2
Day -1
Day 1
Day 2
Day 3
Informed consent
X
CRU confinementb
X



Inclusion/exclusion criteria
X
X
Medical/medication history (update)c
X
X
Physical examd
X
X
Safety laboratory (including aPTT, PT- INR, Fibrinogen)e
X
X
X
Demographyf
X
HBsAb (reflex test), HBcAb, HCVAb, HBsAg and HIV
X
Pregnancy test (WOCBP only)
X
X
Contraception checkg
X
X
TSH & Free T4
X
X
X
HLA-A*3101 and HLA-B*1502
FSHh
X
Urine drug testingi
X
X
12-lead ECGj
X
X
X
Vital signs (BP/PR/RR)k
X
X
X
COVID-19 questionnairel
X
X
COVID-19 testingm
X
X
COVID-19 check temperaturen
X
X
X
X
PF-07321332/ritonavir administrationo
X
PK Blood Sampling for PF-07321332 and ritonavirp
X
X
X


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Visit Identifier
Abbreviations used in this table may be found in Appendix 9.
Screeninga
Schedule for Period 1
Serious and non-serious AE monitoring
X
→
→
→
→
Prior and Concomitant Treatment(s)
X
→
→
→
→
Suicicality Assessmentr
X
a.
Screening will be performed within 28 days prior to the first dose of PF-07321332/ritonavir. 
b.
Participants will be admitted to the CRU on Day -1. Safety labs can be performed on the day prior to the start of Period 2 in order for the results to be available on Day 3 
start of Period 2. Participants will be discharged on P2 Day 16 following the final assessments. 
c.
Medical history will include a history of prior illegal drug, alcohol, and tobacco use, as well as blood donation within prior 60 days. Medical history will be recorded at 
Screening and updated on Day 1 of Period 1. 
d.
A full PE, without genitourinary evaluation will be performed by trained medical personnel at the investigator site at Screening or Day 1 of Period 1 only (height and 
weight must be obtained at Screening to obtain BMI for eligibility criteria). A limited PE may be performed at other designated time points at the discretion of the 
investigator.
e.
Safety laboratory assessments including urinalysis, hematology, and chemistry will be performed at the indicated timepoints. All the safety laboratory samples must be 
collected following at least a 4 hour fast. Additional safety laboratory assessments may be performed at any time at the discretion of the investigator. 
f.
Demographics will include participant race, ethnicity, age, and gender during the Screening visit. 
g.
On Screening and Day 1, the investigator or his/her designee will discuss with the participant the need to use highly effective contraception consistently and correctly 
according to contraception guidelines.
h.
For postmenopausal (amenorrheic for at least 12 consecutive months) female participants only.
i.
Urine drug (mandatory) and alcohol breath test (at discretion of investigator) will be performed at Screening and on Day -1. These tests may be performed at any other 
time at the discretion of the investigator. 
j.
All ECG assessments (triplicate) will be made after at least a 10 minute rest in a supine position and prior to any blood draws or vital sign measurements. 
k.
Single supine blood pressure and pulse rate will be performed following at least a 5 minute rest in a supine position. BP and PR assessments will be performed after
collection of ECGs and prior to collection of blood draws if scheduled at the same time. RR will also be evaluated.
l.
Check exposure to positive participant, residence or travel in area of high incidence and COVID-19 related signs and symptoms. To be done at Screening and no more 
that 48 hours before confinement to the CRU.
m.
The testing for COVID-19 pathogen by RT-PCR will be performed at each visit. For participants admitted for residence, a subsequent COVID-19 test will be performed 
after 4 days (ie, upon completion of 4 × 24 hours in house), or if they develop COVID-19 like symptoms.
n.
To be done at least daily during residence.
o.
PF-07321332/ritonavir will be administered orally as a single dose following an overnight fast of at least 10 hours. . 
p.
One (approximately 4 mL) blood sample for PK analysis of PF-07321332 and ritonavir will be taken at the following timepoints: Day 1 pre-dose, and at 0.5, 1, 1.5, 2, 4, 
6, 8, 12, 16, 24, and 48 hours post-dose.
 
r.
C-SSRS Lifetime/Baseline assessment at Screening and ET if applicable
CCI
C
C


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P1 (PF-07321332/ritonavir alone): PK Sampling Schedule (Day 1 – Day 3)
Visit Identifier
Treatment Period on PK Days
Study Day
Day 1
Day 2
Day 3
Planned Hours Post Dose after dosing on
Day 1
0a
0.5
1
1.5
2
4
6
8
12
16
24
48a
Study intervention administration
X
PK blood sampling 
X
X
X
X
X
X
X
X
X
X
X
X
12-lead ECG
X
X
X
X
Vital Signs (BP/PR/RR)
X
X
X
X
a.
Predose sample collection.
P2 (PF-07321332/ritonavir with carbamazepine): Days 1-16
Visit Identifier
Abbreviations used in this table may 
be found in Appendix 9.
Schedule for Period 2
Follow-
Up
Early Termination/
Discontinuation
Days Relative to Day 1
Day 
1
Day 
2
Day 
3
Day 
4
Day 
5
Day 
6
Day 
7
Day 
8
Day 
9
Day 
10
Day 
11
Day 
12
Day 
13
Day 
14
Day 
15
Day 
16
28-35 
Daysj
CRU confinement















Safety laboratory (including aPTT, 
PT- INR, Fibrinogen)a
X
X
X
X
X
X
Contraception check
X
X
X
Pregnancy test (WOCBP only)
X
X
12-lead ECGb
X
X
X
X
X
X
X
Vital signs (BP/PR/RR) c
X
X
X
X
X
X
X
X
X
X
X
TSH & Free T4
X
X
X
X
X
X
COVID testing
X
COVID-19 check temperatured
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Carbamazepine administratione
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
PF-07321332/ritonavir administrationf
X
PK Blood Sampling for PF-07321332 
and ritonavirg
X
X
X
X
Serious and non-serious adverse event 
monitoring
















X
X
Concomitant treatment
















X
X
Suicidality assessmenth
X














X
X


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Visit Identifier
Abbreviations used in this table may 
be found in Appendix 9.
Schedule for Period 2
Follow-
Up
Early Termination/
Discontinuation
Days Relative to Day 1
Day 
1
Day 
2
Day 
3
Day 
4
Day 
5
Day 
6
Day 
7
Day 
8
Day 
9
Day 
10
Day 
11
Day 
12
Day 
13
Day 
14
Day 
15
Day 
16
28-35 
Daysj
Discharge from CRUi















X
a.
Safety laboratory assessments including urinalysis, hematology and chemistry. All the safety laboratory samples must be collected following at least a 4 hour fast. Additional 
safety laboratory assessments may be performed any time at the discretion of the Investigator. 
b.
All ECG assessments (triplcate) will be made after at least a 10 minute rest in a supine position and prior to any blood draws or vital sign measurements. 
c.
Single supine blood pressure and pulse rate will be performed following at least a 5 minute rest in a supine position. BP and PR assessments will be performed after collection 
of ECGs and prior to collection of blood draws if planned together. RR will also be evaluated.
d.
To be done at least daily during residence.
e.
Participants will receive carbamazepine starting at 100 mg BID on Days 1, 2 and 3, and then will titrate up to 200 mg on Days 4-7 in P2. Carbamazeppine will eventually be
titrated up to 300 mg BID stably in the rest of P2 from Days 8 to 15 (see Figure 1). Carbamazepine (Days 1-15 [P2]) can be administered with or without food on all 
study days except on Study Day 14 when dosing will be under fasting conditions. There are no water restrictions for carbamazepine dosing.  
f.
PF-07321332/ritonavir will be administered orally as a single dose on P2 Day 14.
g.
One (approximately 4 mL) blood sample for PK analysis of PF-07321332 and ritonavir will be taken at the following timepoints: P2 Day 14 pre-dose, and at 0.5, 1, 1.5, 2, 4, 
6, 8, 12, 16, 24, and 48 hours post-dose.
h.
C-SSRS Lifetime/Baseline assessment at screening, since last visit on Days 1 and 16 in P2 and ET if applicable
i.
Participants will be eligible for discharge on P2 Day 16 at the discretion of the investigator following PK sampling at 48 hours post dose.
j.
Contact may occur via telephone and must occur 28 to 35 days from administration of the final dose of study intervention.
P2 (PF-07321332/ritonavir with carbamazepine): PK Sampling Schedule (Days 14-16)
Visit Identifier
Treatment Period on PK Days
P2 Study Day
Day 14
Day 15
Day 16
Planned Hours Post 1st Dose 
after Dosing on Day 14
0a
0.5
1
1.5
2
4
6
8
12
16
24
48
Study intervention administration
X
X
X
PK blood sampling 
X
X
X
X
X
X
X
X
X
X
X
X
12-lead ECG
X
X
X
X
X
Vital Signs (BP/PR/RR)
X
X
X
X
X
a.
Predose sample collection.


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2. INTRODUCTION
PF-07321332 is a potent and selective inhibitor of the SARS-CoV-2 3CL protease that is 
currently being developed as an oral treatment of COVID-19. Ritonavir is a strong CYP3A4
inhibitor being used to inhibit the metabolism of PF-07321332 in order to increase plasma 
concentrations of PF-07321332 to values that are anticipated to be efficacious.
2.1. Study Rationale 
In vitro and in vivo metabolite profiling suggests that the primary clearance mechanism for 
PF-07321332 is CYP3A4 mediated oxidation. In a reaction phenotyping study using human 
liver microsomes in the presence of selective CYP inhibitors, CYP3A4 was predicted to be 
the major contributor (fm = 0.99) to the in vitro oxidative metabolism of PF-07321332. As 
such, in the FIH study, C4671001, the CYP3A4 inhibitor ritonavir was used to enhance the 
exposure of PF-07321332 in order to achieve plasma levels that are anticipated to be 
efficacious. Preliminary PK data following multiple oral administrations of 
PF‑07321332/ritonavir at doses of 75/100 mg, 250/100 mg, and 500/100 mg q12h suggest 
that the renal pathway may also play a significant role in PF-07321332 excretion when 
co-administered with ritonavir, with approximately 32.5% (PF‑07321332 500 mg/ritonavir 
100 mg) to 64.6% (PF‑07321332 75 mg/ritonavir 100 mg) of the drug excreted unchanged in 
urine across doses at steady-state, and renal clearance ranging between 3.5 to 4.4 L/h across 
doses. Ritonavir is extensively metabolized, primarily by CYP3A4.1 Based on available data 
to date, it is possible that induction of CYP3A4 (ie, carbamazepine) may lead to further 
decreased exposures of PF‑07321332/ritonavir. Therefore, results of this study will provide 
guidance for dosing with inducers of CYP3A4.
The purpose of this study is to estimate the effect of a strong inducer of CYP3A4, 
carbamazepine on the PK of PF-07321332/ritonavir in healthy participants.
2.2. Background 
In December 2019, COVID-19 was identified as a new, potentially fatal, respiratory infection 
caused by the novel coronavirus, SARS-CoV-2. The WHO declared COVID-19 a Public 
Health Emergency of International Concern on 20 January 2020 and further characterized the 
disease outbreak as a pandemic on 11 March 2020.2
PF-07321332 is an orally bioavailable 3CLpro inhibitor shown to be effective against 
SARS-CoV-2 3CLpro (Ki = 0.00311 µM) in a biochemical enzymatic assay. Since the 
3CLpro from human coronaviruses are structurally similar and share a high degree of 
conservation at the active site of the enzyme, the ability of PF-07321332 to inhibit the 
3CLpro of other coronaviruses (SARS-CoV-1 and HCoV-229E, MERS, HCoV-OC43, 
HCoV-HKU1, and HCoV-NL63) was also confirmed, indicating a potential for broad 
spectrum anti-coronavirus activity. The coronavirus 3CL protease is a virally encoded 
enzyme that is critical to the SARS-CoV-2 replication cycle, analogous to other obligatory 
virally encoded proteases (eg, HIV Protease, HCV Protease).3 PF-07321332 is being 
developed as an oral treatment in patients with COVID-19 infection. 


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Ritonavir is a strong CYP3A4 inhibitor being used to inhibit the metabolism of PF-07321332 
in order to increase plasma concentrations of PF-07321332 to values that are anticipated to 
be efficacious. Ritonavir is not expected to have any pharmacological impact on the 
SARS-CoV-2 virus. Ritonavir is being used only as a pharmacokinetic boosting agent.
2.2.1. Nonclinical Pharmacology
Details of the nonclinical pharmacology of PF-07321332 can be found in the current IB.
2.2.2. Nonclinical Pharmacokinetics and Metabolism
Hepatic CYP3450 enzymes were identified as the main pathway for clearance of 
PF-07321332 in vitro in liver microsomes (mouse, rat, hamster, rabbit, monkey, and human), 
hepatocytes (rat, monkey, and human), and in vivo in rat and monkey after repeat oral dosing 
(Study PF-07321332_09Nov20_084546). In a reaction phenotyping study using human liver 
microsomes in the presence of selective CYP inhibitors, CYP3A4 was predicted to be the 
major contributor (fm = 0.99) to the in vitro oxidative metabolism of PF-07321332. No 
significant CYP3A5 contribution is expected to the metabolism of PF-07321332. 
(Study PF-07321332_21Nov20_072016). Urinary excretion of PF-07321332 following 
single IV or oral doses in rats was approximately 11%, suggesting minor urinary 
contributions to the overall elimination of PF-07321332. 
Additional information of the nonclinical PK and metabolism of PF-07321332 is available in 
the current IB.
2.2.3. Nonclinical Safety
There were no adverse findings observed in repeat-dose toxicity studies in rats and monkeys 
up to 2 weeks duration and the NOAELs were the highest dose administered (1000 mg/kg 
and 600 mg/kg in the rat and monkey studies, respectively). PF-07321332-related
non-adverse, test article-related clinical findings included sporadic occurrence of emesis with 
slight body weight decreases in monkeys. Monitorable and reversible clinical pathology 
findings included those possibly suggestive of low-grade inflammation (in rats and monkeys) 
or alterations in the coagulation pathways (in rats only) without clinical or microscopic 
correlates. Other non-adverse clinical pathology findings were likely due to the emesis and 
subsequent dehydration in monkeys. In rats administered 1000 mg/kg/day, lower mean 
absolute and relative heart weights (females) and higher absolute and relative liver weights 
(both sexes) were observed relative to controls. The lower heart weights had no microscopic 
correlates and were fully reversed at the end of the 2-week recovery period. Higher liver 
weights correlated with reversible, non-adverse microscopic findings of minimal to mild 
severity in the liver and thyroid gland consistent with adaptive changes related to microsomal 
enzyme induction.

PF-07321332 was not mutagenic or clastogenic in in vitro genetic toxicity studies and 
was negative in the in vivo rat micronucleus assay incorporated into the GLP 
repeat-dose rat toxicity study. 


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•
The nonclinical studies performed adequately support the oral administration of 
PF-07321332 in the clinic for up to 14 days.
Further details of the nonclinical safety program are provided in the current IB.
2.2.4. Clinical Overview
Safety, tolerability and pharmacokinetics of PF-07321332 in healthy adult participants is 
currently being explored in an ongoing Phase 1 FIH study (C4671001). Study C4671001 is a 
four-part study consisting of SAD (PART-1), MAD (PART-2), relative bioavailability/food 
effect (PART-3), and metabolism and excretion study (PART-4). PART-1 and -2 are 
randomized, double-blind, sponsor-open, and placebo controlled to evaluate safety, 
tolerability, and PK of single and multiple escalating oral doses of PF-07321332, 
respectively. PART-3 is randomized and open-label to evaluate relative bioavailability and 
food effect of an oral tablet formulation. PART-4 is an open-label, non-randomized, single 
period to evaluate the metabolism and excretion of PF-07321332.
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CCI
CCI


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2.3. Benefit/Risk Assessment
•
PF-07321332/ritonavir alone or in combination with carbamazepine is not expected to 
provide any clinical benefit to healthy participants in this study. 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 adverse events of PF-07321332 may be found in the IB which is the SRSD for this 
study. The SRSDs for ritonavir and carbamazepine are the corresponding USPIs.
CCI
CCI


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2.3.1. Risk Assessment
Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
Study Intervention(s): PF-07321332
Emesis
Sporadic emesis were observed at ≥100 mg/kg/day of PF-
07321332 in the 15-day NHP- toxicology study (See IB). 
Based on preliminary data, no emesis was observed in the 
FIH Study C4671001 at single doses of PF-07321332 up to 
1500 mg alone and up to 750 mg administered with ritonavir 
(100 mg at -12h, 0h, 12h), and at repeated daily doses 
administered orally for 10 days of up to 500 mg PF-
07321332 BID with 100 mg ritonavir BID.
As this is an investigational agent, there is some 
risk that is mitigated by close observation of AEs, 
etc. If needed, palliative care or antiemetics may 
be provided.
Neuronal and pulmonary effects
Transient effect in rat neuronal and pulmonary endpoints 
were observed in rat toxicology study at the high dose level 
(1000 mg/kg as single dose; See IB). Based on preliminary 
data, no AEs suggestive of neuronal or pulmonary effects 
were observed in the FIH Study C4671001 at single doses of 
PF-07321332 up to 1500 mg alone and up to 750 mg 
administered with ritonavir (100 mg at -12h, 0h, 12h), and at 
repeated daily doses administered orally for 10 days of up to 
500 mg PF-07321332 BID with 100 mg ritonavir BID.
Vital signs, including respiratory rate, will be 
monitored for pulmonary effect. There will be 
close observation of AEs for any signs of 
neuronal effect. 
Hemodynamic effects
Low level inflammation (increase in fibrinogen) in 15-day 
NHP toxicology study and changes in platelets, globulin and 
albumin/globulin ratio and coagulation system (increase in 
PT and aPTT) in 14 day rat toxicology study (See IB). No 
relevant laboratory changes in inflammatory markers have 
been observed in the FIH Study C4671001 at single doses of 
PF-07321332 up to 1500 mg alone and up to 750 mg 
administered with ritonavir (100 mg at -12h, 0h, 12h), and at 
repeated daily doses administered orally for 10 days of up to 
500 mg PF-07321332 BID with 100 mg ritonavir BID.
Fibrinogen, platelets, PT-INR and aPTT, albumin 
and total proteins will be monitored. 


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Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
Thyroid function studies
In 14 day rat toxicology study at high dose of PF-07321332
(1000 mg/kg/day) thyroid gland changes observed were of 
low severity and without evidence of tissue damage. In the 
FIH Study C4671001, 3 participants had TEAEs of elevated 
TSH levels across treatment groups (PF-07321332 or 
placebo with ritonavir 100 mg BID) in the MAD part of the 
study. There was no clinical correlation with these TSH 
changes and free T4 remained within reference range at all 
times.
TSH and free T4 will be evaluated to monitor 
thyroid function
Study Intervention(s): Ritonavir
Gastrointestinal disturbances (including 
diarrhea, nausea, vomiting and 
abdominal pain).
Frequently reported adverse reaction in HIV patients at 
600 mg BID.
Lower dose of 100 mg twice daily is used in this 
study. There will be close observation of AEs. If 
needed, anti-emetics may be provided. 
Neurological disturbances (eg, 
paresthesia, including oral paresthesia, 
dysgeusia and dizziness).
Frequently reported adverse reaction in HIV patients at 
600 mg BID.
Lower dose used in this study. There will be close 
observation of AEs. 
Rash (most commonly reported as 
erythematous and maculopapular, 
followed by pruritic).
Frequently reported adverse reaction in HIV patients at 
600 mg BID.
Lower dose used in this study. There will be close 
observation of AEs and monitoring through 
targeted physical exams. If needed, palliative care 
may be provided. 
Fatigue/Asthenia
Frequently reported adverse reaction in HIV patients at 
600 mg BID.
Lower dose used in this study. There will be close 
observation of AEs and monitoring through 
targeted physical exams.
Limited case reports of renal toxicity
Although ritonavir therapy is not generally considered 
nephrotoxic, a limited number of cases of acute kidney 
injury secondary to ritonavir have been reported post-
marketing in HIV patients.
Lower dose used in this study. There will be close 
observation of AEs and renal function.


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Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
Study Intervention (s): Carbamazepine
Serious and sometimes fatal 
dermatologic reactions, including TEN 
and SJS.
These reactions are estimated to occur in 1 to 6 per 10,000 
new users in countries with mainly Caucasian populations, 
but the risk in some Asian countries is estimated to be about 
10 times higher. Studies in patients of Chinese ancestry have 
found a strong association between the risk of developing 
SJS/TEN and the presence of HLA-B*1502, an inherited 
allelic variant of the HLA-B gene that is found almost 
exclusively in patients with ancestry across broad areas of 
Asia. 
Exclusion criteria includes genetic testing for the 
HLA-B*1502 allele. There will be close 
observation of AEs and monitoring through 
targeted physical exams, such as gum and oral 
mucosa, etc. If needed, palliative care may be 
provided.
Aplastic anemia and agranulocytosis
Data from a population-based case-control study 
demonstrate that the risk of developing these reactions is 5-8 
times greater than in the general population. However, the 
overall risk of these reactions in the untreated general 
population is low, approximately 6 patients per one million 
population per year for agranulocytosis and 2 patients per 
one million population per year for aplastic anemia.
There will be close observation of AEs and 
monitoring through targeted physical exams and 
safety laboratory testing.
Increased risk of suicidal thoughts or 
behavior in patients taking these drugs 
for any indication.
The finding of increased risk with AEDs of varying 
mechanisms of action and across a range of indications 
suggests that the risk applies to all AEDs used for any 
indication
C-SSRS testing at baseline in P1 and P2 Day 16; 
participants can be monitored as they are in 
house, ad-hoc monitoring after discharge and 
during follow-up after 28-35 days.


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2.3.2. Benefit Assessment
PF-07321332/ritonavir and carbamazepine will not provide any clinical benefit to healthy 
participants in this study. Any anticipated benefit to participants would be in terms of 
contribution to the process of developing a new therapy in an area of unmet medical need.
2.3.3. Overall Benefit/Risk Conclusion
PF-07321332/ritonavir and carbamazepine are 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/ritonavir and carbamazepine are justified by the anticipated benefit, in terms of 
contribution to the process of developing a new therapy in an area of unmet medical need.
3. OBJECTIVES AND ENDPOINTS
Objectives
Endpoints
Primary:
Primary:

To estimate the effect of carbamazepine on the 
PK of PF-07321332 after a single dose of 
PF-07321332/ritonavir (reference) compared 
to the PK of PF-07321332 after a single dose 
of PF-07321332/ritonavir, following multiple 
dosing with carbamazepine (test).

Plasma PF-07321332 PK parameters: Cmax,
AUCinf (or AUClast if AUCinf cannot be reliably 
estimated).
Secondary: 
Secondary: 

To estimate the effect of carbamazepine on the 
PK of ritonavir after a single dose of 
PF-07321332/ritonavir (reference) compared
to the PK of ritonavir after a single dose of 
PF-07321332/ritonavir, following multiple
dosing with carbamazepine (test).

To evaluate the safety and tolerability of 
PF-07321332/ritonavir alone and, following 
multiple dosing with carbamazepine.

To characterize additional PK parameters of 
both PF-07321332 and ritonavir after a single 
dose of PF-07321332/ritonavir (reference)
compared to the PK of both PF-07321332 and 
ritonavir, following multiple dosing with 
carbamazepine. 

Plasma ritonavir PK parameters: Cmax, AUCinf (or 
AUClast if AUCinf cannot be reliably estimated).

Safety: treatment-emergent adverse events, 
clinical laboratory tests, vital signs, PE, and 
ECGs.

Plasma PF-07321332 and ritonavir PK 
parameters: Tmax, AUClast, CL/F, Vz/F, and t½, as 
data permit.
4. STUDY DESIGN
4.1. Overall Design
This is a Phase 1, fixed sequence, 2-period study to estimate the effect of a strong CYP3A4 
inducer, carbamazepine, on the PK of PF-07321332 and ritonavir in healthy participants.


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This study will consist of 2 periods. P1 will include PF-07321332 300 mg/ritonavir 100 mg 
as a single oral dose and P2 will include carbamazepine which will start from 100 mg BID on 
Days 1, 2, and 3, and then, will titrate up to 200 mg BID on Days 4, 5, 6, and 7 in P2.
Carbamazepine will titrate up to and maintain at 300 mg BID dose in the rest of P2 from 
Days 8 to 15 (Figure 1). A total of approximately 12 healthy male and/or female participants 
will be enrolled into the study. The treatment will consist of a single fixed sequence. 
Participants who discontinue from the study may be replaced at the sponsor’s discretion in 
collaboration with the Investigator. 
Figure 1.
Titration Scheme of Carbamazepine
The purpose of this study is to characterize the effects of carbamazepine on the single dose
PK of PF-07321332 300 mg/ritonavir 100 mg. Safety and tolerability will also be assessed 
throughout the duration of the study.
Healthy participants will be screened to determine eligibility within 28 days prior to study 
treatment. Medical history and results of PE, physical measurements, vital signs, 12-lead 
ECGs (triplicate), and clinical laboratory evaluations will determine eligibility. Participants 
will report to the CRU at least 12 hours prior to Day 1 dosing in P1 and will be required to 
stay in the CRU for 18 days and 17 nights. 
In P1, each enrolled participant will receive a single dose PF-07321332 300 mg/ritonavir
100 mg administered orally as a single dose. Serial PK samples will be collected up to 48
hours after single dose administration to determine PK parameters. 
P2 will begin on Study Day 3 (referred to as P2 Day 1). In general, P2 will include a 15-day 
dosing of carbamazepine on a titrated schedule. Specifically, carbamazepine will start from 
100 mg BID on Days 1, 2, and 3, and then, will titrate up to 200 mg BID on Days 4, 5, 6, and 
7 in the P2. Carbamazepine will eventually titrate up to and maintain at 300 mg BID stably in 
the rest of P2 from Days 8 to 15 (Figure 1). On Day 14 in P2, a single oral dose of PF-


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07321332 300 mg/ritonavir 100 mg will be administered after multiple-dosed 
carbamazepine. PK sampling will be included in both Periods 1 and 2 to determine PK 
parameters. Participants will be discharged from the CRU on Study Day 16 following 
completion of all assessments. 
The total planned duration of participation, from the Screening visit to the last Follow-up 
phone call, is approximately 11 to12 weeks.
Eligible participants will be admitted to the CRU on Day -1 (at least 12 hours prior to Day 1 
dosing of PF-07321332 300 mg/ritonavir 100 mg on Day 1, P1) and will be confined in the 
CRU for 18 days and 17 nights. On the morning of Day 1 (P1), the participants will receive a 
single oral dose of PF-07321332 300 mg and ritonavir 100 mg after fasting at least 10 hours. 
Serial blood samples at specified intervals will be collected up to 48 hours post-dose for PK 
assessments. Starting in the morning on Day 1 (P2), carbamazepine 100 mg BID ( no fasting 
is required) will be administered orally on Days 1, 2, and 3, and then titrate up to 200 mg 
BID on Days 4, 5, 6, and 7. Carbamazepine will eventually titrate up to and maintain at 300 
mg BID in the rest of P2 from Days 8 to 15. Carbamazepine (Days 1-15 [P2]) can be 
administered with or without food on all study days except on Study Day 14 when dosing 
will be under fasting conditions. There are no water restrictions for carbamazepine dosing.
On P2 Day 14, a single dose of PF-07321332 300 mg/ritonavir 100 mg will be administered 
as a single dose after fasting at least 10 hours. Serial blood samples at specified intervals will 
be collected up to 48 hours after single dose adminstration for PK assessments of both PF-
07321332 and ritonavir.
Safety assessments will be performed during Screening, on Day -1 prior to dosing, and at 
specified time points. PEs, vital sign measurements, and clinical laboratory tests will be 
conducted, and AEs will be monitored to assess safety. The total participation time (eg, CRU 
confinement time for study procedures) for each participant in this study is approximately 
18 days/17 nights (excluding screening and follow-up contact).
A safety follow-up call will be made to participants approximately 28 to 35 days from 
administration of the final dose of study intervention.
4.2. Scientific Rationale for Study Design
In vitro and in vivo metabolite profiling suggests that the primary clearance mechanism for 
PF-07321332 is CYP3A4 mediated oxidation (fm = 0.99). As such, in the FIH study, 
C4671001, the CYP3A4 inhibitor ritonavir was used to enhance the exposure of 
PF-07321332 in order to achieve plasma levels that are anticipated to be efficacious. 
Preliminary PK data following multiple oral administrations of PF-07321332/ritonavir at 
doses ranging from 75/100 mg to 500/100 mg q12h suggest that the renal pathway may also 
play a significant role in PF-07321332 excretion when co-administered with ritonavir (32.5% 
to 64.6% of the drug excreted unchanged in urine across doses at steady-state). Ritonavir is 
extensively metabolized, primarily by CYP3A4.1 Mechanistically, inhibition of CYP3A4 
could further decrease the metabolism of PF-07321332 and ritonavir, and thereby increase 
circulating exposures. Based on available data to date, it is possible that induction of 


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CYP3A4 (ie, carbamazepine) may lead to further decreased exposure of 
PF‑07321332/ritonavir. The objective of this study is to evaluate the effect of a probe 
CYP3A4 inducer, carbamazepine at steady-state on a single dose of PF-07321332/ritonavir.
The inducer to be utilized in this study is carbamazepine, which is a strong inducer of 
CYP3A. For these characteristics, along with its safety profile, carbamazepine has often been 
utilized as a perpetrator drug for CYP3A induction PK drug interaction studies.4,5 Since 
PF-07321332 and ritonavir are substrates of CYP3A, concomitant administration with 
carbamazepine along with PF-07321332/ritonavir may lead to decreased systemic exposures
of PF-07321332 and ritonavir. This may require PF-07321332/ritonavir dose adjustment 
when it is utilized with medications that are strong CYP3A inducers. Results of this study
will provide guidance for dosing recommendations with inducers of CYP3A4. 
4.2.1. Choice of Contraception/Barrier Requirements 
Human reproductive safety data are limited for PF-07321332, but there is no suspicion of 
human teratogenicity based on the intended pharmacology of the compound. Therefore, the 
use of a highly effective method of contraception is required (see Appendix 4).
4.2.2. Collection of Retained Research Samples
Retained Research Samples will be collected and stored for further analyses which may, for 
example, provide greater understanding of the study intervention.
4.3. Justification for Dose
A dose of 300 mg PF-07321332, pharmacokinetically enhanced with 100 mg ritonavir, to be 
administered as a single dose is planned in this study. This is the anticipated Phase 2/3 dose 
of PF-07321332/ritonavir of 300/100 mg.
When co-administered with ritonavir, doses of PF-07321332 up to 750 mg single dose and 
500 mg q12h for 10 days were generally safe and well tolerated based on preliminary data 
form the Phase 1 Study C4671001. There have been no deaths or serious adverse events or 
SUSARs reported. Based on review of preliminary (unaudited) data, all reported adverse 
events have been of mild intensity. There were no clinically meaningful findings in vital 
signs, ECG, or potential Hy’s Law cases reported during the study.
The dose of ritonavir to be used in this study is 100 mg administered once a day in 
combination with PF-07321332. This dose is the typical dose of ritonavir when used as a PK 
enhancer. 
The standard dose of carbamazepine for treatment to prevent and control seizures ranges 
between 800 mg and 1200 mg daily. Doses as high as 1600 mg daily have been used in 
adults . Carbamazipine is also used to relieve certain types of nerve pain (such as trigeminal 
neuralgia). Considering the dose of carbamazepine in clinical use is not compulsively required 
for DDI study, both the titration schedule and the maximum dose of 300 mg BID were


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recommended by FDA in a communication received by Pfizer on Date23 Jun 2021. It is also 
the titration schema and maximum dose utilized in many DDI studies.4,6,7
4.4. End of Study Definition
The end of the study is defined as the date of last scheduled procedure shown in the SoA for 
the last participant in the trial.
A participant is considered to have completed the study if he/she has completed all parts of 
the study, including the last scheduled procedure shown in the SoA.
5. STUDY POPULATION
This study can fulfill its objectives only if appropriate participants are enrolled. 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 or female participants must be 18 to 60 years of age, inclusive, at the time of 
signing the ICD.
Type of Participant and Disease Characteristics:
2. Male and female participants who are overtly healthy as determined by medical 
evaluation including medical history, PE, laboratory tests, and cardiac assessment.

Refer to Appendix 4 for reproductive criteria for male (Section 10.4.1 ) and 
female (Section 10.4.2 ) participants
3. Participants who are willing and able to comply with all scheduled visits, treatment 
plan, laboratory tests, and other study procedures.
4.
Female participants of childbearing potential must have a negative (urine or serum) 
pregnancy test.
Weight: 
5. BMI of 17.5 to 30.5 kg/m2; and a total body weight >50 kg (110 lb).


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Informed Consent:
6. Capable of giving signed informed consent as described in Appendix 1, which 
includes compliance with the requirements and restrictions listed in the ICD and in 
this protocol.
5.2. Exclusion Criteria
Participants are excluded from the study if any of the following criteria apply:
Medical Conditions:
1. Positive test (RT-PCR) result for SARS-CoV-2 infection at the time of Screening or 
Day -1.
2. Evidence or history of clinically significant hematological, renal, endocrine, 
pulmonary, gastrointestinal, cardiovascular, hepatic, psychiatric, neurological, or 
allergic disease (including drug allergies, but excluding untreated, asymptomatic, 
seasonal allergies at the time of dosing).
3. Clinically relevant abnormalities requiring treatment (eg, acute myocardial infarction, 
serious tachy or bradyarrhythmias) or indicating serious underlying heart disease 
(eg, prolonged PR or QT interval, cardiomyopathy, underlying structural heart 
disease, Wolff Parkinson–White syndrome). 
4. Any condition possibly affecting drug absorption (eg, gastrectomy, cholecystectomy)
5. History of HIV infection, hepatitis B, or hepatitis C; positive testing for HIV, HBsAg, 
HBcAb, or HCVAb. Hepatitis B vaccination is allowed.
6. Any conduction abnormality (including but not specific to left or right complete 
bundle branch block, or AV block [2nd degree or higher]).
7. Subjects shown to carry or be positive for HLA-B*1502 and HLA-A*3101
(genotyping alleles/markers related with carbamazepine-associated Stevens–Johnson 
syndrome or toxic epidermal necrolysis)
8. History of aplastic anemia and agranulocytosis
9. History of bone marrow suppression
10. History of a a mixed seizure disorder that includes atypical absence seizures (could 
induce frequency of generalized convulsion.), 
11. Other medical or psychiatric condition including recent (within the past year) or 
active suicidal ideation/behavior or laboratory abnormality or other conditions or 
situations related to COVID-19 pandemic (eg, Contact with positive case, residence, 


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or travel to an area with high incidence) that may increase the risk of study 
participation or, in the investigator’s judgment, make the participant inappropriate for 
the study.
Prior/Concomitant Therapy:
12. Use of prescription or nonprescription drugs and dietary and herbal supplements 
within 7 days or 5 half-lives (whichever is longer) prior to the first dose of study 
intervention. (Refer to Section 6.8 Concomitant Therapy for additional details).
13. Current use of any prohibited concomitant medication(s) or those unwilling/unable to 
use a permitted concomitant medication(s). Refer to Section 6.8 Concomitant 
Therapy.
14. Participants who have been vaccinated with COVID-19 vaccines within the past week 
(7 days) of dosing or are to be vaccinated with these vaccines at any time during the 
study confinement period.
15. Herbal supplements and hormonal methods of contraception (including oral and 
transdermal contraceptives, injectable progesterone, vaginal ring, and postcoital 
contraceptive methods) and hormone replacement therapy must have been 
discontinued at least 28 days prior to the first dose of investigational product. 
Depo-Provera must be discontinued at least 6 months prior to the first dose of study 
treatment.
16. Participants taking MAOIs should discontinue MAOI for a minimum of 14 days prior 
to dosing in the current study.
Prior/Concurrent Clinical Study Experience:
17. 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). Investigation drug does not include EUA 
vaccines.
Diagnostic Assessments:
18. A positive urine drug test.
19. 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.
20. Baseline 12-lead ECG (triplicate) that demonstrates clinically relevant abnormalities 
that may affect participant safety or interpretation of study results (eg, baseline QTcF 


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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. If QTcF exceeds 450 msec, or QRS exceeds 
120 msec, the ECG should be repeated 2 more times and the average of the 3 QTcF or 
QRS values should be used to determine the participant’s eligibility. Computer
interpreted- ECGs should be overread by a physician experienced in reading ECGs 
before excluding a participant.
21. 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 >1.0 × ULN;
•
Total bilirubin level ≥1.5 × ULN; participants with a history of Gilbert's 
syndrome may have direct bilirubin measured and would be eligible for this study 
provided the direct bilirubin level is ≤ULN.
•
eGFR <90 mL/min/1.73m2 (10%) based on the CKD-EPI equation
Other Exclusions:
22. 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).
23. Blood donation (excluding plasma donations) of approximately 1 pint (500 mL) or 
more within 60 days prior to dosing.
24. History of sensitivity to heparin or heparin-induced thrombocytopenia.
25. Unwilling or unable to comply with the criteria in the Lifestyle Considerations
section of this protocol.
26. 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. 
27. History of sensitivity reactions to ritonavir or carbamazepine or any of the 
formulation components of PF-07321332, ritonavir, or carbamazepine.


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5.3. Lifestyle Considerations
The following guidelines are provided:
5.3.1. Meals and Dietary Restrictions

Participants must abstain from all food and drink (except water) at least 4 hours prior 
to any safety laboratory evaluations and 10 hours prior to administration
PF-07321332/ritonavir and the collection of the predose PK sample and morning 
PF-07321332/ritonavir administration on Day 1 (P1) and Day 14 (P2).

Carbamazepine (Days 1-15 [P2]) can be administered with or without food on all 
study days except on Study Day 14 when dosing will be under fasting conditions.
There are no water restrictions for carbamazepine dosing. 

On days where no PK sampling is required, participants can resume normal intake of
both food and water.

Noncaffeinated drinks (except grapefruit or grapefruit related-citrus fruit juices—see 
below) may be consumed with meals and the evening snack.

Lunch can be provided approximately 4 hours after dosing the last dose of the 
morning of either carbamazepine or PF-07321332/ritonavir.  

Dinner can be provided approximately 9 to 10 hours after dosing the last dose of the 
morning of either carbamazepine or PF-07321332/ritonavir.  

An evening snack may be permitted.

Participants will refrain from consuming red wine, grapefruit, or grapefruit
related-citrus fruits (eg, Seville oranges, pomelos, fruit juices) from 7 days prior to 
the first dose of study intervention until collection of the final PK blood sample. 

While participants are confined, their total daily nutritional composition should be 
approximately 55% carbohydrate, 30% fat, and 15% protein. The daily caloric intake 
per participant should not exceed approximately 3200 kcal.
5.3.2. Caffeine, Alcohol, and Tobacco

Participants will abstain from caffeine containing products for 24 hours prior to the 
start of dosing until collection of the final PK sample of each study period. 

Participants will abstain from alcohol for 24 hours prior to admission (except as 
stated above for red wine) to the CRU and continue abstaining from alcohol until 
collection of the final PK sample of each study period. Participants may undergo an 
alcohol breath test or blood alcohol test at the discretion of the investigator.


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
Participants will abstain from the use of tobacco or nicotine containing products for 
24 hours prior to dosing and during confinement in the CRU.
5.3.3. 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.
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) considering that their risk for pregnancy may have changed since 
the last visit. In addition, the investigator or designee will instruct the participant to call 
immediately if the selected contraception method is discontinued or if pregnancy is known or 
suspected in the participant or partner.
5.4. Screen Failures
Screen failures are defined as participants who consent to participate in the clinical study but 
are not subsequently enrolled in the study. Screen failure data are collected and remain as 
source and are not reported on the CRF.
Individuals who do not meet the criteria for participation in this study (screen failure) may be 
rescreened. 
6. STUDY INTERVENTION(S) AND CONCOMITANT THERAPY
Study intervention is defined as any investigational intervention(s), marketed product(s), 
placebo, medical device(s), or study procedure(s) intended to be administered to a study 
participant according to the study protocol.
For the purposes of this protocol, study intervention refers to PF-07321332/ritonavir and 
carbamazepine.
6.1. Study Intervention(s) Administered

PF-07321332 100mg tablet will be provided by Pfizer 

Ritonavir 100 mg tablets will be supplied locally by the CRU

Carbamazepine 100mg ER tablet will be supplied locally by the CRU


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CRU will use 2 × 100 mg tablets for 200 mg dose and 3 × 100 mg tablets for 300 mg dose.
6.1.1. Administration
Investigational products will be administered orally and according to the conditions 
described in the SoA section and Protocol Section 5.3.1 Meals and Dietary Restrictions.
In Period 1, Day 1 following an overnight fast of at least 10 hours, participants will receive 
300 mg PF-07321332 (as 3 × 100 mg tablet), administered orally with 100 mg ritonavir (as 
1 × 100 mg tablet) administered orally as a single dose starting at approximately 0800 hours 
(plus or minus 2 hours). PF-07321332 and ritonavir will be dosed simultaneously (within no 
more than 5 minutes of each other). 
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 protocol.
In Period 2, on Days 1 through 15, inclusive, participants will receive carbamazepine
(starting 100 mg BID and titrating up to 300 mg BID, at approximately 0800 hours (plus or 
minus 2 hours). Carbamazepine (Days 1-15 [P2]) can be administered with or without food 
on all study days except on Study Day 14 when dosing will be under fasting conditions.
There are no water restrictions for carbamazepine dosing. Carbamezapine 100 mg BID will 
be administered orally on Days1, 2, and 3, and titrated up to 200 mg BID on Days 4, 5, 6, and 
7. Carbamazepine will eventually titrae up to and maintain at 300 mg BID stably in the rest 
of P2 from Days 8 to 15.
Approximately 15-30 min after the carbamazepine dose, on P2 Day 14, participants will 
receive 300 mg PF-07321332 (as 3 × 100 mg tablet), administered orally with 100 mg 
ritonavir (as 1 × 100 mg tablet) administered orally, starting at approximately 0815 to 
0830 hours (plus or minus 10 min). PF-07321332 and ritonavir will be dosed simultaneously 
(within no more than 5 minutes of each other).
There are no water restrictions for carbamazepine dosing on all study days.
6.2. Preparation, Handling, Storage, and Accountability
1.
The investigator or designee must confirm appropriate temperature conditions have 
been maintained during transit for all study interventions received and any 
discrepancies are reported and resolved before use of the study intervention. 
2.
Only participants enrolled in the study may receive study intervention and only 
authorized site staff may supply or administer study intervention. All study 
interventions must be stored in a secure, environmentally controlled, and monitored 
(manual or automated recording) area in accordance with the labeled storage 
conditions with access limited to the investigator and authorized site staff. At a 
minimum, daily minimum and maximum temperatures for all site storage locations 
must be documented and available upon request. Data for nonworking days must 


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indicate the minimum and maximum temperatures since previously documented for 
all site storage locations upon return to business.
3.
Any storage conditions stated in the SRSD will be superseded by the storage 
conditions stated on the label.
4.
Study interventions should be stored in their original containers.
5.
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.
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.
See the package insert (carbamazepine) for instructions on how to prepare the study 
intervention for administration. Study intervention should be prepared and dispensed by an 
appropriately qualified and experienced member of the study staff (eg, physician, nurse, 
physician’s assistant, nurse practitioner, pharmacy assistant/technician, or pharmacist) as 
allowed by local, state, and institutional guidance. A second staff member will verify the 
dispensing.
6.3. Measures to Minimize Bias: Randomization and Blinding
6.3.1. Allocation to Study Intervention
The investigator’s knowledge of the treatment should not influence the decision to enroll a 
particular participant or affect the order in which participants are enrolled.
The investigator will assign participant numbers to the participants as they are screened for 
the study. All participants enrolled will receive treatment according to the dose/schedule.
6.4. Study Intervention Compliance
When participants are dosed at the site, they will receive study intervention directly from the 
investigator or designee, under medical supervision. The date and time of each dose 
administered in the clinic will be recorded in the source documents and recorded in the CRF.
The dose of study intervention and study participant identification will be confirmed at the 
time of dosing by a member of the study site staff other than the person administering the 


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study intervention. Study site personnel will examine each participant’s mouth to ensure that 
the study intervention was ingested.
6.5. Dose Modification
No dose modification is anticipated.
6.6. Continued Access to Study Intervention After the End of the Study
No intervention will be provided to study participants at the end of their study participation.
6.7. Treatment of Overdose
For this study, any dose of PF-07321332 greater than 600 mg or ritonavir greater than 
200 mg or carbamazepine greater than 600 mg within a 24-hour time period (2 hours) will 
be considered an overdose.
There is no specific treatment for an overdose of either PF-07321332 or ritonavir or 
carbamazepine.
In the event of an overdose, the investigator should:

Contact the medical monitor within 24 hours.

Closely monitor the participant for any AEs/SAEs and laboratory abnormalities for at 
least 5 half-lives or 28 calendar days after the overdose of PF-07321332 or ritonavir 
(whichever is longer).

Document the quantity of the excess dose as well as the duration of the overdose in 
the CRF.

Overdose is reportable to Pfizer Safety only when associated with an SAE.

Obtain a blood sample for PK analysis within 1 days from the date of the last dose of 
study intervention if requested by the medical monitor (determined on a case-by-case 
basis).
6.8. Concomitant Therapy
Use of prescription or nonprescription drugs and dietary and herbal supplements are 
prohibited within 7 days or 5 half-lives (whichever is longer) prior to the first dose of study 
intervention. Limited use of nonprescription medications that are not believed to affect 
participant safety or the overall results of the study may be permitted on a case-by-case basis 
following approval by the sponsor. Acetaminophen/paracetamol may be used at doses 
of ≤1 g/day.
Herbal supplements and hormonal methods of contraception (including oral and transdermal 
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and hormone replacement therapy must have been discontinued at least 28 days prior to the 
first dose of investigational product.
Participants taking MAO inhibitors should discontinue MAO inhibitor for a minimum of 
14 days prior to dosing in the current study.
As carbamazepine is primarily metabolized by CYP3A4, the potential exists for interactions
between carbamazepine and any agent that inhibits CYP3A4. Agents that are inhibitors are 
expected to increase plasma levels of carbamazepine: cimetidine, clarithromycin, 
acetazolamide, gluosetime, grapefruit juice, itraconazole, nefazadone, protease inhibitors, 
valproate, and verapamil. Thus if a participant will have been titrated to a stable dose (ie, 
300 mg BID) of carbamazepine, it is reasonable to expect that a dose reduction for 
carbamazepine may be necessary.
The potential also exists for patients taking inducers of CYP3A4 that would be expected to 
decrease plasma levals of carbamazepine: ciplastin, doxorubnincin HCL, Gelbamate, 
rifampin, phenobarbital, phenytoin, and theophylline. Thus if a participant will have been 
titrated to a stable dose (ie, 300 mg BID) of carbamazepine, and then begins a course of 
treatment with one of these inducers, it is reasonable to expect that a dose increase for 
carbamazepine may be necessary.
All concomitant treatments taken during the study must be recorded with indication, daily 
dose, and start and stop dates of administration. All participants will be questioned about 
concomitant treatment at each clinic visit.
Treatments taken within 28 days before the first dose of study intervention will be 
documented as a prior treatment. Treatments taken after the first dose of study intervention 
will be documented as concomitant treatments.
6.8.1. Rescue Medicine 
There is no rescue therapy to reverse the AEs observed with PF-07321332, ritonavir or 
carbamazepine; standard medical supportive care must be provided to manage the AEs. 
7. DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL
7.1. Discontinuation of Study Intervention
It may be necessary for a participant to permanently discontinue study intervention. Reasons 
for permanent discontinuation of study intervention include the following;

AE requiring discontinuation in investigator’s view,

Pregnancy,

Positive COVID-19 test (ie, RT-PCR).


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
If study intervention is permanently discontinued, the participant will not remain in 
the study for further evaluation. See the SoA for data to be collected at the time of 
discontinuation of study intervention.
7.1.1. ECG Changes
A participant who meets either bulleted criterion based on the average of triplicate ECG 
readings will be withdrawn from the study intervention. 

QTcF >500 msec.

Change from baseline: QTcF >60 msec and QTcF >450 msec.
If a clinically significant finding is identified (including, but not limited to, changes from 
baseline in QTcF after enrollment), the investigator or qualified designee will determine if 
the participant can continue in the study and if any change in participant management is 
needed. This review of the ECG printed at the time of collection must be documented. Any 
new clinically relevant finding should be reported as an AE.
7.1.2. Potential Cases of Acute Kidney Injury
Abnormal values in SCr concurrent with presence or absence of increase in BUN that meet 
the criteria below, in the absence of other causes of kidney injury, are considered potential 
cases of acute kidney injury and should be considered important medical events. 
An increase of ≥0.3 mg/dL (or ≥26.5 µmol/L) in SCr level relative to the participant’s own 
baseline measurement should trigger another assessment of SCr as soon as practically 
feasible, preferably within 48 hours from awareness.
If the second assessment (after the first observations of ≥0.3 mg/dL [or ≥26.5 µmol/L] in SCr
relative to the participant’s own baseline measurement) is ≥0.4 mg/dL (or ≥35.4 µmol/L), the 
participant should be discontinued from the study and adequate, immediate, supportive 
measures taken to correct apparent acute kidney injury.
Participants should return to the investigator site and be evaluated as soon as possible, 
preferably within 48 hours from awareness of the second assessment confirming abnormal 
SCr result. This evaluation should include laboratory tests, detailed history, and physical 
assessment. In addition to repeating SCr, laboratory tests should include serum BUN, serum 
creatine kinase, and serum electrolytes (including at a minimum potassium, sodium, 
phosphate/phosphorus, and calcium), in addition to urinary dipstick, urine microscopic 
examination, and urinary indices. All cases confirmed on repeat testing as meeting the 
laboratory criteria for acute kidney injury, with no other cause(s) of laboratory abnormalities 
identified, should be considered potential cases of drug-induced kidney injury irrespective of 
availability of all the results of the investigations performed to determine etiology of the 
abnormal SCr. If ≥2 healthy participants are noted to have 2 consecutive SCr results of 
≥0.3 mg/dL (or ≥26.5 µmol/L), an assessment of whether the finding may be considered an 
adverse drug reaction should be undertaken.


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7.2. Participant Discontinuation/Withdrawal From the Study
A participant may withdraw from the study at any time at his/her own request. Reasons for 
discontinuation from the study include the following:

Refused further study procedures

Lost to follow-up

Death

Study terminated by sponsor

Investigator 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.
If a participant withdraws from the study, he/she may request destruction of any remaining 
samples taken and not tested, and the investigator must document any such requests in the 
site study records and notify the sponsor accordingly.
If the participant withdraws from the study and also withdraws consent (see Section 7.2.1) 
for disclosure of future information, no further evaluations should be performed and no 
additional data should be collected. The sponsor may retain and continue to use any data 
collected before such withdrawal of consent.
7.2.1. Withdrawal of Consent 
Participants who request to discontinue receipt of study intervention will remain in the study 
and must continue to be followed for protocol specified follow-up procedures. The only 
exception to this is when a participant specifically withdraws consent for any further contact 
with 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 


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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 a required 
study visit:

The site must attempt to contact the participant and reschedule the missed visit as 
soon as possible. Counsel the participant on the importance of maintaining the 
assigned visit schedule and ascertain whether the participant wishes to and/or should 
continue in the study.

Before a participant is deemed lost to follow-up, the investigator or designee must 
make every effort to regain contact with the participant (where possible, 3 telephone 
calls and, if necessary, a certified letter to the participant’s last known mailing 
address or local equivalent methods). These contact attempts should be documented 
in the participant’s medical record.

Should the participant continue to be unreachable, he/she will be considered to have 
withdrawn from the study. 
8. STUDY ASSESSMENTS AND PROCEDURES
The investigator (or an appropriate delegate at the investigator site) must obtain a signed and 
dated ICD before performing any study specific procedures.
Study procedures and their timing are summarized in the SoA. Protocol waivers or 
exemptions are not allowed.
Safety issues should be discussed with the sponsor immediately upon occurrence or 
awareness to determine whether the participant should continue or discontinue study 
intervention.
Adherence to the study design requirements, including those specified in the SoA, is essential 
and required for study conduct.
All screening evaluations must be completed and reviewed to confirm that potential 
participants meet all eligibility criteria. The investigator will maintain a screening log to 
record details of all participants screened and to confirm eligibility or record reasons for 
screening failure, as applicable.
Participants will be screened within 28 days prior to administration of the study intervention 
to confirm that they meet the study population criteria for the study. If the time between 


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screening and dosing exceeds 28 days as a result of unexpected delays (eg, delayed drug 
shipment), then participants do not require rescreening if the laboratory results obtained prior 
to first dose administration meet eligibility criteria.
Every effort should be made to ensure that protocol-required tests and procedures are 
completed as described. However, it is anticipated that from time to time there may be 
circumstances outside the control of the investigator that may make it unfeasible to perform 
the test. In these cases, the investigator must take all steps necessary to ensure the safety and 
well-being of the participant. When a protocol required test cannot be performed, the 
investigator will document the reason for the missed test and any corrective and preventive 
actions that he or she has taken to ensure that required processes are adhered to as soon as 
possible. The study team must be informed of these incidents in a timely manner.
If an IV catheter is utilized for blood sample collections, ECGs and vital sign assessments 
(pulse rate and BP) should be collected prior to the insertion of the catheter.
For samples being collected and shipped, detailed collection, processing, storage, and 
shipment instructions and contact information will be provided to the investigator site prior 
to initiation of the study.
The total blood sampling volume for individual participants in this study is approximately 
185 mL. The actual collection times of blood sampling may change. Additional blood 
samples may be taken for safety assessments at times specified by Pfizer, provided the total 
volume taken during the study does not exceed 550 mL during any period of 60 consecutive 
days.
To prepare for study participation, participants will be instructed on the information in 
Protocol Section 5.3 Lifestyle Considerations and Section 6.8 Concomitant Therapy.
8.1. Efficacy Assessments
Not applicable.
8.2. Safety Assessments
Planned time points for all safety assessments are provided in the SoA. Unscheduled clinical 
laboratory measurements may be obtained at any time during the study to assess any 
perceived safety issues.
8.2.1. Physical Examinations
A complete PE 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 PE will include, at a minimum, assessments of general appearance, the respiratory 
and cardiovascular systems, and participant reported symptoms.


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PEs 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. 
PE findings collected during the study will be considered source data and will not be required 
to be reported, unless otherwise noted. Any untoward PE findings that are identified during 
the active collection period and meet the definition of an AE or SAE (Appendix 3) must be 
reported according to the processes in Section 8.3.1 to Section 8.3.3.
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.
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 (other body locations, eg, tympanic, are acceptable 
provided the same method is used and documented throughout the study). No eating, 
drinking, or smoking is allowed for 15 minutes prior to the measurement.
8.2.3. Electrocardiograms
12-lead ECGs (triplicate) 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 


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complex. Alternative lead placement methodology using torso leads (eg, Mason-Likar) 
should not be used given the potential risk of discrepancies with ECGs acquired using 
standard limb lead placement. All scheduled ECGs should be performed after the participant
has rested quietly for approximately 10 minutes in a supine position. 
To ensure safety of the participants, a qualified individual at the investigator site will make 
comparisons to baseline measurements. Additional ECG monitoring will occur if a) a 
postdose QTcF interval is increased by ≥60 msec from the baseline and is >450 msec for 
participants with normal renal function and >470 msec for participants with impaired renal 
function; or b) an absolute QT value is ≥500 msec for any scheduled ECG. If either of these 
conditions occurs, then 2 additional ECGs will be collected approximately 2 to 4 minutes 
apart to confirm the original measurement. If the QTc values from these repeated ECGs 
remain above the threshold value, then a single ECG must be repeated at least hourly until 
QTc values from 2 successive ECGs fall below the threshold value that triggered the repeat 
measurement.
If a) a postdose QTcF interval remains ≥60 msec from the baseline and is >450 msec for 
participants with normal renal function and >470 msec for participants with impaired renal 
function; or b) an absolute QT value is ≥500 msec for any scheduled ECG for greater than 
4 hours (or sooner, at the discretion of the investigator); or c) QTcF intervals get 
progressively longer, the participant should undergo continuous ECG monitoring. A 
cardiologist should be consulted if QTcF intervals do not return to less than the criteria listed 
above after 8 hours of monitoring (or sooner, at the discretion of the investigator).
In some cases, it may be appropriate to repeat abnormal ECGs to rule out improper lead 
placement as contributing to the ECG abnormality. It is important that leads be placed in the 
same positions each time in order to achieve precise ECG recordings. If a machine read QTc 
value is prolonged, as defined above, repeat measurements may not be necessary if a 
qualified medical provider’s interpretation determines that the QTcF values are in the 
acceptable range.
ECG values of potential clinical concern are listed in Appendix 7.
8.2.4. Clinical Safety Laboratory Assessments
See Appendix 2 for the list of clinical safety laboratory tests to be performed and the SoA for 
the timing and frequency. All protocol required laboratory assessments, as defined in 
Appendix 2, must be conducted in accordance with the laboratory manual and the SoA. 
Unscheduled clinical laboratory measurements may be obtained at any time during the study 
to assess any perceived safety issues.
The investigator must review the laboratory report, document this review, and record any 
clinically relevant changes occurring during the study in the AE section of the CRF.
Clinically significant abnormal laboratory findings are those which are not associated with 
the underlying disease, unless judged by the investigator to be more severe than expected for 
the participant's condition.


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All laboratory tests with values considered clinically significantly abnormal during 
participation in the study or within 48 hours after the last dose of study intervention should 
be repeated until the values return to normal or baseline or are no longer considered clinically 
significant by the investigator or 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.
Urine drug (mandatory) and alcohol breath test (at discretion of investigator) will be 
performed at Screening and on Day -1. These tests may be performed at any other time at the 
discretion of the investigator.
8.2.5. COVID-19 Specific Assessments 
Participants will be tested for SARS-COV-2 infection by RT-PCR prior to being admitted to 
the clinic for confinement and a subsequent SARS-CoV-2 test will be performed after 4 days 
(ie, upon completion of 4 × 24 hours in house), or if they develop COVID-19 like symptoms. 
Additional testing may be required by local regulations or by the Principal Investigator.
8.2.6. Pregnancy Testing 
Pregnancy tests may be urine or serum tests, but must have a sensitivity of at least 
25 mIU/mL. Pregnancy tests will be performed in WOCBP at the times listed in the SoA.
Following a negative pregnancy test result at screening, appropriate contraception must be 
commenced and a second negative pregnancy test result will be required at the baseline visit 
prior the participant’s receiving the study intervention. Pregnancy tests will also be done 
whenever 1 menstrual cycle is missed during the active treatment period (or when potential 
pregnancy is otherwise suspected) and at the end of the study. Pregnancy tests may also be 
repeated if requested by IRBs/ECs or if required by local regulations. If a urine test cannot be 
confirmed as negative (eg, an ambiguous result), a serum pregnancy test is required. In such 
cases, the participant must be excluded if the serum pregnancy result is positive.
8.2.7. Suicidal Ideation and Behavior Risk Monitoring
The C-SSRS is an interview based rating scale to systematically assess suicidal ideation and 
suicidal behavior. Versions are available for Screening/Baseline (Lifetime).
The C-SSRS should be collected at time specified in the SoA table by appropriately trained 
PCRU staff. The C-SSRS can also be administered at any time in the study at the discretion 
of the investigator based on any reasonable concern.
At each suicidal assessment as per SoA, participants felt to have significant suicidal ideation 
with actual plan and intent or suicidal behavior, must be evaluated by a clinician/mental 
health professional skilled in the evaluation of suicidality in the participants by virtue of 


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training or experience who will determine if it is safe for the participant to continue in the 
trial. Specific criteria that indicate a need for such an assessment are:

Suicial ideation associate with actual intent and/or plan in the past year

Previous history of suicide behaviors in the past 10 years

In the investigator’s judgment a risk assessment or exclusion is warranted.
A written copy of the risk assessment to be included in the subject’s clinical record.
Other possible suicidality adverse events or other clinical observations may, based on the 
judgment of the investigator, also trigger a risk assessment and require a narrative. When 
there is a positive response to any question on the C-SSRS, the investigator should determine 
whether an adverse event has occurred.
Any subject that responds yes to items 4 and 5 on the suicidal ideation subscale of the 
C-SSRS or yes to any behavioral question-at the screening visit or baseline or post-baseline 
visit should simply be excluded from the study.
8.3. Adverse Events, Serious Adverse Events, and Other Safety Reporting
The definitions of an AE and an SAE can be found in Appendix 3.
AEs may arise from symptoms or other complaints reported to the investigator by the 
participant (or, when appropriate, by a caregiver, surrogate, or the participant's legally 
authorized representative), or they may arise from clinical findings of the investigator or 
other healthcare providers (clinical signs, test results, etc.).
The investigator and any qualified designees are responsible for detecting, documenting, and 
recording events that meet the definition of an AE or SAE and remain responsible to pursue 
and obtain adequate information both to determine the outcome and to assess whether the 
event meets the criteria for classification as an SAE or caused the participant to discontinue 
the study intervention (see Section 7.1). 
During the active collection period as described in Section 8.3.1, each participant will be 
questioned about the occurrence of AEs in a nonleading manner.
In addition, the investigator may be requested by Pfizer Safety to obtain specific follow-up 
information in an expedited fashion.
8.3.1. Time Period and Frequency for Collecting AE and SAE Information
The time period for actively eliciting and collecting AEs and SAEs (“active collection 
period”) for each participant begins from the time the participant provides informed consent, 
which is obtained before the participant’s participation in the study (ie, before undergoing 
any study related procedure and/or receiving study intervention), through and including a 


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minimum of 28 calendar days, except as indicated below, after the last administration of the 
study intervention.
Follow-up by the investigator continues throughout and after the active collection period and 
until the AE or SAE or its sequelae resolve or stabilize at a level acceptable to the 
investigator.
For participants who are screen failures, the active collection period ends when screen failure 
status is determined.
If the participant withdraws from the study and also withdraws consent for the collection of 
future information, the active collection period ends when consent is withdrawn.
If a participant permanently discontinues or temporarily discontinues study intervention 
because of an AE or SAE, the AE or SAE must be recorded on the CRF and the SAE 
reported using the CT SAE Report Form.
Investigators are not obligated to actively seek information on AEs or SAEs after the 
participant has concluded study participation. However, if the investigator learns of any SAE, 
including a death, at any time after a participant has completed the study, and 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.
Reporting of AEs and SAEs for participants who fail screening are subject to the CRF 
requirements as described in Section 5.4.
8.3.2. Method of Detecting AEs and SAEs
The method of recording, evaluating, and assessing causality of AEs and SAEs and the 
procedures for completing and transmitting SAE reports are provided in Appendix 3.


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Care will be taken not to introduce bias when detecting AEs and/or SAEs. Open-ended and 
nonleading verbal questioning of the participant is the preferred method to inquire about 
AE occurrences.
8.3.3. Follow-up of AEs and SAEs
After the initial AE or SAE report, the investigator is required to proactively follow each 
participant at subsequent visits/contacts. For each event, the investigator must pursue and 
obtain adequate information until resolution, stabilization, the event is otherwise explained, 
or the participant is lost to follow-up (as defined in Section 7.3).
In general, follow-up information will include a description of the event in sufficient detail to 
allow for a complete medical assessment of the case and independent determination of 
possible causality. Any information relevant to the event, such as concomitant medications 
and illnesses, must be provided. In the case of a participant death, a summary of available 
autopsy findings must be submitted as soon as possible to Pfizer Safety. 
Further information on follow-up procedures is given in Appendix 3.
8.3.4. Regulatory Reporting Requirements for SAEs
Prompt notification by the investigator to the sponsor of an SAE is essential so that legal 
obligations and ethical responsibilities toward the safety of participants and the safety of 
a study intervention under clinical investigation are met.
The sponsor has a legal responsibility to notify both the local regulatory authority and other 
regulatory agencies about the safety of a study intervention under clinical investigation. The 
sponsor will comply with country specific regulatory requirements relating to safety 
reporting to the regulatory authority, IRBs/ECs, and investigators.
Investigator safety reports must be prepared for SUSARs according to local regulatory 
requirements and sponsor policy and forwarded to investigators as necessary.
An investigator who receives SUSARs or other specific safety information (eg, summary or 
listing of SAEs) from the sponsor will review and then file it along with the SRSD(s) for the 
study and will notify the IRB/EC, if appropriate according to local requirements.
8.3.5. Environmental Exposure, Exposure During Pregnancy or Breastfeeding, and 
Occupational Exposure
Environmental exposure occurs when a person not enrolled in the study as a participant 
receives unplanned direct contact with or exposure to the study intervention. Such exposure 
may or may not lead to the occurrence of an AE or SAE. Persons at risk for environmental 
exposure include healthcare providers, family members, and others who may be exposed. 
An environmental exposure may include exposure during pregnancy, exposure during 
breastfeeding, and occupational exposure.


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Any such exposure to the study intervention under study are reportable to Pfizer Safety 
within 24 hours of investigator awareness.
8.3.5.1. Exposure During Pregnancy
An EDP occurs if:

A female participant is found to be pregnant while receiving or after discontinuing 
study intervention.

A male participant who is receiving or has discontinued study intervention exposes 
a female partner prior to or around the time of conception.

A female is found to be pregnant while being exposed or having been exposed to 
study intervention due to environmental exposure. Below are examples of 
environmental EDP:

A female family member or healthcare provider reports that she is pregnant after 
having been exposed to the study intervention by ingestion.

A male family member or healthcare provider who has been exposed to the study 
intervention by ingestion then exposes his female partner prior to or around the 
time of conception.
The investigator must report EDP to Pfizer Safety within 24 hours of the investigator’s 
awareness, irrespective of whether an SAE has occurred. The initial information submitted 
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 


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integrity of the terminated fetus should be assessed by gross visual inspection (unless 
preprocedure test findings are conclusive for a congenital anomaly and the findings are 
reported).
Abnormal pregnancy outcomes are considered SAEs. If the outcome of the pregnancy meets 
the criteria for an SAE (ie, ectopic pregnancy, spontaneous abortion, intrauterine fetal 
demise, neonatal death, or congenital anomaly in a liveborn 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 participant is found to be breastfeeding while receiving or after 
discontinuing study intervention.

A female is found to be breastfeeding while being exposed or having been exposed to 
study intervention (ie, environmental exposure). An example of environmental 
exposure during breastfeeding is a female family member or healthcare provider who 
reports that she is breastfeeding after having been exposed to the study intervention 
by ingestion.
The investigator must report exposure during breastfeeding to Pfizer Safety within 24 hours 
of the investigator’s awareness, irrespective of whether an SAE has occurred. The 
information must be reported using the CT SAE Report Form. When exposure during 
breastfeeding occurs in the setting of environmental exposure, the exposure information does 
not pertain to the participant enrolled in the study, so the information is not recorded on 
a CRF. However, a copy of the completed CT SAE Report Form is maintained in the 
investigator site file.


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An exposure during breastfeeding report is not created when a Pfizer drug specifically 
approved for use in breastfeeding women (eg, vitamins) is administered in accord with 
authorized use. However, if the infant experiences an SAE associated with such a drug, the 
SAE is reported together with the exposure during breastfeeding.
8.3.5.3. Occupational Exposure
The investigator must report any instance of occupational exposure to Pfizer Safety within 
24 hours of the investigator’s awareness using the CT SAE Report Form regardless of 
whether there is an associated SAE. Since the information about the occupational exposure 
does not pertain to a participant enrolled in the study, the information is not recorded on 
a CRF; however, a copy of the completed CT SAE Report Form must be maintained in the 
investigator site file.
8.3.6. Cardiovascular and Death Events
Not applicable.
8.3.7. Disease Related- Events and/or Disease Related- Outcomes Not Qualifying as AEs 
or SAEs
Not applicable.
8.3.8. Adverse Events of Special Interest
AESIs are examined as part of routine safety data review procedures throughout the clinical 
trial and as part of signal detection processes.
All AESIs must be reported as an AE or SAE following the procedures described in 
Section 8.3.1 through 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. Pharmacokinetics 
8.4.1. Plasma for Analysis of PF-07321332 and Ritonavir
Blood samples of approximately 4 mL, to provide approximately 1.5 mL plasma, will be 
collected for measurement of plasma concentrations of PF-07321332 and ritonavir as 
specified in the SoA. Instructions for the collection and handling of biological samples will 
be provided in the laboratory manual or by the sponsor. The actual date and time (24-hour 
clock time) of each sample will be recorded.
The actual times may change, but the number of samples will remain the same. All efforts 
will be made to obtain the samples at the exact nominal time relative to dosing. Collection of 
samples up to and including 10 hours after dose administration that are obtained within 
10% of the nominal time relative to dosing (eg, within 6 minutes of a 60 minute sample) will 
not be captured as a protocol deviation, as long as the exact time of the collection is noted on 
the source document and the CRF. Collection of samples more than 10 hours after dose
administration that are obtained ≤1 hour away from the nominal time relative to dosing will 
not be captured as a protocol deviation, as long as the exact time of the collection is noted on 
the source document and the CRF. 


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Samples will be used to evaluate the PK of PF-07321332 and ritonavir. Samples collected for 
analyses of PF-07321332 and ritonavir concentration may also be used to evaluate safety or 
efficacy aspects related to concerns arising during or after the study, for metabolite 
identification and/or evaluation of the bioanalytical method,
 
Genetic analyses will not be performed on these plasma samples 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 and ritonavir 
will be analyzed using a validated analytical method in compliance with applicable SOPs. 
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.
8.4.2. Plasma Qualitative Metabolite Profiling
Metabolite profiling is not being evaluated in this study.
 
 
 
 
8.6. Biomarkers
Biomarkers are not evaluated in this study.
8.6.1. Specified Gene Expression (RNA) Research 
Specified gene expression (RNA) research is not included in this study.
8.6.2. Specified Protein Research 
Specified protein research is not included in this study.
CCI
CCI
CCI


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8.6.3. Specified Metabolomic Research 
Specified metabolomic research is not included in this study.
8.7. Immunogenicity Assessments
Immunogenicity assessments are not included in this study.
8.8. Health Economics
Health economics/medical resource utilization and health economics parameters are not 
evaluated in this study.
9. STATISTICAL CONSIDERATIONS
Detailed methodology for summary and statistical analyses of the data collected in this study 
is outlined here and further detailed in the SAP, which will be maintained by the sponsor. 
The SAP may modify what is outlined in the protocol where appropriate; however, any major 
modifications of the primary endpoint definitions or their analyses will also be reflected in a 
protocol amendment.
9.1. Statistical Hypotheses
No statistical hypothesis will be tested in this study.
9.2. Analysis Sets
For purposes of analysis, the following analysis sets are defined:
Participant Analysis 
Set
Description
PK Concentration
The PK concentration population is defined as all participants 
assigned to investigational product and treated who have at 
least 1 concentration measured.
PK Parameter
The PK parameter analysis population is defined as all 
participants assigned to investigational product and treated 
who have at least 1 of the PK parameters of primary interest 
measured.
Safety Analysis Set
All participants randomly assigned to study intervention and 
who take at least 1 dose of study intervention. Participants 
will be analyzed according to the product they actually 
received.
9.3. Statistical Analyses
The SAP will be developed and finalized before any analyses are performed and will 
describe the analyses and procedures for accounting for missing, unused, and spurious data.


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This section is a summary of the planned statistical analyses of the primary and secondary 
endpoints.
9.3.1. Other Safety Analyses
All safety analyses will be performed on the safety population.
AEs, ECGs, BP, pulse rate, 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.
9.3.2. Statistical Methods for PK Data
The plasma concentrations of PF-07321332 and ritonavir will be listed and descriptively 
summarized by nominal PK sampling time and treatment. Individual participant, as well as 
mean and median profiles of the plasma concentration time data will be plotted by treatment 
for each analyte using actual (for individual) and nominal (for mean and median) times 
respectively. Mean and median profiles will be presented on both linear and semi-log scales. 
For comparison of AUCinf and Cmax with and without carbamazepine, box and whisker plots 
of these parameters will be plotted by treatment for each analyte. 
Natural log transformed parameters (AUCinf, AUClast, and Cmax) of PF-07321332 and 
ritonavir will be analyzed using a mixed effect model with treatment as fixed effect and 
participant as a random effect. Estimates of the adjusted mean differences (Test-Reference)
and corresponding 90% CIs will be obtained from the model. The adjusted mean differences 
and 90% CIs for the differences will be exponentiated to provide estimates of the ratio of 
adjusted geometric means (Test/Reference) and 90% CI for the ratios. PF-07321332/ritonavir
administered alone will be the Reference treatment and PF-07321332/ritonavir 
coadministered with carbamazepine will be the Test treatment.
Additional specifications about the tables, listings, and figures will be outlined in the SAP.
9.3.3. Derivation of Pharmacokinetic Parameters Prior to Analysis
The plasma PK parameters for PF-07321332 will be derived from the concentration time
profiles as detailed in Table 1. Actual PK sampling times will be used in the derivation of PK 


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parameters. In the case that actual PK sampling times are not available, nominal PK sampling 
time will be used in the derivation of PK parameters.
Table 1.
Plasma PK Parameters
Parameter
Analyte
Definition
Method of Determination
AUClast*
PF-07321332/ritonavir
Area under the plasma 
concentration-time profile 
from time zero to the time 
of the last quantifiable 
concentration (Clast)
Linear/Log trapezoidal method.
AUCinf
PF-07321332/ritonavir
Area under the plasma 
concentration-time profile 
from time 0 extrapolated to 
infinite time
AUClast + (Clast*/kel), Where Clast* is 
the predicted plasma concentration 
at the last quantifiable time point 
estimated from the log-linear 
regression analysis.
Cmax
PF-07321332/ritonavir
Maximum plasma 
concentration
Observed directly from data.
Tmax*
PF-07321332/ritonavir
Time for Cmax
Observed directly from data as time 
of first occurrence.
t½*
PF-07321332/ritonavir
Terminal elimination 
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 will 
be used in the regression.
CL/F*
PF-07321332/ritonavir
Apparent clearance
Dose/AUCinf
Vz/F*
PF-07321332/ritonavir
Apparent volume of 
distribution
Dose/(AUCinf×kel).
*
As data permit.
9.4. Interim Analyses
No formal interim analysis will be conducted for this study. As this is an open-label
study, the sponsor may conduct unblinded reviews of the data during the course of the study 
for the purpose of safety assessment, facilitating PK/PD modeling, and/or supporting clinical 
development.
9.5. Sample Size Determination
A sample size of 12 participants will provide adequate precision to estimate the effects of 
carbamazepine on the PK of PF-07321332. The expected widths of the 90% CIs with 80% 
coverage probability are shown in the following table for a range of possible effects. 
Parameter
Estimated Effect 
(100*Test/Reference)
90% CI
CI Width
AUCinf
60%
70%
80%
90%
53%, 68%
62%, 79%
71%, 90%
80%, 102%
15%
17%
20%
22%


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Parameter
Estimated Effect 
(100*Test/Reference)
90% CI
CI Width
100%
88%, 113%
25%
Cmax
60%
70%
80%
90%
100%
55%, 65%
65%, 76%
74%, 87%
83%, 97%
92%, 108%
9%
11%
13%
14%
16%
These estimates are based on the assumption that within-participant standard deviations are 
0.14 and 0.091 for lnAUCinf and lnCmax, respectively, as obtained from ongoing clinical study 
C4671001 in healthy participants.
12 participants will be enrolled in the study. Participants who withdraw from the study may 
be replaced at the discretion of the investigator upon consultation with the sponsor.


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10. SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS
10.1. Appendix 1: Regulatory, Ethical, and Study Oversight Considerations
10.1.1. Regulatory and Ethical Considerations
This study will be conducted in accordance with the protocol and with the following:

Consensus ethical principles derived from international guidelines, including the 
Declaration of Helsinki and CIOMS International Ethical Guidelines;

Applicable ICH GCP guidelines;

Applicable laws and regulations, including applicable privacy laws.
The protocol, protocol amendments, ICD, SRSD(s), and other relevant documents 
(eg, advertisements) must be reviewed and approved by the sponsor, submitted to an IRB/EC 
by the investigator, and reviewed and approved by the IRB/EC before the study is initiated.
Any amendments to the protocol will require IRB/EC approval before implementation of 
changes made to the study design, except for changes necessary to eliminate an immediate 
hazard to study participants.
Protocols and any substantial amendments to the protocol will require health authority 
approval prior to initiation except for changes necessary to eliminate an immediate hazard to 
study participants.
The investigator will be responsible for the following:

Providing written summaries of the status of the study to the IRB/EC annually or 
more frequently in accordance with the requirements, policies, and procedures 
established by the IRB/EC;

Notifying the IRB/EC of SAEs or other significant safety findings as required by 
IRB/EC procedures;

Providing oversight of the conduct of the study at the site and adherence to 
requirements of 21 CFR, ICH GCP guidelines, the IRB/EC, European regulation 
536/2014 for clinical studies (if applicable), European Medical Device Regulation 
2017/745 for clinical device research (if applicable), and all other applicable local 
regulations.
10.1.1.1. Reporting of Safety Issues and Serious Breaches of the Protocol or ICH GCP
In the event of any prohibition or restriction imposed (ie, clinical hold) by an applicable 
regulatory authority in any area of the world, or if the investigator is aware of any new 
information that might influence the evaluation of the benefits and risks of the study 
intervention, Pfizer should be informed immediately.


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


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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 form and/or 
paper 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 ID. In case of 
data transfer, the sponsor will protect the confidentiality of participants’ personal data 
consistent with the clinical study agreement and applicable privacy laws.
10.1.4. Committees Structure
10.1.4.1. Data Monitoring Committee 
This study will not use a DMC.
10.1.5. 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 data from these trials available 
24 months after study completion. Participant level- data will be anonymized in accordance 
with applicable privacy laws and regulations. CSRs will have personally identifiable 
information 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.
10.1.6. Data Quality Assurance
All participant data relating to the study will be recorded on printed or electronic CRF unless 
transmitted to the sponsor or designee electronically (eg, laboratory data). The investigator is 
responsible for verifying that data entries are accurate and correct by physically or 
electronically signing the CRF.
Guidance on completion of CRFs will be provided in the CRF Completion Requirements 
document.


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


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10.1.7. Source Documents
Source documents provide evidence for the existence of the participant and substantiate the 
integrity of the data collected. Source documents are filed at the investigator site.
Data reported on the CRF or entered in the eCRF that are from source documents must be 
consistent with the source documents or the discrepancies must be explained. The 
investigator may need to request previous medical records or transfer records, depending on 
the study. Also, current medical records must be available.
Definition of what constitutes source data and its origin can be found in the Source 
Document Locator, which is maintained by the sponsor’s designee (Pfizer Clinical Research 
Unit).
Description of the use of the computerized system is documented in the Source Document 
Locator, which is maintained by the sponsor’s designee (Pfizer Clinical Research Unit).
The investigator must maintain accurate documentation (source data) that supports the 
information entered in the CRF.
Study monitors will perform ongoing source data verification to confirm that data entered 
into the CRF by authorized site personnel are accurate, complete, and verifiable from source 
documents; that the safety and rights of participants are being protected; and that the study is 
being conducted in accordance with the currently approved protocol and any other study 
agreements, ICH GCP guidelines, and all applicable regulatory requirements.
10.1.8. 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.
Reasons for the early closure of a study site by the sponsor may include but are not limited 
to:

Failure of the investigator to comply with the protocol, the requirements of the 
IRB/EC or local health authorities, the sponsor's procedures, or the ICH GCP 
guidelines;

Inadequate recruitment of participants by the investigator;


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
Discontinuation of further study intervention development.
If the study is prematurely terminated or suspended, the sponsor shall promptly inform the 
investigators, the ECs/IRBs, the regulatory authorities, and any CRO(s) used in the study of 
the reason for termination or suspension, as specified by the applicable regulatory 
requirements. The investigator shall promptly inform the participant and should assure 
appropriate participant therapy and/or follow-up.
Study termination is also provided for in the clinical study agreement. If there is any conflict 
between the contract and this protocol, the contract will control as to termination rights.
10.1.9. 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.
10.1.10. 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 system.


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To facilitate access to appropriately qualified medical personnel for study-related medical 
questions or problems, participants are provided with an ECC at the time of informed 
consent. The ECC contains, at a minimum, (a) protocol and study intervention identifiers, (b) 
participant’s study identification number, (c) site emergency phone number active 
24 hours/day, 7 days per week.
The ECC is intended to augment, not replace, the established communication pathways 
between the investigator, site staff, and study team. The ECC is to be used by healthcare 
professionals not involved in the research study only, as a means of reaching the investigator 
or site staff related to the care of a participant. 


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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 2.
Protocol-Required Safety Laboratory Assessments
Hematology
Chemistry
Urinalysis
Other
Hemoglobin
Hematocrit
RBC count
MCV
MCH
MCHC
Platelet count
WBC count
Total neutrophils 
(Abs)
Eosinophils (Abs)
Monocytes (Abs)
Basophils (Abs)
Lymphocytes (Abs)
BUN/urea and creatinine
Glucose (fasting)
Calcium
Sodium
Potassium
Chloride
Total CO2 (bicarbonate)
AST, ALT
Total bilirubin
Alkaline phosphatase
Uric acid
Albumin
Total protein
Local Dipstick:
pH
Glucose (qual)
Protein (qual)
Blood (qual)
Ketones
Nitrites
Leukocyte esterase
Laboratory:
Microscopy and 
culturea
•
SARS-CoV-2 RT-PCR
•
TSH
•
Free T4
•
Urine drug screeningb
•
Pregnancy test (β-hCG)c
•
aPTT
•
PT-INR
•
Fibrinogen
At screening only
•
FSHd
•
HIV
•
HBsAge
•
HBcAbe
•
HCVAb 
•
HBsAbe
•
HLA-B*1502 & HLA-A*
3101
a.
Only if urine dipstick is positive for blood, protein, nitrites, or leukocyte esterase and culture only if 
bacteriuria.
b.
At screening and Day -1; The minimum requirement for drug screening includes cocaine, THC, 
opiates/opioids, benzodiazepines, and amphetamines (others are site and study specific).
c.
Serum or urine β-hCG for female participants of childbearing potential.
d.
For confirmation of postmenopausal status only.
e.
HBsAb will be performed as reflex testing for any participant who is HBsAg and HBcAb positive.
The investigator must review the laboratory report, document this review, and record any 
clinically relevant changes occurring during the study in the AE section of the CRF.
Any remaining serum/plasma from samples collected for clinical safety laboratory 
measurements at baseline and at all times after dose administration may be retained and 
stored for the duration of the study.
 
 
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10.3. Appendix 3: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting
10.3.1. Definition of AE
AE Definition

An AE is any untoward medical occurrence in a patient or clinical study 
participant, temporally associated with the use of study intervention, whether or 
not considered related to the study intervention.

Note: An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease (new or exacerbated) 
temporally associated with the use of study intervention.
Events Meeting the AE Definition

Any abnormal laboratory test results (hematology, clinical chemistry, or 
urinalysis) or other safety assessments (eg, ECG, radiological scans, vital sign 
measurements), including those that worsen from baseline, considered clinically 
significant in the medical and scientific judgment of the investigator. Any 
abnormal laboratory test results that meet any of the conditions below must be 
recorded as an AE:

Is associated with accompanying symptoms;

Requires additional diagnostic testing or medical/surgical intervention;

Leads to a change in study dosing (outside of any protocol-specified dose 
adjustments) or discontinuation from the study, significant additional 
concomitant drug treatment, or other therapy.

Exacerbation of a chronic or intermittent preexisting condition, including either 
an increase in frequency and/or intensity of the condition.

New condition detected or diagnosed after study intervention administration,
even though it may have been present before the start of the study.

Signs, symptoms, or the clinical sequelae of a suspected drug--drug interaction.

Signs, symptoms, or the clinical sequelae of a suspected overdose of either study 
intervention or a concomitant medication. Overdose per se will not be reported as 
an AE or SAE unless it is an intentional overdose taken with possible 
suicidal/self--harming intent. Such overdoses should be reported regardless of 
sequelae.


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


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d. Results in persistent or significant disability/incapacity

The term disability means a substantial disruption of a person’s ability to conduct 
normal life functions.

This definition is not intended to include experiences of relatively minor medical 
significance, such as uncomplicated headache, nausea, vomiting, diarrhea, 
influenza, and accidental trauma (eg, sprained ankle), that may interfere with or 
prevent everyday life functions but do not constitute a substantial disruption.
e.
Is a congenital anomaly/birth defect
f.
Is a suspected transmission via a Pfizer product of an infectious agent, 
pathogenic or non-pathogenic, is considered serious.
The event may be suspected from clinical symptoms or laboratory findings 
indicating an infection in a participant exposed to a Pfizer product. The terms 
“suspected transmission” and “transmission” are considered synonymous. These 
cases are considered unexpected and handled as serious expedited cases by 
pharmacovigilance personnel. Such cases are also considered for reporting as 
product defects, if appropriate.
g. Other situations:

Medical or scientific judgment should be exercised by the investigator in 
deciding whether SAE reporting is appropriate in other situations, such as 
significant medical events that may jeopardize the participant or may require 
medical or surgical intervention to prevent one of the other outcomes listed in the 
above definition. These events should usually be considered serious.

Examples of such events include invasive or malignant cancers, intensive 
treatment in an emergency room or at home for allergic bronchospasm, blood 
dyscrasias or convulsions that do not result in hospitalization, or development of 
drug dependency or drug abuse.
10.3.3. Recording/Reporting and Follow-up of AEs and/or SAEs During the Active 
Collection Period
AE and SAE Recording/Reporting
The table below summarizes the requirements for recording AEs on the CRF and for 
reporting SAEs on the CT SAE Report Form to Pfizer Safety throughout the active 
collection period. These requirements are delineated for 3 types of events: (1) SAEs; (2) 
nonserious AEs; and (3) exposure to the study intervention under study during 
pregnancy or breastfeeding, and occupational exposure. 


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It should be noted that the CT SAE Report Form for reporting of SAE information is not 
the same as the AE page of the CRF. When the same data are collected, the forms must 
be completed in a consistent manner. AEs should be recorded using concise medical 
terminology and the same AE term should be used on both the CRF and the CT SAE 
Report Form for reporting of SAE information.
Safety Event
Recorded on the CRF
Reported on the CT SAE 
Report Form to Pfizer 
Safety Within 24 Hours 
of Awareness
SAE
All
All
Nonserious AE
All
None
Exposure to the study 
intervention under study 
during pregnancy or 
breastfeeding
All AEs/SAEs associated 
with exposure during 
pregnancy or breastfeeding
Note: Instances of EDP or 
EDB not associated with an 
AE or SAE are not captured 
in the CRF.
All instances of EDP are 
reported (whether or not 
there is an associated 
SAE)*
All instances of EDB are 
reported (whether or not 
there is an associated 
SAE).**
Environmental or 
occupational exposure 
to the product under 
study to a non-
participant (not 
involving EDP or EDB).
None. Exposure to a study 
non-participant is not 
collected on the CRF.
The exposure (whether or 
not there is an associated 
AE or SAE) must be 
reported.***
*
EDP (with or without an associated AE or SAE): any pregnancy information 
is reported to Pfizer Safety using CT SAE Report Form and EDP 
Supplemental Form; if the EDP is associated with an SAE, then the SAE is 
reported to Pfizer Safety using the CT SAE Report Form. 
** 
EDB is reported to Pfizer Safety using the CT SAE Report Form which 
would also include details of any SAE that might be associated with the 
EDB. 
***
Environmental or Occupational exposure: AEs or SAEs associated with 
occupational exposure are reported to Pfizer Safety using the CT SAE 
Report Form.


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


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


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


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SAE Reporting to Pfizer Safety via CT SAE Report Form

Facsimile transmission of the CT SAE Report Form is the preferred method to 
transmit this information to Pfizer Safety.

In circumstances when the facsimile is not working, notification by telephone is 
acceptable with a copy of the CT SAE Report Form sent by overnight mail or 
courier service.

Initial notification via telephone does not replace the need for the investigator to 
complete and sign the CT SAE Report Form pages within the designated 
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10.4. Appendix 4: Contraceptive and Barrier Guidance
10.4.1. Male Participant Reproductive Inclusion Criteria
Male participants are eligible to participate if they agree to the following requirements during 
the intervention period and for at least 28 days after the last dose of study intervention, which
corresponds to the time needed to eliminate reproductive safety risk of the study 
intervention(s):

Refrain from donating sperm.
PLUS either:

Be abstinent from heterosexual intercourse with a female of childbearing potential as 
their preferred and usual lifestyle (abstinent on a long term- and persistent basis) and 
agree to remain abstinent.
OR

Must agree to use contraception/barrier as detailed below:

Agree to use a male condom and should also be advised of the benefit for a 
female partner to use a highly effective method of contraception as a condom may 
break or leak when having sexual intercourse with a woman of childbearing 
potential who is not currently pregnant.

In addition to male condom use, a highly effective method of contraception may be 
considered in WOCBP partners of male participants (refer to the list of highly 
effective methods below in Section 10.4.4).
10.4.2. Female Participant Reproductive Inclusion Criteria
A female participant is eligible to participate if she is not pregnant or breastfeeding, and at 
least 1 of the following conditions applies:

Is not a WOCBP (see definitions below in Section 10.4.3).
OR

Is a WOCBP and using a contraceptive method that is highly effective (with a failure 
rate of <1% per year), preferably 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.


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
A WOCBP agrees not to donate eggs (ova, oocytes) for the purpose of reproduction 
during this period. The investigator should evaluate the effectiveness of the 
contraceptive method in relationship to the first dose of study intervention.
The investigator is responsible for review of medical history, menstrual history, and recent 
sexual activity to decrease the risk for inclusion of a woman with an early undetected 
pregnancy. 
10.4.3. Woman of Childbearing Potential
A woman is considered fertile following menarche and until becoming postmenopausal 
unless permanently sterile (see below).
If fertility is unclear (eg, amenorrhea in adolescents or athletes) and a menstrual cycle cannot 
be confirmed before the first dose of study intervention, additional evaluation should be 
considered.
Women in the following categories are not considered WOCBP:
1. Premenopausal female with 1 of the following:

Documented hysterectomy;

Documented bilateral salpingectomy;

Documented bilateral oophorectomy.
For individuals with permanent infertility due to an alternate medical cause other than 
the above, (eg, mullerian agenesis, androgen insensitivity), investigator discretion 
should be applied to determining study entry.
Note: Documentation for any of the above categories can come from the site 
personnel’s review of the participant’s medical records, medical examination, or 
medical history interview. The method of documentation should be recorded in the 
participant’s medical record for the study.
2. Postmenopausal female.

A postmenopausal state is defined as no menses for 12 months without an 
alternative medical cause. In addition:

A high FSH level in the postmenopausal range must be used to confirm a 
postmenopausal state in women under 60 years old and not using hormonal 
contraception or HRT. 

A female on HRT and whose menopausal status is in doubt will be required to 
use one of the non-estrogen hormonal highly effective contraception methods 


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if they wish to continue their HRT during the study. Otherwise, they must 
discontinue HRT at least 28 days prior to the first dose of investigational 
product.
10.4.4. Contraception Methods
Contraceptive use by men or women should be consistent with local availability/regulations 
regarding the use of contraceptive methods for those participating in clinical trials.
Highly Effective Methods That Have Low User Dependency
1. Copper IUD
2. Bilateral tubal occlusion (eg, bilateral tubal ligation).
3. Vasectomized partner.

A vasectomized partner is a highly effective contraceptive method provided that 
the partner is the sole sexual partner of the WOCBP and the absence of sperm has 
been confirmed. If not, an additional highly effective method of contraception 
should be used. The spermatogenesis cycle is approximately 90 days.
Highly Effective Methods That Are User Dependent
4. 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;

Cervical cap, diaphragm, or sponge with spermicide;

A combination of male condom with either cervical cap, diaphragm, or sponge with 
spermicide (double-barrier methods).


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


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


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10.7. Appendix 7: ECG Findings of Potential Clinical Concern
ECG Findings That May Qualify as AEs

Marked sinus bradycardia (rate <40 bpm) lasting minutes.

New PR interval prolongation >280 msec.

New prolongation of QTcF to >480 msec (absolute) or by ≥60 msec from 
baseline.

New onset- atrial flutter or fibrillation, with controlled ventricular response rate:
ie, rate <120 bpm.

New onset- type I second-degree- (Wenckebach) AV block of >30 seconds’
duration.

Frequent PVCs, triplets, or short intervals (<30 seconds) of consecutive 
ventricular complexes.
ECG Findings That May Qualify as SAEs

QTcF prolongation >500 msec.

New ST-T changes suggestive of myocardial ischemia.

New onset- left bundle branch block (QRS >120 msec).

New onset- right bundle branch block (QRS >120 msec).

Symptomatic bradycardia.

Asystole:

In awake, symptom free- participants in sinus rhythm, with documented 
periods of asystole ≥3.0 seconds or any escape rate <40 bpm, or with an 
escape rhythm that is below the AV node. 

In awake, symptom free- participants with atrial fibrillation and bradycardia 
with 1 or more pauses of at least 5 seconds or longer. 

Atrial flutter or fibrillation, with rapid ventricular response rate: rapid = rate 
>120 bpm.

Sustained supraventricular tachycardia (rate >120 bpm) (“sustained” = short 
duration with relevant symptoms or lasting >1 minute).


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


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10.8. Appendix 8: Prohibited and Precautionary Concomitant Medications That May 
Result in DDI
The prohibited concomitant medications listed below should not be taken with PF-07321332
and ritonavir during dosing and up to 4 days after the final dose of ritonavir.
The Pfizer study team is to be notified of any prohibited medications taken during the study. 
This list of drugs prohibited or precautionary for potential DDI concerns with the IMP may 
be revised during the course of the study with written notification from sponsor, to include or 
exclude specific drugs or drug categories for various reasons (eg, emerging DDI results for 
the IMP, availability of new information in literature on the DDI potential of other drugs).
This is not an all-inclusive list. Site staff should consult with the sponsor or designee with 
any questions regarding potential DDI.
Prohibited Medications
Medications that are Strong Inducers of CYP3A4a
Drug Class
Specific Medication
Clinical Comments
Anti-infectives
Rifampin
Potential to impact the PK of PF-
07321332 and ritonavir
Anti-epileptic
Phenytoin, carbamazepine
Herbal Products
St. John's wort
Medications Dependent on CYP3A4 for Clearance, with Drug Interactions with
PF-07321332/ritonavira
Alpha 1-Adrenoreceptor 
Antagonist
Alfuzosin
Risk of hypotension, syncope
Antianginal
Ranolazine
Risk of cardiac arrhythmias 
Antiarrhythmics 
Amiodarone, Bepridil, Flecainide, 
Propafenone, Quinidine, 
Dronedarone, Encainide
Risk of cardiac arrhythmias 
Antihistamines
Astemizole, Terfenadine
Risk of cardiac arrhythmias
Ergot Derivatives
Dihydroergotamine, Ergonovine, 
Ergotamine, Methylergonovine
Risk of acute ergot toxicity 
(peripheral vasospasm and ischemia 
of the extremities)
HMG CoA Reductase 
Inhibitors 
Lovastatin, Simvastatin 
Risk of rhabdomyolysis; consider 
alternative agent: pravastatin
Neuroleptic
Pimozide
Risk of cardiac arrhythmias 
PDE-5 inhibitors
Sildenafil (Revatio) - PAH
Risk of visual disturbances, 
hypotension, prolonged erection, and 
syncope
Sedatives/hypnotics
Oral Midazolam, Triazolam
Risk of prolonged sedation or 
respiratory depression
a.
If a drug is not listed, it should not automatically be assumed it is safe to co-administer.


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Precautionary Medications
Medications to be Used with Caution when Co-administered with PF-07321332/ritonavira
Drug Class 
Specific Drugs 
Clinical Comments 
Anticonvulsants
Lamotrigine, 
Valproate
Phenytoin
Carbamazepine
Coadministration may decrease 
lamotrigine, valproate, and phenytoin 
concentrations. 
Coadministration may increase 
carbamazepine concentrations. Careful 
monitoring of adverse effects.
Alternative agents: Gabapentin 
Topiramate
Anticoagulants
Rivaroxaban
Increased risk of bleeding; consider 
alternative anticoagulant.
Antidepressant
Trazadone, Desipramine, Fluoxetine 
Paroxetine, Sertraline
May increase antidepressant 
concentration.
Anti-infective
Erythromycin
Coadministration may increase 
erythromycin concentration. 
Antifungals
Itraconazole
Voriconazole
Coadministration may increase 
itraconazole concentration. Monitor for 
adverse effects.
Coadministration may decrease 
voriconazole concentration.
Calcium Channel 
Blockers 
Diltiazem, Verapamil, Felodipine, 
Nicardipine, Nisoldipine, Amlodipine
Coadministration may increase 
concentrations. The impact on the PR 
interval of co-administration of ritonavir 
with other drugs that prolong the PR 
interval (including calcium channel 
blockers) has not been evaluated. If 
coadministration is indicated, consider a 
dose reduction (amlodipine
recommended dose reduction of 50%). 
Close monitoring is recommended.
Cardiac Glycosides
Digoxin
Coadministration increases digoxin 
concentration.
Contraceptives
Hormonal contraception
Recommend barrier method
Hepatitis C direct 
acting antivirals
Boceprevir, Glecaprevir/Pibrentasvir
Simeprevir, 
Sofosbuvir/Velpatasvir/Voxilaprevir
Ombitasvir/Paritaprevir/Ritonavir, 
Dasabuvir
Coadministration is not recommended as 
it resulted in increased plasma 
concentrations of Hep C antiviral; 
Caution or not recommended.
HIV Protease 
Inhibitors
NNRTs, Fusion 
Inhibitors
Lopinavir, Amprenavir, Indinavir, 
Nelfinavir, Saquinavir
Abacavir, Didanosine, Zidovudine
Coadministration may increase HIV 
protease inhibitor concentrations; 
coadminister with caution.
HMG CoA reductase 
inhibitors
Atorvastatin, Rosuvastatin
Use with caution; risk of myopathy 
including rhabdomyolysis. Use lowest 
dose of statin.
Alternative agents: Pravastatin.
Hypoglycemics
Glipizide, Tolbutamide
Potentially decrease glipizide and 
tolbutamide concentrations. 


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Precautionary Medications
Repaglinide
Potentially increase repaglinide 
concentrations. 
Immunosuppressants
Cyclosporine, Tacrolimus, Sirolimus
Coadministration may increase 
immunosuppressant concentrations. 
Narcotic Analgesics
Methadone, Fentanyl
Moderate to weak decreases in 
methadone AUC have been observed
Fentanyl concentration may increase.
a.
If a drug is not listed, it should not automatically be assumed it is safe to co-administer.


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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

ongoing/continuous event
3CL
3C-like
3CLpro
3C-like protein
Ab
Antibody
Abs
Absolute
ADL
activities of daily living
AE
adverse event
AED
antiepileptic drug
ALT
alanine aminotransferase
aPTT
activated partial thromboplastin time
AST
aspartate aminotransferase
AUC
area under the concentration-time curve
AUCinf
area under the plasma concentration-time curve from time 0 
extrapolated to infinity
AUClast
area under the plasma concentration time curve from time 0 to the 
time of the last measurable concentration
AV
Atrioventricular
BBS
Biospecimen Banking System
BID
twice a day
BMI
body mass index
BP
blood pressure
bpm
beats per minute
BUN
blood urea nitrogen
C-SSRS
Columbia-Suicide Severity Ratiing Scale 
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/F
apparent clearance of drug from eg, plasma
Clast
last observed (quantifiable) plasma concentration
Cmax
maximum observed plasma concentration
CO2
carbon dioxide (bicarbonate)
COVID-19
coronavirus disease 2019
CRF
case report form
CRO
contract research organization
CRU
clinical research unit
CSR
Clinical Study Report
CT
clinical trial


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Abbreviation
Term
CTMS
clinical trial management system
CYP
cytochrome P450 
CYP3450
cytochrome P450, family 3
CYP3A
cytochrome P450 3A
CYP3A4
cytochrome P450 3A4 
CYP3A5
cytochrome P450 3A5
DCT
data collection tool
DDI
drug-drug interaction 
DILI
drug-induced liver injury
DMC
Data Monitoring Committee
EC
ethics committee
ECC
Emergency Contact Card
ECG
Electrocardiogram
eCRF
electronic case report form
EDB
exposure during breastfeeding
EDP
exposure during pregnancy
eGFR
estimated glomerular filtration rate
EMA
European Medicines Agency
ER
extended release
ET
early termination
EU
European Union
EUA
Emergency Use Authorization
EudraCT
European Clinical Trials Database
FIH
first-in-human
fm
fraction metabolized
FSH
follicle stimulating hormone
GCP
Good Clinical Practice
GGT
gamma-glutamyl transferase
GLP
Good Laboratory Practice
HBcAb 
hepatitis B core antibody
HBsAb
hepatitis B surface antibody
HBsAg 
hepatitis B surface antigen
HCL
Hydrochloride
HCoV-229E
human coronavirus 229E
HCoV-HKU1
human coronavirus HKU1
HCoV-NL63
human coronavirus NL63
HCoV-OC43
human coronavirus OC43
HCV
hepatitis C virus
HCVAb
hepatitis C antibody
HIV
human immunodeficiency virus
HMG CoA
3-hydroxy-3-methyl-glutaryl-CoA
CCI


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Abbreviation
Term
hr(s)
hour(s)
HR
heart rate
HRT
hormone replacement therapy
IB
Investigator's Brochure
ICD
informed consent document
ICH
International Council for Harmonisation
ID
Identification
IMP
investigational medicinal product
IND
Investigational New Drug 
INR
international normalized ratio
IP
investigational product
IPAL
Investigational Product Accountability Log
IQMP
Independent Qualified Medical Practitioners
IRB
Institutional Review Board
IV
Intravenous
kel
terminal phase rate constant calculated by a linear regression of 
the log-linear concentration-time curve.
Ki 
inhibition constant
LBBB
left bundle branch block
LFT
liver function test
lnCmax
log-transformed Cmax
Loge
natural logarithm
MAD
multiple ascending dose
MAO
monoamine oxidase
MAOI
monoamine oxidase inhibitors
MCH
mean corpuscular hemoglobin
MCHC
mean corpuscular hemoglobin concentration
MCV
mean corpuscular volume
MERS
Middle East respiratory syndrome 
mg
Milligram
mL
Milliliter
msec
Millisecond
N/A
not applicable
NHP
non-human primate
NNRT
non-nucleoside reverse transcriptase 
NOAEL
no observed adverse effect level
P1
Period 1
P2
Period 2
PAH
pulmonary arterial hypertension
PCR
polymerase chain reaction
PD
pharmacodynamic(s)
PDE-5
phosphodiesterase type 5


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Abbreviation
Term
PE
physical examination
pH
potential of hydrogen
PK
pharmacokinetic(s)
PO
Orally
PR
pulse rate
PT
prothrombin time
PT-INR
prothrombin time-international normalized ratio
PVC
premature ventricular contraction/complex
q12h
every 12 hours
BID
once daily
QT
time from the beginning of the QRS complex to the end of the 
T wave
QTc
corrected QT interval
QTcF
corrected QT (Fridericia method)
qual
Qualitative
RBC
red blood cell
RNA
ribonucleic acid
RR
respiratory rate 
RT-PCR
reverse-transcriptase polymerase chain reaction
SAD
single ascending dose
SAE
serious adverse event
SAP
Statistical Analysis Plan
SARS-CoV-1
severe acute respiratory syndrome coronavirus 2
SARS-CoV-2
severe acute respiratory syndrome coronavirus 2
SCr
serum creatinine
SJS
Stevens-Johnson syndrome 
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 event
TEN
toxic epidermal necrolysis
THC
Tetrahydrocannabinol
Tmax
time to first occurrence of Cmax
TSH
thyroid stimulating hormone
ULN
upper limit of normal
US
United States
USPI
United States Prescribing Information
Vz/F
apparent volume of distribution


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Abbreviation
Term
WBC
white blood cell
WHO
World Health Organization
WOCBP
woman/women of childbearing potential


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11. REFERENCES
1
IIsu A, Granneman G, Bertz R. Ritonavir: Clinical pharmacokinetics and interactions 
with other anti-HIV agents. Clin Pharmacokinet. 1998;35(4):275-91.
2
World Health Organization. WHO Situation Report 51. 11 March 2020. Geneva, 
Switzerland: World Health Organization; 2020. Available from: 
https://www.who.int/emergencies/diseases/novel-coronavirus-2019/situation-reports. 
Accessed: 29 March 2020.
3
Anand K, Ziebuhr J, Wadhwani P, et al. Coronavirus main proteinase (3CLpro) 
structure: basis for design of anti-SARS drugs. Science. 2003;300(5626):1763-7.
4
Andreasen AH, Brøsen K, Damkier P. A comparative pharmacokinetic study in healthy 
volunteers of the effect of carbamazepine and oxcarbazepine on cyp3a4. Epilepsia. 2007 
Mar;48(3):490-6. doi: 10.1111/j.1528-1167.2007.00924.x. PMID: 17346248.
5
Bertilsson L, Tybring G, Widén J, et al. Carbamazepine treatment induces the CYP3A4 
catalysed sulphoxidation of omeprazole, but has no or less effect on hydroxylation via 
CYP2C19. Br J Clin Pharmacol. 1997 Aug;44(2):186-9. doi: 10.1046/j.1365-
2125.1997.00630.x. PMID: 9278208; PMCID: PMC2042829.
6
Dalton MJ, Powell JR, Messenheimer JA Jr, Clark J. Cimetidine and carbamazepine: a 
complex drug interaction. Epilepsia. 1986 Sep-Oct;27(5):553-8. doi: 10.1111/j.1528-
1157.1986.tb03583.x. PMID: 3757941.,
7
Stockis A, Chanteux H, Rosa M, Rolan P. Brivaracetam and carbamazepine interaction 
in healthy subjects and in vitro. Epilepsy Res. 2015 Jul;113:19-27. doi: 
10.1016/j.eplepsyres.2015.03.003. Epub 2015 Mar 19. PMID: 25986188.

SAP_001.pdf: 
Protocol C4671014 (PF-07321332) Statistical Analysis Plan
PFIZER GENERAL BUSINESS 
Page 1
Protocol C4671014
A PHASE 1, OPEN-LABEL, FIXED SEQUENCE, 2-PERIOD 
CROSSOVER STUDY TO ESTIMATE THE EFFECT OF 
CARBAMAZEPINE ON THE PHARMACOKINETICS OF PF-07321332 
BOOSTED WITH RITONAVIR IN HEALTHY PARTICIPANTS
Statistical Analysis Plan 
(SAP)
Version:
1.0
SAP Author:
Date:
21 SEP 2021  
PPD
PPD


Protocol C4671014 (PF-07321332) Statistical Analysis Plan
PFIZER GENERAL BUSINESS 
Page 2
TABLE OF CONTENTS
LIST OF TABLES.....................................................................................................................3
LIST OF FIGURES ...................................................................................................................3
APPENDICES ...........................................................................................................................4
1. VERSION HISTORY............................................................................................................5
2. INTRODUCTION .................................................................................................................5
2.1. Study Objectives, Endpoints .....................................................................................5
2.1.1. Primary Objective.........................................................................................5
2.1.2. Secondary Objectives ...................................................................................5
2.2. Study Design .............................................................................................................6
3. ENDPOINTS AND BASELINE VARIABLES: DEFINITIONS AND 
CONVENTIONS ..................................................................................................................8
3.1. Primary Endpoint(s) ..................................................................................................8
3.2. Secondary Endpoint(s) ..............................................................................................8
3.3. Safety Endpoints .......................................................................................................8
3.3.1. Adverse Events.............................................................................................8
3.3.2. Laboratory Data............................................................................................8
3.3.3. Vital Signs Data............................................................................................9
3.3.4. ECG Data......................................................................................................9
3.3.5. Other Safety Data .........................................................................................9
3.4. Pharmacokinetic(PK) Endpoints...............................................................................9
4. ANALYSIS SETS (POPULATIONS FOR ANALYSIS)...................................................10
4.1. For Purposes of Analysis, the Following Analysis Sets are Defined......................10
4.2. Treatment Misallocations........................................................................................10
4.3. Protocol Deviations.................................................................................................11
4.3.1. Deviations Assessed Prior to Randomization.............................................11
4.3.2. Deviations Assessed Post-Randomization..................................................11
5. GENERAL METHODOLOGY AND CONVENTIONS....................................................11
5.1. Hypotheses and Decision Rules ..............................................................................11
5.2. General Methods .....................................................................................................11
5.2.1. Statistical Analyses.....................................................................................11


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5.3. Methods to Manage Missing Data ..........................................................................13
5.3.1. Concentrations Below the Limit of Quantification ....................................13
5.3.2. Deviations, Missing Concentrations and Anomalous Values.....................13
5.3.3. Pharmacokinetic Parameters.......................................................................14
6. ANALYSES AND SUMMARIES ......................................................................................14
6.1. Study Conduct and Participant Disposition ............................................................14
6.1.1. Demographic and Clinical Examination Data............................................14
6.1.2. Discontinuation(s).......................................................................................14
6.2. Safety Summaries and Analyses .............................................................................15
6.2.1. Adverse Events...........................................................................................15
6.2.2. Laboratory Data..........................................................................................15
6.2.3. Vital Signs Data..........................................................................................15
6.2.4. ECG Data....................................................................................................15
6.2.5. Concomitant Medications and Nondrug Treatments..................................16
6.2.6. COVID-19 test results ................................................................................16
6.2.7. Suicidal Ideation and Behavior Risk Data..................................................16
6.2.8. Screening and Other Special Purpose Data ................................................16
7. INTERIM ANALYSES.......................................................................................................16
8. REFERENCES ....................................................................................................................17
9. APPENDICES .....................................................................................................................18
LIST OF TABLES
Table 1.
Summary of Changes..................................................................................5
Table 2.
Plasma PK Parameters................................................................................9
Table 3.
Plasma PK Parameters to be Summarized Descriptively by Analyte 
and Treatment ...........................................................................................12
Table 4.
QTcF Categorical Thresholds...................................................................15
LIST OF FIGURES
Figure 1.
The Schematic Represents the Study Design .............................................7
Figure 2.
Titration Scheme for Carbamazepine.........................................................7


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PFIZER GENERAL BUSINESS 
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APPENDICES
Appendix 1. SAS CODE FOR ANALYSES...........................................................................18


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PFIZER GENERAL BUSINESS 
Page 5
1. VERSION HISTORY
Table 1.
Summary of Changes
Version/
Date
Associated Protocol 
Amendment
Rationale
Specific Changes
1.0/ 21 SEP 2021
N/A
N/A
N/A
2. INTRODUCTION
This statistical analysis plan (SAP) provides the detailed methodology for summary and 
statistical analyses of the data collected in Study C4671014.  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.
PF-07321332 is a potent and selective inhibitor of the SARS-CoV-2 3CL protease that is
currently being developed as an oral treatment of COVID-19. Ritonavir is a strong CYP3A4
inhibitor being used to inhibit the metabolism of PF-07321332 in order to increase plasma
concentrations of PF-07321332 to values that are anticipated to be efficacious.  The purpose 
of this study is to estimate the effect of carbamazepine, a strong inducer of CYP3A4 on the 
PK of PF-07321332/ritonavir in healthy participants.
2.1. Study Objectives, Endpoints
2.1.1. Primary Objective

To estimate the effect of carbamazepine on the PK of PF-07321332 after a single 
dose of PF-07321332/ritonavir (reference) compared to the PK of PF-07321332 after 
a single dose of PF-07321332/ritonavir, following multiple dosing with 
carbamazepine (test).
2.1.2. Secondary Objectives

To estimate the effect of carbamazepine on the PK of ritonavir after a single dose of 
PF-07321332/ritonavir (reference) compared to the PK of ritonavir after a single 
dose of PF-07321332/ritonavir, following multiple dosing with carbamazepine (test).

To evaluate the safety and tolerability of PF-07321332/ritonavir alone and, following 
multiple dosing with carbamazepine.

To characterize additional PK parameters of both PF-07321332 and ritonavir after a 
single dose of PF-07321332/ritonavir (reference) compared to the PK of both 
PF-07321332 and ritonavir, following multiple dosing with carbamazepine.


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2.2. Study Design
This is a Phase 1, fixed sequence, 2-period study to estimate the effect of a strong CYP3A4
inducer, carbamazepine, on the PK of PF-07321332 and ritonavir in healthy participants.  A 
total of approximately 12 healthy male and/or female participants will be enrolled into the
study. The purpose of this study is to characterize the effects of carbamazepine on the single
dose PK of PF-07321332 300 mg/ritonavir 100 mg. Safety and tolerability will also be
assessed throughout the duration of the study. This study will consist of 2 periods. Period 1
(P1) will include PF-07321332 300 mg/ritonavir 100 mg as a single oral dose, and Period 2
(P2) will include a 15-day dosing of carbamazepine administered orally. Carbamazepine 
will start from 100 mg BID on Days 1, 2, and 3, and then, will titrate up to 200 mg BID on
Days 4, 5, 6, and 7 in P2. Carbamazepine will eventually titrate up to and maintain at 
300 mg BID stably in the rest of P2 from Days 8 to 15 (Figure 2 below). On Day 14 in the 
P2, a single dose of PF-07321332 300 mg/ritonavir 100 mg will be administered after 
multiple-dosed carbamazepine. PK sampling will be included in both Periods 1 and 2 to 
determine PK parameters.
Safety assessments will be performed during Screening, on Day -1 prior to dosing, and at
specified time points. PEs, vital sign measurements, and clinical laboratory tests will be
conducted, and AEs will be monitored to assess safety. The total participation time (eg, CRU
confinement time for study procedures) for each participant in this study is approximately
18 days/17 nights (excluding screening and follow-up contact). A safety follow-up call will 
be made to participants 28 to 35 days from administration of the dose of study intervention.
The total planned duration of participation, from the Screening visit to the last Follow-up 
phone call, is approximately 11 to 12 weeks.
Participants who withdraw from the study may be replaced at the discretion of the
investigator upon consultation with the sponsor. 


Protocol C4671014 (PF-07321332) Statistical Analysis Plan
PFIZER GENERAL BUSINESS 
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Figure 1.
The Schematic Represents the Study Design
Figure 2.
Titration Scheme for Carbamazepine
The end of the study is defined as the date of last scheduled procedure shown in the Schedule 
of Activities for the last participant in the trial.
A participant is considered to have completed the study if he/she has completed all parts of
the study, including the last scheduled procedure shown in the Schedule of Activities.


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3. ENDPOINTS AND BASELINE VARIABLES: DEFINITIONS AND 
CONVENTIONS
3.1. Primary Endpoint(s)

Plasma PF-07321332 PK parameters: Cmax, AUCinf (or AUClast if AUCinf cannot be 
reliably estimated).
3.2. Secondary Endpoint(s)

Plasma ritonavir PK parameters: Cmax, AUCinf (or AUClast if AUCinf cannot be 
reliably estimated).

Safety: treatment-emergent adverse events, clinical laboratory tests, vital signs, PE, 
and ECGs.

Plasma PF-07321332 and ritonavir PK parameters: Tmax, AUClast, CL/F, Vz/F, and 
t½, as data permit.
3.3. Safety Endpoints
The following data are considered in standard safety summaries (see protocol for collection 
days and list of parameters):

adverse events,

laboratory data,

vital signs data,

ECG results.
3.3.1. Adverse Events
An adverse event will be considered a Treatment-Emergent Adverse Event (TEAE) if the 
event started during the effective duration of treatment.  All events that start on or after the 
first dosing day and time/ start time, if collected, but before the last dose plus the lag time 
(28-35 days) will be flagged as TEAEs.  The algorithm will not consider any events that 
started prior to the first dose date.  Any events occurring following start of treatment.
Events that occur in a non-treatment period (for example, Follow-up) will be counted as 
treatment emergent and attributed to the previous treatment taken.
3.3.2. Laboratory Data
Safety laboratory tests will be performed as described in the protocol.


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To determine if there are any clinically significant laboratory abnormalities, the 
haematological, clinical chemistry (serum) and urinalysis safety tests will be assessed against 
the criteria specified in the sponsor reporting standards.  The assessment will take into 
account whether each participant’s baseline test result is within or outside the laboratory 
reference range for the particular laboratory parameter.
Baseline is defined as the last planned pre-dose measurement taken in each study period.
3.3.3. Vital Signs Data
Supine measurements will be taken at times detailed in the Schedule of Activities given in 
the protocol.
Baseline is the last planned pre-dose recording in each study period.
3.3.4. ECG Data
Triplicate QT interval, QTcF, PR, RR, QRS and heart rate will be recorded at each 
assessment time indicated in the Schedule of Activities given in the protocol.  The average of
the triplicate readings collected at each assessment time will be calculated for each ECG 
parameter.  Baseline will be defined as the average of the triplicate predose recordings in 
each study period.
If not supplied, QTcF will be derived using Fridericia’s heart rate correction formula:
QTcF = QT / (RR)1/3
where RR = 60/HR (if not provided)
3.3.5. Other Safety Data
If any additional safety data is collected and databased it will be listed only.
3.4. Pharmacokinetic(PK) Endpoints
The plasma PK parameters for PF-07321332 will be derived from the concentration time
profiles. Actual PK sampling times will be used in the derivation of PKparameters. In the 
case that actual PK sampling times are not available, nominal PK sampling time will be used 
in the derivation of PK parameters.
Table 2.
Plasma PK Parameters
PK Parameter
Analysis Scale
PF-07321332 and Ritonavir
AUClast
ln
A, D
AUCtau (if provided)
ln
A, D
AUCinf*
ln
A, D
Cmax
ln
A, D
Tmax
R
D


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t1/2*
R
D
CL/F*
ln
D
VZ/F*
ln
D
Key:
A=analyzed using statistical model, D=displayed with descriptive statistics,
ln=natural-log transformed, R=raw (untransformed), *=if data permits
4. ANALYSIS SETS (POPULATIONS FOR ANALYSIS)
4.1. For Purposes of Analysis, the Following Analysis Sets are Defined
Population
Description
Enrolled
"Enrolled" means a participant, or his or her legally authorized 
representative’s, agreement to participate in a clinical study 
following completion of the informed consent process and 
screening. A participant will be considered enrolled if the 
informed consent is not withdrawn prior to participating in any 
study activity after screening. Potential participants who are 
screened for the purpose of determining eligibility for the study, 
but do not participate in the study, are not considered enrolled, 
unless otherwise specified by the protocol.
PK Concentration
The PK concentration population is defined as all participants
assigned to investigational product and treated who have at
least 1 concentration measured.
PK Parameter
The PK parameter analysis population is defined as all
participants assigned to investigational product and treated
who have at least 1 of the PK parameters of primary interest
measured.
Safety
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.
4.2. Treatment Misallocations 
All analyses will be performed on an “as-treated” basis and will not include data from 
participants who are randomized but not treated.
If a participant takes a treatment that is not consistent with the treatment they are randomized 
to, for example takes a treatment out of sequence or takes the same treatment twice, then they 
will be reported under the treatment that they actually receive for all safety, and PK analyses, 
where applicable.


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4.3. Protocol Deviations
Participants who experience events that may affect their PK profile (eg, lack of compliance 
with dosing) may be excluded from the PK analysis.  At the discretion of the 
pharmacokineticist a concentration value may also be excluded if the deviation in sampling 
time is of sufficient concern or if the concentration is anomalous for any other reason.
A full list of protocol deviations will be compiled and reviewed to identify major and minor 
deviations prior to database closure.
4.3.1. Deviations Assessed Prior to Randomization
At Screening, the investigator will assess participants against the inclusion and exclusion 
criteria as set out in Sections 5.1 and 5.2 of the protocol.
4.3.2. Deviations Assessed Post-Randomization
A full list of protocol deviations for the study report will be compiled prior to database 
closure.  Any significant deviation from the protocol will be reviewed prior to database 
closure and a decision taken regarding evaluation for each analysis population.
5. GENERAL METHODOLOGY AND CONVENTIONS
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.
5.1. Hypotheses and Decision Rules
No statistical hypothesis will be tested in this study. There are no statistical decision rules.
5.2. General Methods
The interactive effect on PK parameters will be determined by constructing 90% confidence 
intervals around the estimated difference between the Test and Reference treatments using a 
mixed effects model based on natural log transformed data.  The mixed effects model will be 
implemented using SAS Proc Mixed, with REML estimation method and Kenward-Roger 
degrees of freedom algori. 
5.2.1. Statistical Analyses
The plasma concentrations of PF-07321332 and ritonavir will be listed and descriptively
summarized by nominal PK sampling time and treatment. Individual participants, as well as
mean and median profiles of the plasma concentration time data will be plotted by treatment
for each analyte using actual (for individual) and nominal (for mean and median) times
respectively. Mean and median profiles will be presented on both linear and semi-log scales.
For comparison of AUCinf and Cmax with and without carbamazepine, box and whisker plots 
of these parameters will be plotted by treatment for each analyte.


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Natural log transformed parameters (AUCinf, AUClast, and Cmax) of PF-07321332 and
ritonavir will be analyzed using a mixed effect model with treatment as fixed effect and
participant as a random effect. Estimates of the adjusted mean differences (Test-Reference)
and corresponding 90% CIs will be obtained from the model. The adjusted mean differences
and 90% CIs for the differences will be exponentiated to provide estimates of the ratio of
adjusted geometric means (Test/Reference) and 90% CI for the ratios.
PF-07321332/ritonavir administered alone will be the Reference treatment and 
PF-07321332/ritonavir coadministered with carbamazepine will be the Test treatment.
Residuals from the model will be examined for normality and the presence of outliers via 
visual inspection of plots of residuals vs predicted values and normal probability plots of 
residuals but these will not be included in the clinical study report.  If there are major 
deviations from normality or outliers then the effect of these on the conclusions will be 
investigated through alternative transformations and/or analyses excluding outliers.  
Justification for any alternative to the planned analysis will be given in the report of the 
study.
Table 3.
Plasma PK Parameters to be Summarized Descriptively by Analyte and 
Treatment
Parameter
Summary Statistics
AUCinf*, AUClast, 
AUCtau (if provided), 
Cmax, CL/F*, VZ/F*
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, cv%, standard deviation, 
minimum, maximum.
*: if data permit.
Box and whisker plots for individual participant parameters (AUCinf, AUClast and Cmax) will 
be presented by analyte and treatment and overlaid with geometric means.
Supporting data from the estimation of t½ and AUClast will be listed by analyte and 
treatment: terminal phase rate constant (kel); goodness of fit statistic from the log-linear 
regression (r2); and the first, last, and number of time points used in the estimation of kel.  
This data may be included in the clinical study report.
Presentations for PF-07321332 and ritonavir concentrations will include:

A listing of all concentrations sorted by participant ID, period 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.


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
A summary of concentrations by treatment and nominal time post-dose, where the set 
of statistics will include n, mean, median, standard deviation, coefficient of variation 
(cv), minimum, maximum and the number of concentrations above the lower limit of 
quantification.

Median concentrations time plots (on both linear and semi-log scales) against 
nominal time post-dose by treatment (all treatments on the same plot per scale, based 
on the summary of concentrations by treatment and time post-dose).

Mean concentrations time plots (on both linear and semi-log scales) against nominal
time post-dose by treatment (all treatments on the same plot per scale, based on the 
summary of concentrations by treatment and time post-dose).

Individual concentration time plots by treatment (on both linear and semi-log scales) 
against actual time post-dose (there will be separate spaghetti plots for each treatment 
per scale).

Individual concentration time plots by participant (on both linear and semi-log scales) 
against actual time post-dose [there will be separate plots for each participant
(containing all treatments) per scale].
For summary statistics, median and mean plots by sampling time, the nominal PK sampling 
time will be used, for individual participant plots by time, the actual PK sampling time will 
be used.
5.3. Methods to Manage Missing Data
For the analysis of safety endpoints, the sponsor data standard rules for imputation will be 
applied.
5.3.1. Concentrations Below the Limit of Quantification
In all data presentations (except listings), concentrations below the limit of quantification 
(BLQ) will be set to zero.  (In listings BLQ values will be reported as “<LLQ”, where LLQ 
will be replaced with the value for the lower limit of quantification).
5.3.2. Deviations, Missing Concentrations and Anomalous Values
In summary tables and plots of median profiles, statistics will be calculated having set 
concentrations to missing if 1 of the following cases is true:
1. A concentration has been collected as ND (ie, not done) or NS (ie, no sample),
2. A deviation in sampling time is of sufficient concern or a concentration has been 
flagged anomalous by the pharmacokineticist.


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Note that summary statistics will not be presented at a particular time point if more than 50% 
of the data are missing.
5.3.3. Pharmacokinetic Parameters
Actual PK sampling times will be used in the derivation of PK parameters.
If a PK parameter cannot be derived from a participant’s concentration data, the parameter 
will be coded as NC (ie, not calculated). (Note that NC values will not be generated beyond 
the day that a participant discontinues).
In summary tables, statistics will be calculated by setting NC values to missing; and statistics 
will be presented for a particular treatment with ≥3 evaluable measurements.  For statistical 
analyses (ie, analysis of variance), PK parameters coded as NC will also be set to missing; 
and analyses will not be performed for a particular parameter if more than 50% of the data 
are NC.
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
6.1. Study Conduct and Participant Disposition
Participant evaluation groups will show end of study participant disposition and will show 
which participants were analyzed for safety (adverse events and laboratory data).  Frequency 
counts will be supplied for participant discontinuation(s) by treatment.
Data will be reported in accordance with the sponsor reporting standards.
6.1.1. Demographic and Clinical Examination Data
A breakdown of demographic data will be provided for age, race, weight, body mass index, 
and height.  Each will be summarized by sex at birth and ‘All Participants’ in accordance 
with the sponsor reporting standards.
6.1.2. Discontinuation(s)
Participant discontinuations, temporary discontinuations or dose reductions due to adverse 
events will be detailed and summarized by treatment.
Data will be reported in accordance with the sponsor reporting standards.


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6.2. Safety Summaries and Analyses
All safety analyses will be performed on the safety population.  A set of summary tables split 
by treatment will be produced to evaluate any potential risk associated with the safety and 
toleration of administering study treatments.
6.2.1. Adverse Events
Adverse events will be reported in accordance with the sponsor reporting standards by 
treatment (PF-07321332 300 mg/ritonavir 100 mg alone (Period 1) and multiple dose 
carbamazepine coadministered with single dose PF-07321332 300 mg/ritonavir 100 mg
Period 2 until end of study).
6.2.2. Laboratory Data
Laboratory data will be listed and summarized by treatment in accordance with the sponsor 
reporting standards.  Baseline is as defined in Section 3.3.2.
6.2.3. Vital Signs Data
For each planned time-point, baseline values and change from baseline values within each 
treatment will be summarized with descriptive statistics and categorical incident counts 
(using sponsor default standards).  Baseline is as defined in Section 3.3.3.
These data will be listed in accordance with the sponsor reporting standards.
6.2.4. ECG Data
Baseline and changes from baseline in PR, QT, QRS, heart rate and QTcF will be 
summarized by treatment and time post-dose.  Baseline is as defined in Section 3.3.4.
ECG endpoints and changes from baseline (QTcF, PR, QRS), over all planned measurements 
taken post-dose, will also be summarized descriptively by treatment using categories as 
defined in the ECG Findings of Potential Clinical Concern appendix of the protocol and for 
QTcF values corresponding to ICH E141 thresholds below.  Numbers and percentages of 
participants meeting the categorical criteria will be provided and individual values listed in 
the study report.
Table 4.
QTcF Categorical Thresholds
Parameter
Mild (msec)
Moderate (msec)
Severe (msec)
QTcF (msec)
450 < max ≤480
480 < max ≤500
max >500
QTcF (msec) increase from 
baseline
30 ≤ max ≤60
max >60
These data will be listed in accordance with the sponsor reporting standards.


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6.2.5. Concomitant Medications and Nondrug Treatments
All concomitant medication(s) as well as non-drug treatment(s) will be provided in the 
listings.
6.2.6. COVID-19 Test Results
Participants will be tested for SARS-COV-2 infection by PCR prior to being admitted to the 
CRU for confinement and a subsequent SARS-CoV-2 test will be performed after 4 days
(ie, upon completion of 4 × 24 hours in house), or if they develop COVID-19 like symptoms.  
The test results per visit and for each treatment will be provided in listings.
6.2.7. Suicidal Ideation and Behavior Risk Data
If available, this data will be provided in listings.
6.2.8. Screening and Other Special Purpose Data
Prior medication(s) and non-drug treatment(s), serum FSH concentrations, medical history, 
physical examination, HBcAb, HBsAb, HBsAg, HCVAb, HLA-A*3101, HLA-B*1502 and 
HIV test will be assessed at Screening.
Urine drug screen will be done at Screening and Period 1 Day -1.  Serum or urine pregnancy 
test for all females of childbearing potential and contraception check will be done at 
Screening, Period 1 Day -1 and Period 2 Day 16.
Data for prior medication(s) and non-drug treatment(s), urine drug screen, serum or urine 
pregnancy test for all females of childbearing potential, contraception check and 
alcohol/tobacco use will be listed.  For rest of the parameters data will not be brought in-
house, and therefore will not be listed.
7. INTERIM ANALYSES
None.


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8. REFERENCES
1.
ICH E14 - The clinical evaluation of QT/QTc interval prolongation and proarrhythmic 
potential for non-antiarrhythmic drugs.  CHMP/ICH/2/04.


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9. APPENDICES
Appendix 1. SAS CODE FOR ANALYSES
Programming Note: 

The statistical analysis of ritonavir should be stored in a statistics exploratory folder 
within the program for regulatory purpose.
An example of the PROC MIXED code is provided below:
proc mixed data=tab.pk;
class trt participant;
model l&var=trt/ ddfm=KR;
random participant /subject=participant;
lsmeans trt;
estimate 'Test vs Reference' trt -1  1  /cl alpha=0.1;
ods 'Estimates' out=est&var;
ods 'lsmeans' out=ls&var;
ods 'covparms' out=cov&var;
ods 'tests3' out=tst&var;
run;
/* Letter assignments for treatments (trt) within the estimate statement above are as follows;
A = PF-07321332/ritonavir alone (Reference);
B = PF-07321332/ritonavir + carbamazepine (Test)
*/