Clinical trial NCT04535167
Conditions: Viral Disease
Keywords: COVID-19 SARS-COV-2
Sponsor: Pfizer
Start date: 2020-09-09; Completion date: 2021-06-07
Enrollment: 26 participants; Allocation: RANDOMIZED; Intervention model: FACTORIAL

Brief summary:
It is Phase 1b, 2-part, double-blind, placebo-controlled study to evaluate safety, tolerability, and pharmacokinetics of PF-07304814, in patients hospitalized with SARS-CoV-2 virus infection.

Detailed description:
It is a 2-part study in hospitalized COVID-19 patients.

* Part 1 is to evaluate safety, tolerability, PK and markers of clinical activity of escalating doses of PF-07304814 given as 24-hour IV infusion.

  2 planned and 3 optional cohorts with 8 participants each are planned.
* Part 2 is to evaluate safety, tolerability, PK and markers of clinical activity of escalating doses of PF- 07304814 given as 120-hour infusion.

  2 planned and 2 optional cohorts with 8 participants each are planned

Arms: arm 1: Part 1:

Cohort 1-5

Part 2:

Cohort 6-9 arm 2: Part 1:

Cohort 1-5

Part 2:

Cohort 6-9
Interventions: intervention 1: PF-07304814 intervention 2: Placebo
Intervention descriptions: intervention 1: PF-07304814 is an anti-viral, formulated for intravenous delivery intervention 2: Placebo will be formulated for intravenous delivery

Protocol documents:
Prot_000.pdf: 
PF-07304814
Protocol C4611001
Final Protocol Amendment 4, 15 December 2020
PFIZER CONFIDENTIAL
Page 1
A PHASE 1B, 2-PART, DOUBLE-BLIND, PLACEBO-CONTROLLED, 
SPONSOR-OPEN STUDY, TO EVALUATE THE SAFETY, TOLERABILITY AND 
PHARMACOKINETICS OF SINGLE ASCENDING (24-HOUR, PART 1) AND
MULTIPLE ASCENDING (120-HOUR, PART 2) INTRAVENOUS INFUSIONS OF 
PF-07304814 IN HOSPITALIZED PARTICIPANTS WITH COVID-19
Study Intervention Number:
PF-07304814
Study Intervention Name:
N/A
US IND Number:
EudraCT Number:
2020-003905-73
Protocol Number:
C4611001
Phase:
Phase 1b
Short Title: A Phase 1b First-In-Human Study to Evaluate Safety, Tolerability, And 
Pharmacokinetics Following Single Ascending And Multiple Ascending Doses, of 
PF-07304814 In Hospitalized Participants With COVID-19
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 C4611001
Final Protocol Amendment 4, 15 December 2020
PFIZER CONFIDENTIAL
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Protocol Amendment Summary of Changes Table
Document History
Document
Version Date
Summary and Rationale for Changes
Amendment 
4
15 December 
2020
This amendment is undertaken following acquisition of 
14-day toxicology data and discussions with regulatory 
authorities which allowed for the study design to include 
the possibility of escalating the dose in Part 2. All 
sections of the protocol were impacted. The substantial 
changes are presented below:
1. Updated study design to replace Part 2 designation 
from “Extended Infusion” to “Multiple Ascending 
Dose (MAD)” (all sections).
2. Updated study design to add 1 additional planned 
cohort and 1 additional optional cohort in Part 2 
making a total of 2 planned and 2 optional cohorts in 
Part 2. (Section 1 and Section 4).
3. Updated planned number of participants from 56 to 
72 to account for 2 additional cohorts being added in 
Part 2 (Section 1 and Section 4).
4. Added starting dose in first cohort in Part 2, 
Cohort 6 (Section 1 and Section 4).
5. Updated non-clinical and clinical overview 
summaries (Section 2).
6. Updated benefit/risk assessment (Section 2).
7. Added statement that any dose escalation decision in 
Part 2 will occur only after discussion with
competent regulatory authorities, thereby removing 
the need for IRC in Part 2.
8. Updated dose escalation and stopping rules to 
address both Part 1 and Part 2 (Section 6).
Other substantial changes: 
1. Added additional study intervention formulation 
(powder form) to be used for participants enrolled in 




PF-07304814
Protocol C4611001
Final Protocol Amendment 4, 15 December 2020
PFIZER CONFIDENTIAL
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required PK blood draw at 12 hr and 32 hr in 
Part 1: SAD (24-h infusion).
ii. Removed PK blood draws at 12 hr and 132 hr in 
Part 2: Extended Infusion (120-h infusion).
iii. Updated total blood sampling volume to account 
for reduced PK blood draws.
Rationale: The frequency of blood draws reduced as 
per request by the FDA.

Sections Impacted: 
Section 1.3: SoA Table Part 2: Extended Infusion
Section 10.2: Clinical Laboratory Tests
Change: Added coagulation panel as additional 
assessment.
Rationale: The assessment frequency of coagulation 
markers was increased to align with other safety labs 
in Part 2. 

Sections Impacted: 
Section 1.2: Schema
Section 2.3: Benefit/Risk Assessment
Section 4.1: Overall Design
Section 4.3: Justification for Dose
Changes: 
i.
Changed number of planned Cohorts in Part 1 
from 3 to 2 and number of optional cohorts from 2 to 
3 – in Schema.
ii.
Updated highest planned dose in Part 1 from 
5000 mg to 1000 mg.
iii.
Removed the values/estimations of doses for 
Cohort 3 in Part 1 and Cohort 6 and 7 in Part 2. 
Rationale: Due to the revised PK stopping limits and 
to align with feedback received from the FDA, doses 
higher than 1000 mg will be determined after review 
of the safety and PK data of previous cohorts. For 
Part 1, these newly identified doses may be evaluated 


PF-07304814
Protocol C4611001
Final Protocol Amendment 4, 15 December 2020
PFIZER CONFIDENTIAL
Page 5
in optional cohorts (Cohort 3-5) in Part 1. Doses in
Part 2 (Cohort 6 and Cohort 7) will be determined
after careful review of available data from Part 1, as 
well as emerging data from study C4611007 and 
agreement with the competent regulatory authority. 

Sections Impacted: 
Section 2.2.1.3: Non-clinical Safety
Section 2.2.2: Clinical Overview
Section 4.3: Justification for Dose
Section 6.6: Dose Modification
Change: PK stopping limits revised to align with 
exposures from the 70 mg/kg 14-day continuous 
infusion in non-human primates.
Rationale: The purpose to lower the PK stopping 
limits of the study is to limit participant risk and is in 
alignment with feedback received from the FDA.

Sections Impacted: 
Section 2.3: Benefit/Risk Assessment
Section 5.2: Exclusion Criteria
Changes:
i. Added the additional risk of thrombotic event, 
DVT or PE, due to study intervention.
ii. Added exclusion criterion for participants with 
history of venous thromboembolic event, 
including deep venous thrombosis or pulmonary 
embolism.
Rationale: Changes made to reduce overall 
participant risk as the study population is at higher 
risk of developing thrombotic complications as a 
result of disease progression.

Sections Impacted: 
Section 5.2: Exclusion Criteria
Section 6.5: Concomitant Therapy
Section 10.4 Female Participant Reproductive 
Inclusion Criteria
Change: Added criteria to exclude women using 


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Final Protocol Amendment 4, 15 December 2020
PFIZER CONFIDENTIAL
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hormonal therapy as contraception method or as 
replacement therapy to manage post-menopausal 
symptoms.
Rationale: Hormones used for female contraception 
or as replacement therapies may increase the risk of 
developing thrombotic events.

Sections Impacted: 
Section 3: Objectives, Estimands, and Endpoints
Section 9.4.2. Secondary Endpoint: 
Pharmacokinetic Analyses
Change: Plasma PK parameters from Part 1 
updated. Only C24 and C24 (dn) will be reported. 
Rationale: Due to reduced PK sampling in Part 1, 
some PK parameters cannot be accurately estimated, 
therefore, not reported. 
This amendment is making the following 
non substantial changes:

Sections Impacted

Section 1.3: Schedule of Activities (Part 1 and
Part 2)

Section 8.2.3: Electrocardiograms
Change: Added additional time window for ECG 
assessments.

Sections Impacted:
Section 1.2: Schema
Section 4.1.1: Overall Design Part 1: SAD
Change: Changed 1.0-fold to 1-fold

Section 2.2.2: Clinical Overview
Change: Changed the sentence from “The study is 
planned to begin in Oct-2020” to “The study began 
in Oct-2020” to align with the Amendment date.
Amendment 
16 October 
This amendment is making the following substantial 


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Protocol C4611001
Final Protocol Amendment 4, 15 December 2020
PFIZER CONFIDENTIAL
Page 7
2
2020
changes:
•
Sections Impacted: 
Section 1.3: SoA Table 
Section 8: Study Assessments and Procedures 
Change: 
i. Removed PK blood draws at 0.5 hr, 26 hr, and 
30 hr and made 2 hr PK blood draw optional in Part 
1: SAD (24-h infusion).
ii. Made 6 hr blood draws for selected biomarkers 
(including plasma PD biomarker, serum PD 
biomarker, and banked biospecimen [Prep D1]) 
optional in Part 1: SAD (24-h infusion).
iii.
Removed biomarker blood collection for 
specified viral genetics in Part 1: SAD (24-h 
infusion) and Part 2: Extended Infusion (120-h 
infusion).
iv.Removed 12-lead triplicate ECG assessments at 0.5 
hr and 2 hr timepoints in Part 1: SAD (24-hr 
infusion).
Rationale: The frequency of blood draws reduced 
or made optional to lessen burden on the patient. 
Similarly, frequency of collection of ECG reduced 
on Day 1 to lower the burden on the site 
coordinator/nurse and to limit the contact with the 
patient.  
•
Sections Impacted: 
Protocol Title 
Section 1: Protocol Summary (Synopsis)
Section 2: Introduction
Section 4: Study Design
Section 5: Study Population
Change: Broadened the inclusion range of patient 
severity by allowing patients with severe symptoms 
of COVID-19, with some limitations.
•
Removed exclusion criterion #1d.
 
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Final Protocol Amendment 4, 15 December 2020
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transporters. 
Rationale: PF-00835231 has the potential to be a 
time-dependent inhibitor of CYP3A and inhibitor of 
P-gp, BCRP, OATP1B1/1B3, OCT1, and 
MATE1/2K transporters at higher doses. Therefore, 
additional text was included to highlight this 
possible risk. 
This Amendment is making the following 
non-substantial changes:

Section: 5.2; Exclusion Criterion #12.
Change: Clarification that investigational 
drugs/treatments used as for COVID-19 treatment 
are allowed, when these are given as part of an 
open-label study.

Section 8.5; Pharmacokinetics.
Change: K2EDTA changed to K3EDTA to correct a 
typographical error.

Section 9.6; Data Monitoring Committee or Other 
Independent Oversight Committee.
Change: deleted “internal” from independent IRC as 
it was a typographical error. 

Section 10.2; Appendix 2: Clinical Laboratory tests.
Change: Removed fasting requirement from glucose 
(in Table 10).
Change: Added phosphorus to clinical chemistry 
tests, as requested by the FDA.

Section 10.4.4; Appendix 4: Contraception 
Methods.
Change: Replaced bullets to a numbered list of 
contraception methods.
Original 
protocol
04 August 2020
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Final Protocol Amendment 4, 15 December 2020
PFIZER CONFIDENTIAL
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This amendment incorporates all revisions to date, including amendments made at the 
request of country health authorities and IRBs/ECs.


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Final Protocol Amendment 4, 15 December 2020
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TABLE OF CONTENTS
LIST OF TABLES...................................................................................................................21
1. PROTOCOL SUMMARY...................................................................................................22
1.1. Synopsis ..................................................................................................................22
1.2. Schema ....................................................................................................................26
1.3. Schedule of Activities .............................................................................................29
2. INTRODUCTION ...............................................................................................................36
2.1. Study Rationale .......................................................................................................36
2.2. Background .............................................................................................................36
2.2.1. Non-clinical Overview................................................................................38
2.2.1.1. Non-clinical Pharmacology:......................................................38
2.2.1.2. Nonclinical Pharmacokinetics and Metabolism........................44
2.2.1.3. Non-clinical Safety....................................................................45
2.2.2. Clinical Overview.......................................................................................46
2.2.2.1. Study C4611007 - Ongoing.......................................................47
2.3. Benefit/Risk Assessment.........................................................................................48
2.3.1. Risk Assessment.........................................................................................49
2.3.2. Benefit Assessment.....................................................................................51
2.3.3. Overall Benefit/Risk Conclusion................................................................51
3. OBJECTIVES, ESTIMANDS, AND ENDPOINTS ...........................................................51
4. STUDY DESIGN.................................................................................................................53
4.1. Overall Design.........................................................................................................53
4.1.1. Part 1: SAD.................................................................................................53
4.1.2. Part 2: MAD ...............................................................................................54
4.2. Scientific Rationale for Study Design.....................................................................54
4.3. Justification for Dose ..............................................................................................55
4.3.1. Rationale for Dose Selection ......................................................................55
4.3.2. Starting Dose and Dose Escalation in Part 1: SAD....................................55
4.3.3. Starting Dose and Dose Selection in Part 2: MAD.....................................56
4.4. End of Study Definition ..........................................................................................57
5. STUDY POPULATION......................................................................................................58


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5.1. Inclusion Criteria.....................................................................................................58
5.2. Exclusion Criteria....................................................................................................59
5.3. Lifestyle Considerations..........................................................................................62
5.3.1. Contraception..............................................................................................62
5.4. Screen Failures ........................................................................................................62
5.5. Criteria for Temporarily Delaying Enrolment/Randomization/Study 
Intervention Administration ......................................................................................62
6. STUDY INTERVENTION..................................................................................................62
6.1. Study Intervention(s) Administered........................................................................62
6.1.1. Administration............................................................................................62
6.2. Preparation/Handling/Storage/Accountability ........................................................64
6.2.1. Preparation and Dispensing........................................................................65
6.3. Measures to Minimize Bias: Randomization and Blinding.....................................65
6.3.1. Allocation to Study Intervention ................................................................65
6.3.2. Breaking the Blind......................................................................................66
6.4. Study Intervention Compliance...............................................................................66
6.5. Concomitant Therapy..............................................................................................67
6.5.1. Rescue Medicine.........................................................................................67
6.6. Dose Modification...................................................................................................67
6.6.1. Dose Escalation and Stopping Rules ..........................................................67
6.7. Intervention After the End of the Study..................................................................70
7. DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL...........................................................................70
7.1. Discontinuation of Study Intervention ....................................................................70
7.1.1. Temporary Discontinuation........................................................................71
7.1.2. Rechallenge.................................................................................................71
7.2. Participant Discontinuation/Withdrawal From the Study.......................................71
7.2.1. Withdrawal of Consent...............................................................................72
7.3. Lost to Follow-up....................................................................................................72
8. STUDY ASSESSMENTS AND PROCEDURES...............................................................73
8.1. Efficacy Assessments..............................................................................................74
8.2. Safety Assessments .................................................................................................74


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8.2.1. Physical Examinations................................................................................74
8.2.2. Vital Signs ..................................................................................................74
8.2.3. Electrocardiograms.....................................................................................75
8.2.3.1. Continuous Cardiac Monitoring by Telemetry .........................75
8.2.4. Clinical Safety Laboratory Assessments ....................................................76
8.2.5. Pregnancy Testing ......................................................................................76
8.3. Adverse Events and Serious Adverse Events..........................................................77
8.3.1. Time Period and Frequency for Collecting AE and SAE Information.......77
8.3.1.1. Reporting SAEs to Pfizer Safety...............................................78
8.3.1.2. Recording Nonserious AEs and SAEs on the CRF...................78
8.3.2. Method of Detecting AEs and SAEs ..........................................................78
8.3.3. Follow-up of AEs and SAEs.......................................................................78
8.3.4. Regulatory Reporting Requirements for SAEs...........................................78
8.3.5. Exposure During Pregnancy or Breastfeeding, and Occupational 
Exposure ..........................................................................................................79
8.3.5.1. Exposure During Pregnancy......................................................79
8.3.5.2. Exposure During Breastfeeding ................................................81
8.3.5.3. Occupational Exposure .............................................................81
8.3.6. Cardiovascular and Death Events...............................................................81
8.3.7. Disease Related Events and/or Disease Related Outcomes Not 
Qualifying as AEs or SAEs..............................................................................81
8.3.8. Adverse Events of Special Interest.............................................................82
8.3.8.1. Lack of Efficacy........................................................................82
8.3.9. Medical Device Deficiencies......................................................................82
8.3.10. Medication Errors.....................................................................................82
8.4. Treatment of Overdose............................................................................................82
8.5. Pharmacokinetics ....................................................................................................83
8.5.1. Plasma for Analysis of PF-07304814 and PF-00835231 ...........................83
8.5.3. Urine for Analysis of PK PF-00835231 
 
...........................................................................................................84
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8.8. Biomarkers ..............................................................................................................86
8.8.2. Specified Viral Genetics (RNA).................................................................87
8.8.3. Viral Load Assessment...............................................................................87
8.8.5. Specified Protein Research.........................................................................88
8.8.5.1. Plasma PD Biomarker Assessments..........................................88
8.8.5.2. Serum PD Biomarker Assessments...........................................88
8.9. Immunogenicity Assessments.................................................................................88
8.10. Health Economics .................................................................................................88
9. STATISTICAL CONSIDERATIONS ................................................................................88
9.1. Estimands and Statistical Hypotheses.....................................................................89
9.2. Sample Size Determination.....................................................................................89
9.3. Analysis Sets ...........................................................................................................89
9.4. Statistical Analyses .................................................................................................90
9.4.1. Primary Endpoint: Safety ...........................................................................90
9.4.1.1. Electrocardiogram Analyses......................................................90
9.4.2. Secondary Endpoint: Pharmacokinetic Analyses .......................................91
9.4.2.1. Derivation of Pharmacokinetic Parameters...............................91
9.4.2.2. Statistical Methods for PK Data................................................92
9.4.3. Tertiary/Exploratory Endpoints..................................................................92
9.5. Interim Analyses .....................................................................................................92
9.6. Data Monitoring Committee or Other Independent Oversight Committee.............93
10. SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS..........................................................................................................94
10.1. Appendix 1: Regulatory, Ethical, and Study Oversight Considerations...............94
10.1.1. Regulatory and Ethical Considerations ....................................................94
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10.1.1.1. Reporting of Safety Issues and Serious Breaches of the 
Protocol or ICH GCP.........................................................................94
10.1.2. Financial Disclosure .................................................................................95
10.1.3. Informed Consent Process........................................................................95
10.1.4. Data Protection .........................................................................................96
10.1.5. Dissemination of Clinical Study Data ......................................................96
10.1.6. Data Quality Assurance ............................................................................98
10.1.7. Source Documents....................................................................................99
10.1.8. Study and Site Start and Closure ..............................................................99
10.1.9. Publication Policy...................................................................................100
10.1.10. Sponsor’s Qualified Medical Personnel ...............................................101
10.2. Appendix 2: Clinical Laboratory Tests ...............................................................102
10.3. Appendix 3: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting ....................................................................103
10.3.1. Definition of AE .....................................................................................103
10.3.2. Definition of SAE...................................................................................104
10.3.3. Recording/Reporting and Follow-up of AEs and/or SAEs.....................106
10.3.4. Reporting of SAEs..................................................................................109
10.4. Appendix 4: Contraceptive Guidance .................................................................110
10.4.1. Male Participant Reproductive Inclusion Criteria..................................110
10.4.2. Female Participant Reproductive Inclusion Criteria...............................110
10.4.3. Woman of Childbearing Potential ..........................................................111
10.4.4. Contraception Methods...........................................................................112
10.6. Appendix 6: Liver Safety: Suggested Actions and Follow-up Assessments ......114
10.7. Appendix 7: ECG Findings of Potential Clinical Concern .................................116
10.8. Appendix 8: Prohibited Medications...................................................................118
10.9. Appendix 9: Abbreviations .................................................................................119
11. REFERENCES ................................................................................................................124
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LIST OF TABLES
Table 1.
Assay Conditions to Assess the Antiviral SARS-CoV-1 and 
SARS-CoV-2 Activity of PF-07304814 and PF-00835231 .....................38
Table 2.
Summary of PF-00835231 and Remdesivir Inhibition of SARS-
CoV-2 Expression in A549-ACE2 Cells..................................................39
Table 3.
PF-00835231 and Remdesivir inhibition of SARS CoV2 expression 
in HeLa-ACE2 cells..................................................................................39
Table 4.
Summary of the In Vitro Antiviral Activity, Cytotoxicity, and TI 
for PF-00835231 With and Without the P-gp Efflux Inhibitor, 
CP-100356................................................................................................41
Table 5.
Predicted Human Plasma Total Exposure and Safety Margins of 
PF-00835231 Relative to Exposure Limits at Planned Dose Levels........57
Table 6.
Predicted Human Exposure and Safety Margins of PF-07304814 
Relative to Exposure Limits at Planned Dose Levels...............................57
Table 7.
Plasma PF-07304814 and PF-00835231 PK Parameters Definitions 
for Part 1: SAD (24-h Continuous Infusion) ............................................91
Table 8.
Plasma PF-07304814 and PF-00835231 PK Parameters for Part 2: 
MAD (120-h Continuous Infusion) ..........................................................91
Table 9.
Urine PF-00835231 PK Parameters Definitions for Part 1: SAD 
(24-h Continuous Infusion).......................................................................92
Table 10.
Protocol-Required Safety Laboratory Assessments ...............................102
Table 11.
Common Medications That Inhibit CYP450 3A4a.................................118
Table 12.
Common Medications That Induce CYP450 3A4a.................................118


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1. PROTOCOL SUMMARY
1.1. Synopsis
Short Title: A Phase 1b First-In-Human Study to Evaluate Safety, Tolerability, And 
Pharmacokinetics Following Single Ascending And Multiple Ascending Doses, of 
PF-07304814 In Hospitalized Participants With COVID-19. 
Rationale: The current study is the first clinical administration with PF-07304814 (prodrug), 
and its active moiety, PF-00835231, is a potent and selective inhibitor of the SARS-CoV-2 
3CL protease. It is designed as a 2-part study in hospitalized COVID-19 patients as a 
randomized, double-blind, sponsor-open, parallel group, placebo-controlled trial. Part 1 is to 
evaluate safety, tolerability, PK and markers of clinical activity of escalating doses of 
PF-07304814 given as 24-hour IV infusions. Part 2 is to evaluate safety, tolerability, PK and 
markers of clinical activity of escalating doses of PF-07304814 given as 120-hour IV 
infusions.
Objectives, Estimands, And Endpoints
Objectives
Estimands
Endpoints
Primary: 
Primary:
Primary: 
•
To assess the safety and 
tolerability following single 
and multiple ascending doses 
of PF-07304814 in 
hospitalized participants with 
COVID-19.
N/A
•
Frequency, severity, and causal 
relationship of TEAEs and withdrawals 
due to TEAEs (including infusion site 
reactions).
•
Frequency and magnitude of abnormal 
laboratory findings.
•
Changes from baseline in vital sign 
measurements, pulse oximetry/SpO2, and
12-lead ECG parameters.
Secondary: 
Secondary:
Secondary: 
•
To evaluate the plasma PK of 
PF-07304814 and 
PF-00835231 and urinary PK 
of PF-00835231 following 
single and multiple ascending 
doses in hospitalized 
participants with COVID-19.
N/A
Part 1: SAD
•
PF-07304814 (prodrug) and PF-00835231 
(active moiety) plasma PK:
C24 (end of infusion) and C24 (dn).
•
PF-00835231 urinary PK parameters: Ae, 
Ae%.
Part 2: MAD
•
PF-07304814 (prodrug) and PF-00835231 
(active moiety) plasma PK:
C120 (end of infusion), Cmax, Css, and t½.
Tertiary/Exploratory: 
Tertiary/Exploratory:
Tertiary/Exploratory: 
 
 
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Overall Design:
This is a First-In-Human Phase 1b study to evaluate the safety, tolerability and PK of 
PF-07304814 in participants who are hospitalized for treatment of COVID-19. The 
participants will be receiving SoC therapy for the treatment of mild, moderate, or severe 
COVID-19, but will not be eligible if they require mechanical ventilation or ECMO at 
screening or baseline. All participants will have a confirmed positive test for SARS-CoV-2 
(see Section 5.1 for details) and onset of symptoms within 15 days of Screening. For 
inclusion into Part 2: MAD of the study, participants will be required to have had a positive 
test for SARS-CoV-2 (see Section 5.1 for details) within 72 hours prior to Screening. 
This is a 2-part study in which up to a total of approximately 72 participants on SoC are 
planned to be enrolled. It is a randomized, double-blind, sponsor-open, parallel group, 
placebo-controlled trial. Part 1 is to evaluate safety, tolerability, and PK of escalating doses 
of PF-07304814 given as 24-hour IV infusions. Two planned and 3 optional cohorts with 
8 participants/cohort will be included in Part 1: SAD (24-h continuous infusion).
Precautionary sentinel dosing will be used in each dose-escalating cohort in Part 1. A small 
cohort of 2 participants (1 receiving PF-07304814 and 1 receiving placebo) within a cohort 
will be dosed prior to the remainder of the cohort. Part 2: MAD is to evaluate safety, 
tolerability, and PK of multiple ascending doses of PF-07304814 given as 120-hour IV 
infusions. Two planned and 2 optional cohorts with 8 participants/cohort will be included in 
Part 2.
Number of Participants
A maximum of approximately 72 participants will be enrolled to study intervention such that 
approximately 72 evaluable participants complete the study.
Note: "Enrolled" means a participant's, or his or her legally authorized representative’s, 
agreement to participate in a clinical study following completion of the informed consent 
process. 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.
Participants who discontinue during the trial for reasons other than drug-related safety events 
may be replaced at the discretion of the Sponsor and Investigator.
Intervention Groups and Duration
Part 1: SAD Cohorts of 8 participants each who meet the eligibility criteria will be enrolled.
The 2 sentinel participants will be randomized in a PF-07304814:placebo ratio of 1:1, while 
the remaining 6 participants will be randomized in a ratio of 5 (PF-07304814):1 (placebo).
Both treatments will be administered in a telemetered (for 12 hours post the start of dosing) 
setting as a continuous IV infusion for 24 hours for each dose, in addition to SoC therapy.
They will be required to stay in hospital from at a minimum, Day 1, pre-dose (at least 


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2 hours) through completion of Day 3 evaluations (Follow-up 1). Participants will then return 
for Day 6 (Follow-up 2) activities and a planned final follow-up visit per the SoA on 
Day 30-37 (Follow-up 3) for a total of approximately 4-5 weeks study participation from first 
dose to follow-up, excluding screening. 
Part 2: MAD Cohorts of 8 participants each who meet the eligibility criteria will be enrolled 
and randomized in a PF-07304814:placebo ratio of 6:2. Participants will be required to stay 
in hospital from, at a minimum, Day 1, pre-dose through completion of Day 7 evaluations 
(Follow-up 1). Participants will then return for Day 10 (Follow-up 2) and Day 14 
(Follow-up 3) activities and a final planned follow-up (Follow-up 4) visit per the SoA on 
Days 34-41 for a total of approximately 5-6 weeks study participation from the start of 
dosing to follow-up, excluding screening.
Data Monitoring Committee or Other Independent Oversight Committee: IRC
This study will use an IRC, which is independent of the study team and includes Pfizer 
internal members. In Part 1, emerging data will be reviewed by the Investigator(s) (if 
available), the study team and the IRC. The independent IRC will assess whether it is safe to 
proceed to continued dosing within a cohort following sentinel dosing and whether it is safe 
to dose-escalate to the next dose level. The IRC may also be consulted at other times to 
review safety data.
Statistical Methods
The sample size for both parts of the study has been chosen based on the need to minimize 
first exposure to humans of a new chemical entity and the requirements to provide adequate 
safety and toleration information at each dose level.
Safety data will be presented in tabular and/or graphical format and summarized 
descriptively, where appropriate. No formal analyses are planned for safety data.
PK parameters of PF-07304814 and PF-00835231 will be derived following 24- and 
120-hour infusions. The PK data for PF-07304814 and PF-00835231 will be reported 
separately and will be listed and descriptively summarized as required. No formal inferential 
statistics will be applied to the PK data.


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1.2. Schema
Overall Study Design of C4611001
Doses and dosing scheme presented are projected based on nonclinical data and may be 
modified based on emerging safety, tolerability, and PK data. The projected exposures 
(adjusted based on observed PK) at the modified doses as well as those for the optional 
cohorts will not exceed the exposure limits agreed with competent regulatory authorities.


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Part 1: SAD (24-h Continuous IV Infusion)


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Precautionary sentinel dosing will be used in each dose-escalating cohort in Part 1. A small cohort of 2 participants (1 receiving 
PF-07304814 and 1 receiving placebo) will be dosed prior to the remainder of the cohort. All available safety and tolerability data 
from the 2 sentinel participants up to at least Day 3 at 24 hours post completion of dosing will be reviewed by the Investigator(s) (if 
available), the study team and IRC. The IRC will then determine whether it is safe to proceed to dose the remaining participants in the
cohort.
Part 2: MAD (120h Continuous IV Infusion)
















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2. INTRODUCTION
PF-07304814 is a phosphate prodrug of PF-00835231, a potent and selective inhibitor of the 
SARS-CoV-2 3CL protease, that is being developed as a continuous IV infusion for the 
treatment of patients hospitalized with COVID-19.
2.1. Study Rationale
The current study is the first clinical administration with PF-07304814. It is designed as a 
2-part study in hospitalized COVID-19 patients as a randomized, double-blind, 
sponsor-open, parallel group, placebo-controlled trial. Part 1 is to evaluate safety, tolerability, 
PK and markers of clinical activity of escalating doses of PF-07304814 given as 24-hour IV 
infusions. Part 2 is to evaluate safety, tolerability, PK and markers of clinical activity with
escalating doses of PF-07304814 given as 120-hour IV infusions.
2.2. Background
Disease Overview
In December 2019, COVID-19 was identified as a new, potentially fatal, respiratory infection 
caused by the novel coronavirus, SARS-CoV-2. The WHO declared COVID-19 a Public 
Health Emergency of International Concern on 20 January 2020 and further characterized the 
disease outbreak as a pandemic on 11 March 2020.1
COVID-19 manifests as a wide range of illness, from asymptomatic infection to severe 
pneumonia, ARDS and death. While the majority of cases (approximately 80%) are 
asymptomatic or mild,2 patients who are hospitalized with COVID-19 may have significant 
morbidity and mortality,3,4 and are at increased risk of developing complications such as 
severe inflammation associated with elevations in pro-inflammatory cytokines, ARDS, acute 
cardiac injury, thromboembolic events, hypercoagulability, and/or kidney injury.5-9
Current Treatment Options
As of December 2020, vaccines are not yet widely available to prevent infection with 
SARS-CoV-2 and aside from symptomatic and/or supportive treatments there are few drugs 
approved and available to treat COVID-19. As of June, 2020, only 1 anti-viral drug with 
activity against SARS-CoV-2, Remdesivir, an RNA polymerase inhibitor, has shown clinical 
benefit in hospitalized patients with COVID-19.10 While additional data from studies of 
Remdesivir and other drugs are becoming available, published preliminary reports suggest 
that Remdesivir may not be sufficient as monotherapy in all subsets of patients across the 
spectrum of disease.10 Furthermore, Remdesivir is only available on a limited basis, through 
emergency use authorization in the US,11 authorization for compassionate use in the EU,12
and approved in a small number of countries.13-15


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The FDA has issued EUA to 2 monoclonal antibodies, bamlanivimab and the combination 
casirivimab plus imdevimab, the drug baricitinab, in combination with remdesivir, and 
convalescent plasma for the treatment of COVID-19. The use of monoclonal antibodies is
limited to the outpatient setting in patients at high risk of progressing to severe disease and/or 
hospitalization. At the time of the most recent update to the COVID-19 Treatment Guidelines 
Panel (03 December 2020), the Panel did not believe there was sufficient data to recommend
any of these 4 therapeutics as part of the standard of care.
In addition, the glucocorticoid anti-inflammatory dexamethasone has been recommended in 
the COVID-19 Treatment Guidelines Panel at NIH guidelines for the treatment of on the 
basis of the preliminary report from the RECOVERY trial [DOI: 10.1056/NEJMoa2021436], 
for the treatment of COVID-19 in hospitalized patients who are mechanically ventilated or 
who require supplemental oxygen 
[https://www.covid19treatmentguidelines.nih.gov/immune-based-
therapy/immunomodulators/corticosteroids/].
In spite of these advances, there remains an urgent need for additional safe and more 
effective therapeutic interventions that shorten time to clinical recovery and prevent the 
progression of infection to more severe disease and death. The direct reduction of viral 
replication, through inhibition of other critical viral enzymes, offers an important mechanism 
as monotherapy or in combination, to achieve greater patient benefit.
Rationale for Development of PF-07304814
The SARS 3CL protease is a virally encoded enzyme that is critical to the SARS-CoV-2 life 
cycle, analogous to other obligatory virally encoded proteases (eg, HIV Protease, HCV 
Protease).16 Mutagenesis experiments with other coronaviruses and picornaviruses that are 
related to SARS-CoV-2 (picornavirus-like supercluster) have demonstrated that the activity 
of the 3CL protein (or the corresponding picornaviral 3C enzyme) is essential for viral 
replication. No close human analogs of the SARS 3CL enzyme are known, suggesting that 
appropriate SARS 3CL inhibitors may function as selective anti-SARS and other 
coronaviruses as therapeutic agents.
Inhibition of the SARS 3CL protease is a mechanism of action distinct from that of 
Remdesivir, which is a prodrug of an adenosine nucleoside analogue that interferes with 
SARS-CoV-2 RNA-dependent RNA polymerase. In vitro studies (see Section 2.2.1.1.1), 
indicate that the combination of PF-00835231, the active moiety of the phosphate prodrug of 
PF-07304814, and Remdesivir may have an additive effect with respect to inhibiting viral 
replication of SARS-CoV-2.


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2.2.1. Non-clinical Overview
2.2.1.1. Non-clinical Pharmacology:
2.2.1.1.1. In vitro Pharmacology
PF-00835231 has been determined to be a potent and selective inhibitor of the SARS 3CLpro. 
PF-00835231 inhibited the full length enzyme activity of SARS-CoV-2 3CLpro with an IC50
of 0.00692 µM (Kiapp of 0.0003 µM), and the prodrug, PF-07304814 inhibited the same 
enzyme with an IC50 of 0.443 µM (Ki of 0.174 µM), indicating the active moiety 
PF-00835231 is >600-fold more active than the prodrug. PF‑00835231 inhibited 
SARS-CoV-1 3CLpro with a Kiapp of 0.0047 μM and inhibited the HCoV‑229E 3CLpro with a 
Kiapp of 0.0012 µM.
For the PF-07304814 development program the antiviral activity of the active moiety, 
PF-00835231 and the prodrug, PF-07304814 were assessed in several in vitro SARS-CoV-2 
assays within different laboratories as summarized in Table 1.
Table 1.
Assay Conditions to Assess the Antiviral SARS-CoV-1 and SARS-CoV-2 
Activity of PF-07304814 and PF-00835231
Assay Location
Assay 
Parameters
NYUa
NYUb
SRIc
Regad
Scrippse
Virus strain
USA-WA1/2020
Washington
SARS-CoV-1 
(Toronto 2); 
SARS-CoV-2 
(USA-
WA1/2020)
SARS-CoV-1 
(200300592-
Vietnam); 
SARS-CoV-2 
(BetaCov 
GHB-03021/2020)
USA-
WA1/2020
Cell type
A549-ACE2
Human primary 
HAE
VeroE6-ACE2 
enriched
VeroE6-EGFP
HeLa-ACE2
Cell origin
Human
lung
Human
lung
Monkey 
kidney
Monkey
kidney
Human
cervical
Duration
24, 48 hours
24, 48 hours
3 days
5 days
24 hours
End point
Viral protein
Virus 
production
CPE
CPE
Viral protein
Detection
Immunofluor 
imaging
Plaque assay
CTG
Fluor imaging
Immunofluor 
imaging
a.
Experiments conducted at New York University Langone School of Medicine.
b.
Experiments conducted at New York University Langone School of Medicine.
c.
Experiments conducted at Southern Research Institute in Birmingham, Alabama.
d.
Experiments conducted at Rega Institute, Leuven, Belgium.
e.
Experiments conducted at Scripps Research Institute.
These assays are representative of the current antiviral assessments being used in the field to 
date. The antiviral activities in the physiologically relevant human lung derived cell line, 
A549-ACE2 with a direct viral readout were used as an approximation for Ceff selection 
purposes. The antiviral activity of PF-00835231 and Remdesivir (as a control) were 
evaluated against SARS-CoV-2 A549-ACE2 cells as summarized in Table 2.


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Table 2.
Summary of PF-00835231 and Remdesivir Inhibition of SARS-CoV-2 
Expression in A549-ACE2 Cells
Time post 
infection
EC50 µMa
(95% CI)
EC90 µMa
(95% CI)
CC50 µMa
(95% CI)
TIb
PF-00835231
24 Hours
0.221
(0.137 to 0.356)
0.734
(0.391 to 1.38)
>10
(ND)
>46
48 Hours
0.158
(0.079 to 0.314)
0.439
(0.380 to 0.508)
>10
(ND)
>65
Remdesivir
24 Hours
0.442
(0.240 to 0.814)
1.19
(0.622 to 2.28)
>10
(ND)
>23
48 Hours
0.238
(0.122 to 0.463)
0.592
(0.534 to 0.656)
>10
(ND)
>43
a.
Value is the geometric mean (n=3).
b.
TI calculated as: CC50/EC50.
The inhibitory activity of PF-00835231 on SARS-CoV-2 in A549-ACE2 cells was confirmed 
by data from polarized human airway epithelial (HAE) cells. PF-00835231 maintains the 
potent inhibition of SARS-CoV-2 virus production at 0.025, 0.5, and 10 μM from various 
time points with the most significant reduction of 8-, 30- and 2940-fold, respectively, at 
48 hours post-infection (data not shown) with similar results for Remdesivir, tested in 
parallel as a control. These preliminary results provide an indication that the compound 
activity in this model is similar to what was observed for the A549-ACE2 assay.
The anti-SARS-CoV-2 activity of PF-00835231 was supported by data from another human 
cell line albeit of a different organ origin. In HeLa-ACE2 cells, PF-00835231 inhibited 
SARS CoV2 replication at an average EC50/EC90 of 0.144 µM/0.398 µM, in line with results 
in A549-ACE2 cells (Table 3).
Table 3.
PF-00835231 and Remdesivir inhibition of SARS CoV2 expression in 
HeLa-ACE2 cells
EC50 µM
(95% CI)
EC90 µM
(95% CI)
PF-00835231a
0.144
(0.074 to 0.278)
0.398
(0.143 to 1.10)
Remdesivirb
0.074
(0.063 to 0.087)
0.168
(0.108 to 0.250)
n = number of replicates.
a.
Values are the geometric mean (n=3).
b.
Values are the geometric mean (n=4).


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In addition, for comparative purposes we generated efficacy data in VeroE6 cells as SARS 
antiviral assays are typically performed in Vero cells which support high levels of SARS 
replication. However, they are not considered as relevant as A549-ACE2 due to the fact they 
are not of human origin (African green monkey) as well as derived from a different organ 
type (kidney). In addition, contrary to the virus target cells in lung and bronchus, Vero cells 
are known to express high levels of P-gp, a multi-drug resistance protein that pumps 
xenobiotics out of cells.17 Since PF‑00835231 is a P-gp substrate, anti-viral screening in this 
cell type was done with and without the presence of a P-gp EI, CP-100356. The levels of 
P-gp expression in the cells used in SARS-CoV-2 antiviral assays were analyzed. P-gp was 
shown to be expressed to much higher levels (>380 fold) in Vero76, VeroE6, VeroE6 
enriched for hACE2, VeroE6 stably expressing EGFP than the physiologically relevant 
A549 cells as well as HeLa cells. Data from different labs using Vero cells showed that 
PF-00835231 alone had significantly higher EC50 values than in the presence of 0.5 µM EI.
This observation of PF-00835231 inhibition was reproduceable in tests using VeroE6 cells or 
VeroE6 cells expressing EGFP. Furthermore, increasing the concentration of the EI from 
0.5 to 2 µM when P-gp activity appears sufficiently suppressed, EC50 levels in VeroE6 cells 
are at the similar level as in A549 cells (Table 4).


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Table 4.
Summary of the In Vitro Antiviral Activity, Cytotoxicity, and TI for PF-00835231 With and Without the P-gp 
Efflux Inhibitor, CP-100356
Virus Strain
Host Cell
PF-00835231 ± EI
EC50 µM
CC50 µM
TIa
Geometric Mean (95% CI)
n
Geometric Mean
n
SARS-CoV-2
VeroE6b
- EI (0 µM)
88.9c
76.8 to 103
5
>100c
8
>1.2
+ EI (0.5 µM)
8.21c
3.12 to 21.6
8
>100c
8
>21
+ EI (2 µM)
0.760c
0.449 to 1.29
4
>50c
4
>32
VeroE6d
- EI (0 µM)
39.8c
29.8 to 53.2
10
>100
9
>2.5
+ EI (0.5 µM)
2.93c
1.13 to 7.64
7
>100
6
>35
+ EI (2 µM)
0.236c
0.135 to 0.412
6
>100
6
>400
SARS-CoV-1
Vero76e
- EI (0 µM)
5.0
3.1 to 8.1
4
≥208f
5
>42
+ EI (0.5 µM)
0.11
ND
2
>100
2
>900
VeroE6g
- EI (0 µM)
>100
ND
6
>100
6
ND
+ EI (0.5 µM)
10.8c
3.80 to 30.8
6
>100
6
>11
VeroE6h
- EI (0 µM)
93.8c
ND
1
>100
2
>1.1
+ EI (0.5 µM)
1.91c
0.701 and 5.18i
2
>100
2
>45
HCoV-229Ej
MRC-5
- EI (0 µM)
0.088
0.047 to 0.160
16
≥208f
6
≥2300
+ EI (0.5 µM)
0.19
ND
1
>1
1
>5.3


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MRC-5
- EI (0 µM)
0.0692
0.0561 to 0.0852
7
>100
5
>510
+ EI (0.5 µM)
0.0795
0.0169 to 0.373
3
>100
3
>770
Huh7
- EI (0 µM)
0.0909
0.0638 to 0.129
4
>100
4
>480
+ EI (0.5 µM)
0.0778
0.0316 to 0.192
3
>100
3
>1300
a.
The TI was calculated by dividing CC50/EC50.
b.
SARS-CoV-2 (EPI ISL 407976|2020-02-03/BetaCoV/Belgium/ GHB03021/2020) strain.
c.
EC50 curves were fit to a Hill slope of 3. If cytotoxicity was detected at >30% effect, the corresponding concentration data was eliminated for the determination of EC50.
d.
SARS-CoV-2 (USA_WAI/2020_TVP23156) strain.
e.
SARS-CoV-1 Toronto 2 strain.
f.
PF-00835231 solubility in assay media, pH 6.5 was 208 uM.
g.
SARS-CoV-1 (200300592-Vietnam).
h.
SARS-CoV-1 Toronto 2 strain.
i.
Values listed are the 2 values (when n=2); not the CI.
j.
HCoV-229E is ATCC strain.


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The antiviral activity data of PF-00835231 against SARS-CoV-2 in the various tested cell 
lines of different origins are consistent, including in the unrelated monkey kidney derived 
Vero cells when its P-gp activity was sufficiently suppressed. The EC50 value of ~0.25 µM 
and EC90 value of ~0.5 µM derived from the physiologically relevant A549-ACE2 human 
lung carcinoma cells are supported by data from other cell lines, demonstrating a consistent 
intrinsic potency against SARS-CoV-2.
To understand the activity of PF-00835231 against other coronaviruses in human cell lines 
(normal human lung epithelial cells [MRC-5] and human hepatocellular carcinoma cells 
[Huh7]), the compound was tested for antiviral activity against an alpha coronavirus, 
HCoV-229E, which naturally circulates among humans. Anti-viral activity was observed 
with the compound potently inhibiting HCoV-229E-induced cytopathic effects in both cell 
lines, demonstrating EC50 values ranging from 0.069 to 0.190 µM regardless of the presence 
of the EI (Table 4). In contrast to Vero cell assays, the presence of an EI did not enhance 
PF-00835231 activity, consistent with the known lack of P-gp activity in MRC-5 cells.18
PF‑00835231 binds to the active site of both SARS-CoV-1 and SARS-CoV-2 3CLpros, as 
determined by X-ray co-crystal structures. Both structures are consistent with a covalent and 
reversible interaction of PF-00835231 at the active site catalytic cysteine residue of each 
3CLpro, thus inhibiting the activity of the protease. PF-00835231 was also determined to be 
active against several other human coronavirus 3CLpro, including that of MERS, 
HCoV-OC43, HCoV-HKU1, and HCoV-NL63. This pan-coronavirus 3CLpro inhibition could 
be explained by the similarity of 3CLpro across the Coronaviridae family where critical amino 
acid residues involved in enzyme-inhibitor binding interactions are particularly well 
conserved. For example, PF‑00835231 interacts only with the side chains of coronavirus 
3CLpro amino acids that are completely conserved between SARS-CoV-1 and SARS-CoV-2.
Further details may be found in the IB.
2.2.1.1.2. In vivo Pharmacology
Studies on in vivo pharmacology of PF-07304814 or PF-00835231 have not been reported. 
However, some in vivo model studies have been completed the in-life phase and a 
preliminary analysis is shown below.  
The mouse is not a natural host of SARS-CoV-2 or CoV-1. Although mice have the ACE2 
receptor, it is sufficiently different from the human version of ACE2 such that the viruses are 
unable to infect mice. However, by passage of SARS-CoV-1 virus multiple times in mice, 
the virus Spike (S) protein adapts to enable utilization of the mouse receptor. Mutations were 
present in 3CL protease coding sequence of the mouse-adapted CoV-1 strain, but they were 
distant from the active site which is 100% identical between CoV-1 and CoV-2. The 
resulting virus can infect mice and cause disease, which is characterized by weight loss and 
lung pathology that are consistent with human disease. The virus also replicates to high 
levels in the lungs of the mice. This mouse-adapted model of CoV-1 infection was used to 
evaluate PF-00835231 (the parent molecule to the prodrug, PF-07304814). The experiments 
are on-going. To summarize, mice that were infected with mouse-adapted CoV-1 were 


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treated with PF-00835231 at 100 mg/kg, twice daily (BID) by the SC route. This is a dose 
that was predicted to give an exposure of the drug at Cmin of approximately 500 nM or about 
EC90. In one experiment, treatment was initiated at the time of infection (Day 0) or delayed 
for 1- or 2-days post-infection. Viral titers in the lung were reduced ~2.0, 1.5 and 1.0 log10
with treatment starting on Days 0, 1, and 2 post-infection, respectively. Weight loss and 
histopathologic signs of disease were decreased, particularly when dosing of PF-00835231 
was started on Day 0. In a second experiment, treatment with PF-00835231 was initiated on 
Day 0 and the dose of drug was varied (30, 100, 300 mg/kg, BID, SC). A dose-dependent 
decline in viral titers in the lung was observed for the three doses: ~1.5 log10 at 30 mg/kg; 
~3 log10 at 100 mg/kg; and ≥3.5 log10 at 300 mg/kg. The decline in weight loss caused by the 
virus was reduced by treatment with PF-00835231 at all doses compared to infected, 
untreated mice. The drug exposure at 300 mg/kg in this experiment was 3-4-fold higher than 
that observed previously with 100 mg/kg. Histopathology for this experiment is not available 
currently.
2.2.1.2. Nonclinical Pharmacokinetics and Metabolism
2.2.1.2.1. Nonclinical Pharmacokinetics and Prediction of Human Pharmacokinetics
Preliminary human in vitro metabolism data indicate PF-07304814 is rapidly metabolized by 
alkaline phosphatase in the liver forming the active metabolite PF-00835231. Both 
PF-07304814 and PF-00835231 exhibit similar metabolic profiles in rat, dog, monkey and 
human liver microsomes with no human specific metabolites observed.
Overall, based on human vitro and animal in vivo data the major clearance pathway for 
PF-00835231 is predicted to be via CYP3A4 metabolism (fm 0.76) with minor contributions 
from additional CYPs (fm 0.12) and via renal clearance (fm 0.12).
Preliminary assessments based on in vitro DDI studies and the predicted systemic exposure 
in humans following the projected efficacious dose indicate a low potential for DDI due to 
PF-07304814 or PF-00835231 mediated inhibition of CYP1A2, 2B6, 2C19, 2C8, 2C9, 2D6 
and CYP3A4. PF-00835231 demonstrated weak time-dependent inhibition of CYP3A.
There are potential DDI risks of PF-00835231 as a substrate when co-administered with 
strong inhibitors and inducers of CYP3A4. Preliminary SimCYP modeling indicated an 
approximate 2× or 0.5× change in PF-00835231 AUC when co-administered with a strong 
CYP3A4 inhibitor (eg, itraconazole) or strong inducer (eg, rifampin), respectively. At the 
predicted target Ceff (Section 2.2.1.2.2) exposure, PF-07304814 and PF-00835231 have a low 
potential as a perpetrator for enzymatic or transporter based DDIs. As higher doses are 
explored (ie, 10× the Ceff), PF-00835231 has the potential to time-dependently inhibit 
CYP3A (up to 3× AUC increase using midazolam as a probe substrate), and a potential for a 
transporter DDI by inhibition of P-gp, BCRP, OATP1B1/1B3, OCT1, and MATE1/2K.
In humans the predicted CLp of PF-07304814 is ~10 mL/min/kg, Vdss of 0.1 L/Kg and 
effective t½ ~0.1 hour and the predicted CLp and Vss of PF‑00835231 are 6 mL/min/kg and 
1 L/kg respectively, providing an effective t½ of approximately 2 hours.






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tolerability of 24h and 120h infusions of PF-07304814 in these populations, the sponsor 
proposes a Phase 2/3 adaptive design efficacy study in hospitalized COVID-19 patients 
(C4611002).
As of 18 November, 2020, 4 patient participants in Cohort 1 received a single dose of 
PF-07304814 or placebo, administered as a 24-hour continuous IV infusion in the study 
C4611001. Based on emerging PK data in participants who received PF-07304814, dosing in 
Cohort 1 (500 mg dose) was stopped and dosing in a new cohort, Cohort 3, at 250 mg was
initiated. As of 16 December, 2020, three participants in Cohort 3 have been dosed with 
either PF-07304814 or placebo.
2.2.2.1. Study C4611007 - Ongoing
This is the second clinical administration with PF-07304814, but first in healthy adult 
participants. This is a Phase 1, randomized, double-blind, sponsor open (ie, participant blind, 
investigator blind and sponsor open), placebo-controlled SAD study, with ongoing review of 
safety, tolerability, and PK.
There are 2 interleaving cohorts with a total of approximately 16 participants (approximately 
8 participants in each cohort), with 2-period cross-over in each cohort. For each period, 
approximately 6 participants will have received a single dose of PF-07304814 administered 
as a 24h continuous IV infusion, and approximately 2 participants will have received
placebo. Each participant may have received either a single dose of PF-07304814 or a 
placebo during each period.
The nominal doses of PF-07304814 are 50 mg, 150 mg, 500 mg, and 700 mg for a 24h
continuous infusion. In addition to standard safety assessments, hsCRP, D-dimer, and 
coagulation panel (aPTT, PTT) are monitored to evaluate any potential pro-inflammatory or 
hypercoagulable effect of study intervention. 
The study began in October 2020, and at the time of the data cutoff date 21 November 2020,
safety data from last planned safety labs (Day 5) from the last participant was reviewed.
There were 20 TEAEs reported by 12 participants. All of the TEAEs were categorized as
mild in severity. One AE of injection site pain, reported as mild in severity, was considered 
treatment related by the investigator. For the description of each AEs please refer to the IB
(December 2020). There were no deaths, serious AEs (SAEs), severe AEs, or 
discontinuations due to AEs during the study.
There were no individual laboratory abnormalities assessed as clinically significant by the 
investigator. Across the treatment groups there were no clinically significant changes in the 
inflammatory marker, hs-CRP. Tests evaluating the coagulation system, aPTT, PT, 
fibrinogen and D-dimer, were similarly without clinically significant changes over time. No 
participant developed a value that was clinically significantly elevated or outside the normal 
range. Overall, there was no evidence of a pro-inflammatory effect clinically or based on 
laboratory results, at all dose levels.


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Preliminary pharmacokinetic (PK) data following single dose 24h continuous IV infusion 
at 50, 150, 500 and 700 mg are included in this update with a data cut-off date of 
21 November 2020.
Maximum or near maximum plasma concentrations of the active moiety PF-00835231 were 
generally first observed ~6h post start of the infusion and sustained until the end of the 
infusion. PF-00835231 plasma concentrations declined rapidly afterwards. The t½ values 
were only reportable at 500 and 700 mg and were 2.25 hour and 2.02 hour, respectively. 
Mean Cmax and AUC values appeared to increase in a dose proportional manner in the dose 
range tested. 
Maximum or near maximum plasma concentrations of the phosphate prodrug PF-07304814 
were generally first observed ~3h and sustained until at least 16h post start of the infusion. 
Despite continuous infusion of the prodrug and sustained plasma concentration of the active 
moiety, the concentration of PF-07304814 declined before the end of the infusion. The 
t½ values could not be determined since all plasma samples collected after the 16h post start
of the infusion were BLQs of 40 ng/mL. While the mean Cmax values appeared to increase in 
a dose proportional manner in the dose range tested, the AUC values appeared to increase in 
a slightly greater than dose proportional manner.
More detailed information may be found in the latest IB (December, 2020).
2.3. Benefit/Risk Assessment
More detailed information about the known and expected benefits and risks and reasonably 
expected AEs of PF-07304814 may be found in the latest IB (December, 2020), which is the
SRSD for this study.




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Potential Risk of Clinical Significance
Summary of Data/Rationale for 
Risk
Mitigation Strategy
Central venous catheterization or midline 
use for blood draws (not required by the 
protocol).
Central venous catheterization or 
midline, although not required by 
the protocol, may be indicated in 
some cases according to local 
standard of care and may lead to 
increased risk of DVT in some 
patients.
As of 16-Oct-2020, 2 participants 
in sentinel dosing group of 
Cohort 1 experienced DVT in the 
arm where a midline was 
inserted. One participant received 
the study drug PF-07304814 and 
the other received placebo. The 
placebo and study drug were not 
infused through the midline.
Appropriate anti-coagulant prophylaxis
administration should be considered as per local 
guidelines.
Potential for increased risk of intravenous 
infusion site reaction.
There may be potential risk of 
infusion site reaction due to low 
pH of study intervention and/or 
need for continuous intravenous 
infusion. - These risks are 
described in the SRSD for 
PF-07304814.
Monitoring of infusion site reactions will be 
performed through targeted PE and collection of 
AEs, which will be reviewed on an ongoing basis. 
Infusion solution may be diluted.
Other
Not applicable.






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4. STUDY DESIGN
4.1. Overall Design
This is a First-In-Human Phase 1b study to evaluate the safety, tolerability and PK of 
PF-07304814 in participants who are hospitalized for treatment of COVID-19. The 
participants will be receiving SoC therapy for the treatment of mild, moderate, or severe 
COVID-19, but will not be eligible if they require mechanical ventilation or ECMO at 
screening or baseline. All participants will have a confirmed positive test for SARS-CoV-2
(see Section 5.1 for additional details) and onset of symptoms within 15 days of Screening.
For inclusion into Part 2: MAD of the study, participants will be required to have had a 
positive test for SARS-CoV-2 (See Section 5.1 for details) within 72 hours prior to 
Screening. 
This is a 2-part study in which up to a total of approximately 72 participants on SoC with the 
intervention such that approximately 72 evaluable participants complete the study. It is a 
randomized, double-blind, sponsor-open, parallel group, placebo-controlled trial. 
Part 1: SAD is to evaluate safety, tolerability, and PK of escalating doses of PF-07304814 
given as 24-hour IV infusions. Two planned and 3 optional cohorts with 8 participants/cohort 
will be included in Part 1. Part 2: MAD is to evaluate safety, tolerability, and PK of 
multiple ascending doses of PF-07304814 given as 120-hour IV infusions. Two planned and 
2 optional cohorts with 8 participants/cohort will be included in Part 2.
4.1.1. Part 1: SAD 
Precautionary sentinel dosing will be used in each dose-escalating, ie, increasing dose,
cohort in Part 1. A small cohort of 2 participants (1 receiving PF-07304814 and 1 receiving 
placebo) will be dosed prior to the remainder of the cohort. All available safety and 
tolerability data from the 2 sentinel participants up to at least Day 3 at 24 hours post 
completion of dosing will be reviewed by the Investigator(s) (if available), the study team 
and IRC. The independent IRC will then determine whether it is safe to proceed to dose the 
remaining participants in the cohort.
Cohorts of 8 participants each who meet the eligibility criteria (see Sections 5.1 and 5.2) will 
be enrolled. The 2 sentinel participants will be randomized in a ratio of 1 (PF-07304814): 
1 (placebo), while the remaining 6 participants will be randomized in a ratio of 
5 (PF-07304814):1 (placebo). Both treatments will be administered in a telemetered (for 
12 hours post the start of dosing) setting as a continuous IV infusion for 24 hours for each 
dose, in addition to SoC therapy.
All participants will follow the study procedures as outlined in Section 1.3, SoA. They will 
be required to stay in hospital from at a minimum, Day 1, pre-dose (at least 2 hours) through 
completion of Day 3 evaluations (Follow-up 1). Participants will then return for Day 6 
(Follow-up 2) activities and a planned final follow-up visit per the SoA on Day 30-37
(Follow-up 3) for a total of approximately 4-5 weeks study participation from first dose to 
follow-up, excluding screening. 


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Participants who discontinue for reasons other than drug-related safety events during the trial 
may be replaced at the discretion of the Sponsor and investigator.
Three optional cohorts may be added to further explore the dose range based on emerging 
safety, tolerability and PK assessments. However, the projected exposures at the top dose 
(adjusted based on observed PK) in Part 1: SAD will not exceed the exposure limits agreed 
with competent regulatory authorities.
After reviewing emerging safety, tolerability, and PK data (Section 6.6.1) by the study team,
the Investigator(s) (if available) and IRC, the decision to proceed to the next dose level will 
be made.
4.1.2. Part 2: MAD
Progression to Part 2 will occur if safety, tolerability, and PK data from the Part 1 24-h 
infusion cohorts as well as those from study C4611007 are determined to be supportive and 
acceptable by competent regulatory authorities. The dose progression will be based on 
emerging PK, safety and tolerability data and will not exceed the exposure limits agreed with 
competent authorities. 
Cohorts of 8 participants each who meet the eligibility criteria (see Sections 5.1 and 5.2) will 
be enrolled and randomized in a ratio of 6 PF-07304814:2 placebo. All participants will 
follow the study procedures as outlined in SoA. They will be required to stay in hospital from 
at a minimum, Day 1, pre-dose through completion of Day 7 evaluations (Follow-up 1).
Participants will then return for Day 10 (Follow-up 2) and Day 14 (Follow-up 3) activities 
and a final planned follow-up (Follow-up 4) visit per the SoA on Days 34-41 for a total of 
approximately 5-6 weeks study participation from the start of dosing to follow-up, excluding 
screening.
Participants who discontinue for reasons other than drug-related safety events during the trial 
may be replaced at the discretion of the Sponsor and investigator.
4.2. Scientific Rationale for Study Design
This study will provide data on safety, tolerability, PK, biomarker changes and measures of 
disease activity in hospitalized patients infected with SARS-CoV-2. Since this is a first in 
human study, patients who require mechanical ventilation or suffer from severe, uncontrolled 
co-morbidities will be excluded to balance potential risk versus benefit. Risk is further 
mitigated by a single dose escalation design in Part 1: SAD, with extensive assessment of 
safety and PK. Precautionary sentinel dosing will also be used in each dose-escalating cohort 
in Part 1. A small cohort of 2 participants (1 receiving PF-07304814 and 1 receiving 
placebo) will be dosed prior to the remainder of the cohort. An independent IRC will assess 
whether it is safe to proceed to continued dosing within a cohort following sentinel dosing or 
whether it is safe to dose-escalate to the next dose level. In Part 2, PF-07304814 will be 
administered for a period of 5 days of continuous infusion at a dose based on emerging data 
and with the agreement of the competent regulatory authority. The potential for PF-07304814 












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3. Participants with pre-existing moderate to severe or poorly controlled cardiovascular 
disease including hypertension or diabetes, or moderate to severe or poorly controlled 
chronic lung diseases, including asthma or chronic obstructive pulmonary disease, as 
assessed by the investigator.
4. Participants with a known medical history of ischemic heart disease, heart failure, 
dysrhythmia or other pre-existing cardiac condition that in the opinion of the 
investigator may confuse interpretation of ECG or cardiovascular findings.
5. Participants with a known medical history of recent acute or chronic liver disease (other 
than non-alcoholic hepatic steatosis), including chronic or active hepatitis B or C 
infection, or primary biliary cirrhosis.
6. Participants with history of venous thromboembolic event, including deep venous 
thrombosis or pulmonary embolism. 
7. Participants with known HIV infection who have a CD4+ cell count <500/mm3 and/or 
who are receiving a boosted anti-retroviral treatment regimen.
8. Participants with a known medical history of recurrent seizures.
9. Confirmed concurrent active systemic infection other than COVID-19.
10. Current diagnosis of cancer, unless in remission and untreated.
11. Other medical or psychiatric condition including recent (within the past year) or active 
suicidal ideation/behavior or laboratory abnormality that may increase the risk of study 
participation or, in the investigator’s judgment, make the participant inappropriate for 
the study.
Prior/Concomitant Therapy:
12. Participant is receiving any medications or substances that are strong inhibitors or 
inducers of cytochrome P450 (CYP) 3A4.
13. Participant has received systemic oral, intravenous, or intramuscular corticosteroid 
therapy (>40 mg/day equivalent prednisolone) within the previous 28 days, except as 
required for COVID-19 treatment.
14. Female participant who are taking hormonal therapy for contraception or as estrogen 
replacement therapy, post menopause. 
Prior/Concurrent Clinical Study Experience:
15. Previous administration with any investigational drug within 30 days (or as determined 
by the local requirement) or 5 half-lives preceding the first dose of investigational 
product used in this study (whichever is longer).


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Note: Participants are allowed to participate if receiving local standard of care for 
COVID-19 including Remdesivir, convalescent sera/plasma, monoclonal antibody 
treatments. Participation in an open-label investigational/observational study for 
convalescent serum/plasma is also allowed so long any associated study procedures do 
not, in the opinion of the investigator, interfere with the current study. If other therapies 
receive Emergency Use Authorization status, they may also be allowed after discussion 
with the sponsor.  
Diagnostic Assessments:
16. Screening 12-lead ECG that demonstrates clinically relevant abnormalities that may 
affect participant safety or interpretation of study results (eg, baseline QTcF interval 
>450 msec, complete LBBB, signs of an acute or indeterminate-age myocardial 
infarction, ST-T interval changes suggestive of myocardial ischemia, second- or 
third-degree AV block, or serious brady-arrhythmias or tachyarrhythmias).

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 
participants.
17. Participants with any of the following abnormalities in clinical laboratory tests at 
screening, confirmed by a single repeat test, if deemed necessary:

AST or ALT level ≥3 times the ULN.

Total bilirubin level ≥1.5 times the ULN, unless due to known Gilbert’s 
syndrome.

CLcr <60 mL/min using the Cockcroft-Gault equation.

Absolute neutrophil count <1000/mm3.
Other Exclusions:
18. Females who are pregnant or breastfeeding.
19. 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.


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5.3. Lifestyle Considerations
5.3.1. Contraception
The investigator or his or her designee, in consultation with the participant, will confirm that 
the participant has selected an appropriate method of contraception for the individual 
participant and his or her partner(s) from the permitted list of contraception methods (see
Appendix 4: Contraceptive Guidance, Section 10.4.4) and will confirm that the participant
has been instructed in its consistent and correct use. At time points indicated in the SoA, the 
investigator or designee will inform the participant of the need to use highly effective 
contraception consistently and correctly and document the conversation and the participant’s 
affirmation in the participant’s chart (participants need to affirm their consistent and correct 
use of at least 1 of the selected methods of contraception). In addition, the investigator or 
designee will instruct the participant to call immediately if the selected contraception method 
is discontinued or if pregnancy is known or suspected in the participant or partner.
5.4. Screen Failures
Screen failures are defined as participants who consent to participate in the clinical study but 
are not subsequently assigned to study intervention. A minimal set of screen failure 
information is required to ensure transparent reporting of screen failure participants to meet 
the CONSORT publishing requirements and to respond to queries from regulatory 
authorities. Minimal information includes demography, screen failure details, eligibility 
criteria, and any SAE.
Individuals who do not meet the criteria for participation in this study (screen failure) may be 
rescreened once only. All screening assessments must be repeated during re-screening.
5.5. Criteria for Temporarily Delaying Enrolment/Randomization/Study Intervention
Administration 
Not applicable.
6. STUDY INTERVENTION
Study intervention is defined as any investigational intervention(s), marketed product(s), 
placebo, medical device(s), or study procedure(s) intended to be administered to a study 
participant according to the study protocol.
For the purposes of this protocol, study intervention refers to PF-07304814 or placebo.
6.1. Study Intervention(s) Administered
6.1.1. Administration
Study intervention administration details will be recorded on the CRF Study Intervention(s) 
Administered. The IV will be administered on the contralateral arm from PK sampling.


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The study interventions are:
Part 1: SAD

PF-07304814: treatment duration = 24-hour continuous intravenous infusion. Study 
intervention will be provided as a solution for infusion in a vial. Vials are for single 
use in a single participant for a single dose.

Placebo: treatment duration = 24-hour continuous intravenous infusion.
Part 2: MAD

PF-07304814: treatment duration = 120-hour continuous intravenous infusion. Study 
intervention will be provided as a powder in vial for solution for infusion. Vials are 
for single use in a single participant for a single dose.

Placebo: treatment duration = 120-hour continuous intravenous infusion.
Intervention Name
PF-07304814 Solution for 
Infusion
PF-07304814 Powder for 
Solution for Infusion
Placebo
ARM Name
(group of patients 
receiving a specific 
treatment (or no 
treatment)
PF-07304814
PF-07304814
Placebo
Type
Drug
Drug
Placebo
Dose Formulation
Solution for infusion in a 
vial. 
Vial is single-use only
Powder in a vial for 
solution for infusion.
Vial is single-use only
Solution for infusion in 
a commercial 
presentation in IV bag
Unit Dose Strength(s)
250 mg as a 25 mg/mL 
solution
1000 mg
0 mg
Dosage Level(s)
Planned nominal dose over 
24h continuous infusion in 
Part 1: 
Cohort 1: 500 mg
Cohort 2: 1000 mg single 
dose over 24h.
Planned nominal dose 
over 120h continuous 
infusion in Part 2: 
Cohort 6: 250 mg/day 
x 5 days
Cohort 7: TBD
Only used in Part 2.
Part 1: 24h
Part 2: 120h
Route of 
Administration
Intravenous
Intravenous
Intravenous
Use
Experimental
Experimental
Control
IMP or NIMP
IMP
IMP
NIMP
Sourcing
Provided centrally by the 
sponsor
Provided centrally by the 
sponsor
Provided locally by the 
trial site, subsidiary, or 
designee.


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Intervention Name
PF-07304814 Solution for 
Infusion
PF-07304814 Powder for 
Solution for Infusion
Placebo
Packaging and 
Labeling
Study intervention will be 
provided in vials. Each vial 
will be labeled as required 
per country requirement. 
Please see IP manual for 
additional details.
Study intervention will 
be provided in vials. 
Each vial will be labeled 
as required per country 
requirement. Please see 
IP manual for additional 
details for preparation 
and blinding.
Placebo will be 
provided by the trial 
site in commercial IV 
bags and prepared 
according to the IP 
manual. Please see IP 
manual for additional 
details.
Current/Former 
Name(s) or Alias(es)
PF-07304814
PF-07304814
Placebo
6.2. Preparation/Handling/Storage/Accountability
1. The investigator or designee must confirm appropriate temperature conditions have 
been maintained during transit for all study interventions received and any 
discrepancies are reported and resolved before use of the study intervention.
2. Only participants enrolled in the study may receive study intervention and only 
authorized site staff may supply or administer study intervention. All study 
interventions must be stored in a secure, environmentally controlled, and monitored 
(manual or automated recording) area in accordance with the labeled storage 
conditions with access limited to the investigator and authorized site staff. At a 
minimum, daily minimum and maximum temperatures for all site storage locations 
must be documented and available upon request. Data for nonworking days must 
indicate the minimum and maximum temperatures since previously documented for 
all site storage locations upon return to business.
3. Any excursions from the study intervention label storage conditions should be 
reported to Pfizer upon discovery along with any actions taken. The site should 
actively pursue options for returning the study intervention to the storage conditions 
described in the labeling, as soon as possible. Once an excursion is identified, the 
study intervention must be quarantined and not used until Pfizer provides permission 
to use the study intervention. Specific details regarding the definition of an excursion 
and information the site should report for each excursion will be provided to the site 
in the IP manual.
4. Any storage conditions stated in the SRSD will be superseded by the storage 
conditions stated on the label.
5. Study interventions should be stored in their original containers.
6. See the IP manual for storage conditions of the study intervention once diluted.


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7. The investigator, institution, or the head of the medical institution (where applicable) 
is responsible for study intervention accountability, reconciliation, and record 
maintenance (ie, receipt, reconciliation, and final disposition records), such as the 
IPAL or sponsor-approved equivalent. All study interventions will be accounted for 
using a study intervention accountability form/record. 
8. Further guidance and information for the final disposition of unused study 
interventions are provided in the IP manual. All destruction must be adequately 
documented. If destruction is authorized to take place at the investigator site, the 
investigator must ensure that the materials are destroyed in compliance with 
applicable environmental regulations, institutional policy, and any special instructions 
provided by Pfizer.
Upon identification of a product complaint, notify the sponsor within 1 business day of 
discovery as described in the IP Manual.
6.2.1. Preparation and Dispensing
A qualified staff member will dispense the study intervention in quantities appropriate to the 
dose cohort, participant randomization and according to the SoA.
See the IP manual 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.
PF-07304814 and placebo will be prepared by qualified unblinded site personnel according 
to the IP manual. The study intervention will be administered in a blinded fashion to the
participants.
6.3. Measures to Minimize Bias: Randomization and Blinding
6.3.1. Allocation to Study Intervention
Allocation of participants to treatment groups will proceed through the use of an IRT system.
The site personnel (study coordinator or specified designee) will be required to enter or select 
information including but not limited to the user’s ID and password, the protocol number, 
and the participant number. The site personnel will then be provided with a treatment 
assignment, randomization number. The IRT system will provide a confirmation report 
containing the participant number and randomization number. The confirmation report must 
be stored in the site’s files. 
Study intervention will be administered by continuous infusion starting on Day 1 as
summarized in the SoA.
The study-specific IRT reference manual and IP manual will provide the contact information 
and further details on the use of the IRT system.


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Participants in each cohort will be assigned to receive study intervention according to 
randomization scheme. Investigators will remain blinded to each participant’s assigned study 
intervention throughout the course of the study. In order to maintain this blind, an otherwise 
uninvolved third party will be responsible for the preparation and dispensing of all study 
intervention and will endeavor to ensure that there are no differences in time taken to 
dispense or visual presentation following randomization.
In the event of a Quality Assurance audit, the auditor(s) will be allowed access to unblinded 
study intervention records at the site(s) to verify that randomization/dispensing has been done 
accurately.
6.3.2. Breaking the Blind 
The IRT will be programmed with blind-breaking instructions. In case of an emergency, the 
investigator has the sole responsibility for determining if unblinding of a participant’s 
treatment assignment is warranted. Participant safety must always be the first consideration 
in making such a determination. If the investigator decides that unblinding is warranted, the 
investigator should make every effort to contact the sponsor prior to unblinding a 
participant’s treatment assignment unless this could delay further management of the 
participant. If a participant’s treatment assignment is unblinded, the sponsor must be notified 
within 24 hours after breaking the blind. The date and reason that the blind was broken must 
be recorded in the source documentation and CRF.
The study-specific IRT reference manual and IP manual will provide the contact information 
and further details on the use of the IRT system.
6.4. Study Intervention Compliance
Participants will receive study intervention directly from the investigator or designee, under 
medical supervision. The date and time of each dose administered in the clinic (start and end 
time) will be recorded in the source documents and recorded in the CRF. The dose of study 
intervention and study participant identification will be confirmed at the time of dosing by a 
member of the study site staff other than the person administering the study intervention.
The site will complete the required dosage Preparation Record located in the IP manual. The 
use of the Preparation Record is preferred, but it does not preclude the use of an existing 
appropriate clinical site documentation system. The existing clinical site's documentation 
system should capture all pertinent/required information on the preparation and 
administration of the dose. This may be used in place of the Preparation Record after 
approval from the sponsor and/or designee.
A record of the number of PF-07304814 vials dispensed to and the volume of PF-07304814 
or placebo administered to each participant must be maintained and reconciled with study 
intervention and compliance records. Intervention start and stop times and dates, including 
times for intervention delays and/or dose reductions, will also be recorded in the CRF.


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6.5. Concomitant Therapy 
Medications taken prior to dosing will be documented as prior medications. Medications 
taken after the first dose of study intervention has been administered will be documented as 
concomitant medications. All concomitant medications taken during the study must be 
recorded in study records with indication, daily dose, and start and stop dates of 
administration. Participants will be queried about concomitant medication (including topical 
medications and treatments, over-the-counter and prescription medications and treatments, 
herbals, and vaccinations) at each visit. Any new concomitant medications or dose changes 
to current concomitant medications should be evaluated for potential new or worsening 
adverse events.
Study intervention is to be administered on top of SoC for this study. It is recognized that 
SoC may change during the course of the study, and it is therefore important to meticulously 
capture all SoC in the CRF.
Prohibited medications are shown in Appendix 8: Prohibited Medications.
Hormonal therapy for purposes of contraception or postmenopausal replacement therapy will 
not be allowed to be used in participants (see Appendix 4: Contraceptive Guidance).
6.5.1. Rescue Medicine
There is no rescue therapy to reverse the AEs observed with PF-07304814; standard medical 
supportive care must be provided to manage the AEs.
6.6. Dose Modification
Planned nominal doses are projected based on nonclinical data and may be modified based 
on emerging safety, tolerability, and PK data.
6.6.1. Dose Escalation and Stopping Rules 
Dosing of any individual participant may be stopped at any time if it is the Investigator’s 
opinion that the risks outweigh any potential benefit, based on the available individual 
subject safety data. If possible, the Investigator should contact the Sponsor to discuss before 
discontinuation. For participants in Part 2 progression of COVID-19 disease should not 
automatically lead to stopping dosing, but the Investigator should consider the overall risk 
benefit. Precautionary sentinel dosing will be used in each dose-escalating cohort in Part 1.
A small cohort of 2 participants (1 receiving PF-07304814 and 1 receiving placebo) will be 
dosed prior to the remainder of the cohort. All available safety and tolerability data from the 
2 sentinel participants up to at least Day 3 at 24 hours post completion of dosing will be 
reviewed by the Investigator(s) (if available), the study team and IRC. The independent IRC 
will then determine whether it is safe to proceed to dose the remaining participants in the 
cohort. 


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During the SAD (Part 1) of the study, emerging safety, tolerability, and PK data will be 
reviewed by the Investigator(s) (if available), the study team and IRC. The independent IRC 
will then determine whether it is safe to proceed to the next dose level.
The decision to escalate will be based on a minimum of preliminary PK data through 
24 hours (Day 2), available safety and tolerability data through Day 6, and all reported SAEs 
through to Day 9 in at least 6 participants. In addition, the Investigator(s) (if available), the 
study team and the IRC will review available safety and tolerability data up to Day 3 and all 
reported SAEs up to Day 6 in the remaining 2 participants, along with cumulative safety and 
PK data from prior dose levels.
Progression to Part 2: MAD will occur if safety, tolerability, and PK data from the prior 
Part 1: SAD 24h infusion cohorts are determined to be supportive and acceptable by a 
competent regulatory authority.
During the MAD (Part 2) of the study, emerging safety, tolerability, and PK data will be 
reviewed by the Investigator(s) (if available) and the study team. Competent authorities will 
be consulted before proceeding to the next higher dose cohort. The decision to escalate will 
be based on a minimum of preliminary PK data through 120h (end of infusion), available 
safety and tolerability data through Day 7, and all reported SAEs through to Day 10 in at 
least 6 participants. In addition, the Investigator(s) (if available) and the study team will 
review available safety and tolerability in the remaining 2 participants, along with cumulative 
safety and PK data from prior dose levels.
Dose escalation stopping rules will be used to determine whether the maximal tolerated dose 
has been attained. Dose escalation may be stopped if it is determined that the limits of safety 
and/or tolerability have been reached. If dose escalation is stopped because of any of these 
criteria, additional cohort(s) may receive the same or lower doses of the investigational 
product.
The dose escalation will be terminated based on the following criteria:

If 50% or more of the participants receiving active drug at a given dose level (but not 
participants receiving placebo) develop similar clinically significant laboratory, ECG, 
or vital sign abnormalities, considered to be drug-related, in the same organ class, and 
indicating dose-limiting intolerance.

Severe nonserious AEs, considered as, at least, possibly related to investigational 
product administration, in 2 participants at a given dose level (but not participants 
receiving placebo), independent of within or not within the same system organ class, 
indicating dose-limiting intolerance.

In the event of an SAE in a participant receiving active treatment, causality must be 
fully assessed by the investigator and sponsor. If it is deemed to be not drug related, 
dosing may continue. If it is deemed to be drug related or unknown by either the 
investigator or sponsor, dosing will be paused and the SAE will be evaluated by the 




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6.7. Intervention After the End of the Study
No intervention will be provided to study participants after the end of the study.
7. DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL
7.1. Discontinuation of Study Intervention
In rare instances, it may be necessary for a participant to permanently discontinue study 
intervention (definitive discontinuation). Reasons for definitive discontinuation of study 
intervention include (but are not limited to) the following: AEs, Physician decision, 
withdrawal by participants.
Note that discontinuation of study intervention does not represent withdrawal from the study.
If study intervention is definitively discontinued, the participant will remain in the study to 
be evaluated for safety and other assessments. See the SoA for data to be collected at the time 
of discontinuation of study intervention and follow-up for any further evaluations that need 
to be completed.
In the event of discontinuation of study intervention, it must be documented on the 
appropriate CRF/in the medical records whether the participant is discontinuing further 
receipt of study intervention or also from study procedures, posttreatment study follow-up, 
and/or future collection of additional information.
At the discretion of the Investigator, in the event of a significant safety concern such as 
changes in renal or cardiac function, infusion of the study intervention may be interrupted or 
terminated.
If anaphylaxis or a serious allergic reaction is noted, the study intervention should be 
immediately stopped, and the participant should be discontinued. Additionally, other adverse 
events or confirmed laboratory abnormalities judged by the investigator to be a significant 
safety concern should also lead to immediate stop to study intervention.
The Sponsor, in consultation with the independent IRC and/or a competent regulatory 
agency, may also mandate discontinuation based on review of PK or safety data.
If a participant discontinues study intervention, he/she should complete the “Early 
Termination” visit (SoA).
In addition, intervention will be discontinued for the following changes in ECG.
ECG Changes
A participant who meets either bulleted criteria based on the average of triplicate ECG 
readings that are deemed to be related to the administration of PF-07304814 will be 
withdrawn from the study intervention.


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
QTcF >500 msec.

Change from baseline: QTcF >60 msec.
If a clinically significant finding is identified (including, but not limited to, changes from 
baseline in QTcF after enrolment), 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.
7.1.1. Temporary Discontinuation
In Part 1: SAD, if infusion is temporary interrupted, it should be resumed as soon as possible 
and the complete dose should be administered. Temporary discontinuation for longer than 
2 hours is not permitted. Participants may temporarily discontinue from Part 2: MAD for up 
to 6 hours over the 120-h infusion period (if possible, each interruption should be no longer 
than 2 hours) to reduce risk to the participant at the discretion of the investigator. If study 
intervention administration is restarted the remaining course will be given. Temporary 
discontinuation for longer than 6 hours is not permitted.
7.1.2. Rechallenge
Not applicable.
7.2. Participant Discontinuation/Withdrawal From the Study
A participant may withdraw from the study at any time at his/her own request. Reasons for 
discontinuation from the study include the following:

Refused further follow-up;

Lost to follow-up;

Death;

Physician decision;

Pregnancy;

Study terminated by sponsor.
At the time of discontinuing from the study, if possible, an early discontinuation visit should 
be conducted. See the SoA for assessments to be collected at the time of study 
discontinuation and follow-up and for any further evaluations that need to be completed. 
The early discontinuation visit applies only to participants who are enrolled/randomized and 
then are prematurely withdrawn from the study. Participants should be questioned regarding 
their reason for withdrawal.


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The participant will be permanently discontinued both from the study intervention and from 
the study at that time.
If a participant withdraws from the study, he/she may request destruction of any remaining 
samples taken and not tested, and the investigator must document any such requests in the 
site study records and notify the sponsor accordingly.
If the participant withdraws from the study and also withdraws consent (see Section 7.2.1) 
for disclosure of future information, no further evaluations should be performed and no 
additional data should be collected. The sponsor may retain and continue to use any data 
collected before such withdrawal of consent.
Lack of completion of all or any of the withdrawal/early termination procedures will not be 
viewed as protocol deviations so long as the participant’s safety was preserved.
7.2.1. Withdrawal of Consent
Participants who request to discontinue receipt of study intervention will remain in the study 
and must continue to be followed for protocol-specified follow-up procedures. The only 
exception to this is when a participant specifically withdraws consent for any further contact 
with him or her or persons previously authorized by the participant to provide this 
information. Participants should notify the investigator in writing of the decision to withdraw 
consent from future follow-up, whenever possible. The withdrawal of consent should be
explained in detail in the medical records by the investigator, as to whether the withdrawal is 
only from further receipt of study intervention or also from study procedures and/or 
posttreatment study follow-up and entered on the appropriate CRF page. In the event that 
vital status (whether the participant is alive or dead) is being measured, publicly available 
information should be used to determine vital status only as appropriately directed in 
accordance with local law.
7.3. Lost to Follow-up 
A participant will be considered lost to follow-up if he or she repeatedly fails to return for 
scheduled visits and is unable to be contacted by the study site.
The following actions must be taken if a participant fails to attend a required study visit:

The site must attempt to contact the participant and reschedule the missed visit as 
soon as possible and counsel the participant on the importance of maintaining the 
assigned visit schedule and ascertain whether or not the participant wishes to and/or 
should continue in the study;

Before a participant is deemed lost to follow-up, the investigator or designee must 
make every effort to regain contact with the participant (where possible, 3 telephone 
calls and, if necessary, a certified letter to the participant’s last known mailing 
address or local equivalent methods). These contact attempts should be documented 
in the participant’s medical record;


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
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.
Procedures conducted as part of the participant’s routine clinical management (eg, blood 
count) and obtained before signing of the ICD may be utilized for screening purposes 
provided the procedures met the protocol-specified criteria and were performed within the 
time frame defined in the SoA.
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.
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 as outlined in the lab manual.
The total blood sampling volume for individual participants in this study is approximately 
225 mL in Part 1: SAD and 360 mL in Part 2: MAD. The actual collection times of blood 
sampling may change. Additional blood samples may be taken for safety assessments at 
times specified by Pfizer, provided the total volume taken during the study does not exceed 
550 mL during any period of 60 consecutive days.


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Note: In order to draw blood samples for safety assessments, pharmacokinetics, 
 a central line or midline is not required by the 
study protocol, and should only be placed if clinically warranted; 
•
During dosing of the interventional product, the blood draws for pharmacokinetics 
should be done using the contralateral arm to the one being used for infusion of the 
study intervention. (When a simultaneous blood sample is required for safety 
assessments,
 it is recommended to use 
the same venipuncture).
8.1. Efficacy Assessments
Not applicable.
8.2. Safety Assessments
Planned time points for all safety assessments are provided in the SoA. Unscheduled clinical 
laboratory measurements may be obtained at any time during the study to assess any 
perceived safety issues.
8.2.1. Physical Examinations
A complete physical examination will include, at a minimum, assessments of the 
cardiovascular, respiratory, gastrointestinal, and neurological systems. Height and weight 
will also be measured and recorded (height may be reported by participant if necessary) at 
screening only.
A targeted physical examination will include, at a minimum, assessments of the skin, lungs, 
cardiovascular system, and abdomen (liver and spleen).
Investigators should pay special attention to clinical signs related to previous serious 
illnesses.
8.2.2. Vital Signs
Temperature (Oral, Tympanic, Axillary or Temporal), pulse rate, respiratory rate, pulse 
oximetry/SpO2, and blood pressure will be assessed. It is preferred that body temperature be 
collected using the same method for the same participant throughout the study.
Blood pressure and pulse rate measurements will be assessed in the supine position
preferably with a completely automated device. Manual techniques will be used only if an 
automated device is not available.
Blood pressure and pulse rate measurements should be preceded by at least 5 minutes of rest 
for the participant in a quiet setting without distractions (eg, television, cell phones). Vital 
signs (to be taken before blood collection for laboratory tests) will include 1 pulse rate and 
1 blood pressure measurements.
CCI
CCI


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8.2.3. Electrocardiograms
Triplicate standard 12-lead ECGs utilizing limb leads (with a 10 second rhythm strip) should 
be collected at times (except for single measurement at screening) specified in the SoA
section of this protocol using an ECG machine that automatically calculates the heart rate and 
measures PR, RR, QT, and QTc intervals and QRS complex. Alternative lead placement 
methodology using torso leads (eg, Mason-Likar) is not recommended given the potential 
risk of discrepancies with ECGs acquired using standard limb lead placement. All scheduled
ECGs should be performed after the participant has rested quietly for at least 10 minutes in a 
supine position and taken before blood collection for laboratory tests. 
Once started, triplicate 12-lead ECGs will be completed within 20 minutes of start of the 1st 
reading; the triplicate ECG measurements collected before dose administration on Day 1 will 
serve as each participant’s baseline QTc value. 
If a) a post-dose QTc interval remains ≥60 msec from the baseline and is >450 msec; or 
b) an absolute QTc value is ≥500 msec for any scheduled ECG for greater than 4 hours (or 
sooner, at the discretion of the investigator); or c) QTc intervals get progressively longer, the 
participant should undergo continuous ECG monitoring. A cardiologist should be consulted 
if QTc intervals do not return to less than the criterion listed above after 8 hours of 
monitoring (or sooner, at the discretion of the investigator).
ECG data may be locally read for dose escalation purpose and then will be submitted to a 
central laboratory for measurement and final CSR reporting. The final ECG report from the 
central laboratory should be maintained in the participant’s source documentation and be the 
final interpretation of the ECG recording. Any clinically significant changes from the 
baseline/Day 1 ECG may potentially be AEs (Appendix 7: ECG Findings of Potential 
Clinical Concern) and should be evaluated further, as clinically warranted. 
In some cases, it may be appropriate to repeat abnormal ECGs to rule out improper lead 
placement as contributing to the ECG abnormality. It is important that leads be placed in the
same positions each time in order to achieve precise ECG recordings. If a machine-read QTc 
value is prolonged, as defined above, repeat measurements may not be necessary if a 
qualified medical provider’s interpretation determines that the QTc values are in the 
acceptable range.
ECG values of potential clinical concern are listed in Appendix 7: ECG Findings of Potential 
Clinical Concern.
8.2.3.1. Continuous Cardiac Monitoring by Telemetry
All abnormal rhythms will be recorded and reviewed by the study physician for the presence 
of rhythms of potential clinical concern. The time, duration, and description of the clinically 
significant event will be recorded in the CRF. In addition, a printed record of the tracing(s) of 
the clinically significant rhythm(s) will be made and retained with other source documents.


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Telemetry should be collected using a centralized system to monitor and preserve important 
events for future evaluations. Holter monitoring should not be used in parallel with 
continuous telemetry, unless it is the only means of data storage available at the investigator 
site, or verifiable arrhythmia quantification is required. To establish a baseline, telemetry 
should be recorded for at least 2 hours on Day -1 or before dosing on Day 1 of each cohort in 
Part 1: SAD. This may be done immediately prior to dosing or at some 2-hour continuous 
interval in the 24 hours prior to dosing, as long as the recording is performed when the 
participant is awake. Telemetry may be stopped within a reasonably short period of time 
prior to dosing, in order to avoid interference with study operations conducted immediately 
before dosing. However, it is expected that the telemetry leads will be in place and the 
system connected prior to dosing.
8.2.4. Clinical Safety Laboratory Assessments
See Appendix 2 for the list of clinical safety laboratory tests to be performed and the SoA for 
the timing and frequency. All protocol-required laboratory assessments, as defined in 
Appendix 2: Clinical Laboratory Tests, 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.
All laboratory tests with values considered clinically significantly abnormal during 
participation in the study or within 28 calendar days after the last dose of study intervention 
should be repeated until the values return to normal or baseline or are no longer considered 
clinically significant by the investigator or medical monitor.
If such values do not return to normal/baseline within a period of time judged reasonable by 
the investigator, the etiology should be identified and the sponsor notified.
See Appendix 6 for suggested actions and follow-up assessments in the event of potential 
drug-induced liver injury.
8.2.5. Pregnancy Testing
Pregnancy tests may be urine or serum tests but must have a sensitivity of at least 
25 mIU/mL. Pregnancy tests will be performed in WOCBP at the times listed in the SoA.
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 post treatment if 
this is an in-clinic visit. Pregnancy tests may also be repeated if requested by IRBs/ECs or if 
required by local regulations. If a urine test cannot be confirmed as negative (eg, an 
ambiguous result), a serum pregnancy test is required. In such cases, the participant must be 
excluded if the serum pregnancy result is positive.


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8.3. Adverse Events and Serious Adverse Events
The definitions of an AE and an SAE can be found in Section 10.3.
AEs will be reported by the participant (or, when appropriate, by a caregiver, surrogate, or 
the participant's legally authorized representative).
The investigator and any qualified designees are responsible for detecting, documenting, and 
recording events that meet the definition of an AE or SAE and remain responsible to pursue 
and obtain adequate information both to determine the outcome and to assess whether the 
event meets the criteria for classification as an SAE or caused the participant to discontinue 
the study intervention (see Section 7.1).
Each participant will be questioned about the occurrence of AEs in a nonleading manner.
In addition, the investigator may be requested by Pfizer Safety to obtain specific follow-up 
information in an expedited fashion.
8.3.1. Time Period and Frequency for Collecting AE and SAE Information
The time period for actively eliciting and collecting AEs and SAEs (“active collection 
period”) for each participant begins from the time the participant provides informed consent, 
which is obtained before the participant’s participation in the study (ie, before undergoing 
any study-related procedure and/or receiving study intervention), through and including a 
minimum of 28 calendar days, 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 and Pfizer concurs with that assessment.
For participants who are screen failures, the active collection period ends when screen failure 
status is determined.
If the participant withdraws from the study and also withdraws consent for the collection of 
future information, the active collection period ends when consent is withdrawn.
If a participant definitively discontinues or temporarily discontinues study intervention 
because of an AE or SAE, the AE or SAE must be recorded on the CRF and the SAE 
reported using the CT SAE Report Form.
Investigators are not obligated to actively seek AEs or SAEs after the participant has 
concluded study participation. However, if the investigator learns of any SAE, including a 
death, at any time after a participant has completed the study, and he/she considers the event 
to be reasonably related to the study intervention, the investigator must promptly report the 
SAE to Pfizer using the CT SAE Report Form.


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8.3.1.1. Reporting SAEs to Pfizer Safety
All SAEs occurring in a participant during the active collection period as described in 
Section 8.3.1 are reported to Pfizer Safety on the CT SAE Report Form immediately upon 
awareness and under no circumstance should this exceed 24 hours, as indicated in 
Section 10.3. 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.
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 Section 10.3.
Care will be taken not to introduce bias when detecting AEs and/or SAEs. Open-ended and 
nonleading verbal questioning of the participant is the preferred method to inquire about 
AE occurrences.
8.3.3. Follow-up of AEs and SAEs
After the initial AE/SAE report, the investigator is required to proactively follow each 
participant at subsequent visits/contacts. For each event, the investigator must pursue and 
obtain adequate information until resolution, stabilization, the event is otherwise explained, 
or the participant is lost to follow-up (as defined in Section 7.3).
In general, follow-up information will include a description of the event in sufficient detail to 
allow for a complete medical assessment of the case and independent determination of 
possible causality. Any information relevant to the event, such as concomitant medications 
and illnesses, must be provided. In the case of a participant death, a summary of available 
autopsy findings must be submitted as soon as possible to Pfizer Safety. 
Further information on follow-up procedures is given in Section 10.3.
8.3.4. Regulatory Reporting Requirements for SAEs
Prompt notification by the investigator to the sponsor of an SAE is essential so that legal 
obligations and ethical responsibilities towards the safety of participants and the safety of a 
study intervention under clinical investigation are met.


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The sponsor has a legal responsibility to notify both the local regulatory authority and other 
regulatory agencies about the safety of a study intervention under clinical investigation. The 
sponsor will comply with country-specific regulatory requirements relating to safety
reporting to the regulatory authority, IRBs/ECs, and investigators.
Investigator safety reports must be prepared for SUSARs according to local regulatory 
requirements and sponsor policy and forwarded to investigators as necessary.
An investigator who receives SUSARs or other specific safety information (eg, summary or 
listing of SAEs) from the sponsor will review and then file it along with the SRSD(s) for the 
study and will notify the IRB/EC, if appropriate according to local requirements.
8.3.5. Exposure During Pregnancy or Breastfeeding, and Occupational Exposure
Exposure to the study intervention under study during pregnancy or breastfeeding and 
occupational exposure are reportable to Pfizer Safety within 24 hours of investigator 
awareness.
8.3.5.1. Exposure During Pregnancy
An EDP occurs if: 

A female participant is found to be pregnant while receiving or after discontinuing 
study intervention.

A male participant who is receiving or has discontinued study intervention exposes a 
female partner prior to or around the time of conception.

A female is found to be pregnant while being exposed or having been exposed to 
study intervention due to environmental exposure. Below are examples of 
environmental exposure during pregnancy:

A female family member or healthcare provider reports that she is pregnant after 
having been exposed to the study intervention by ingestion or skin contact.

A male family member or healthcare provider who has been exposed to the study 
intervention by ingestion or skin contact then exposes his female partner prior to 
or around the time of conception.
The investigator must report EDP to Pfizer Safety within 24 hours of the investigator’s 
awareness, irrespective of whether an SAE has occurred. The initial information submitted 
should include the anticipated date of delivery (see below for information related to 
termination of pregnancy).


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


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


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8.3.8. Adverse Events of Special Interest
Not applicable.
8.3.8.1. Lack of Efficacy
Not applicable.
8.3.9. Medical Device Deficiencies
Not applicable.
8.3.10. Medication Errors
Medication errors may result from the administration of the study intervention to the wrong 
participant, or at the wrong time, or at the wrong dose.
Exposures to the study intervention under study may occur in clinical trial settings, such as 
medication errors.
Safety Event
Recorded on the CRF
Reported on the CT SAE Report Form to 
Pfizer Safety Within 24 Hours of Awareness
Medication errors 
All (regardless of whether 
associated with an AE)
Only if associated with an SAE
Medication errors include:

Medication errors involving participant exposure to the study intervention.

Potential medication errors or uses outside of what is foreseen in the protocol that do 
or do not involve the study participant.
Such medication errors occurring to a study participant are to be captured on the medication 
error page of the CRF, which is a specific version of the AE page.
In the event of a medication dosing error, the sponsor should be notified within 24 hours.
Whether or not the medication error is accompanied by an AE, as determined by the 
investigator, the medication error is recorded on the medication error page of the CRF and, if 
applicable, any associated AE(s), serious and nonserious, are recorded on the AE page of the 
CRF.
Medication errors should be reported to Pfizer Safety within 24 hours on a CT SAE Report 
Form only when associated with an SAE.
8.4. Treatment of Overdose
For this study, any dose of PF-07304814 greater than twice the intended dose within a 
24-hour time period (±2 hours) will be considered an overdose.


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Sponsor does not recommend specific treatment for an overdose.
In the event of an overdose, the investigator should:
1. Contact the medical monitor within 24 hours.
2. Closely monitor the participant for any AEs/SAEs and laboratory abnormalities for at 
least 5 half-lives or 28 calendar days after the overdose of PF-07304814 (whichever is 
longer). Closely monitor the participant for any AEs/SAEs.
3. Document the quantity of the excess dose as well as the duration of the overdose in the 
CRF.
4. Overdose is reportable to Safety only when associated with an SAE.
5. Obtain a blood sample for PK analysis within 1 day from the date of the last dose of 
study intervention if requested by the medical monitor (determined on a case-by-case 
basis).
Decisions regarding dose interruptions or modifications will be made by the investigator in 
consultation with the medical monitor based on the clinical evaluation of the participant.
8.5. Pharmacokinetics
8.5.1. Plasma for Analysis of PF-07304814 and PF-00835231
Blood samples of approximately 4 mL, to provide a minimum of 1.5 mL plasma, will be 
collected into appropriately labeled tubes containing K3EDTA for measurement of plasma 
concentrations of PF-07304814 and PF-00835231 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 12 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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8.8.5. Specified Protein Research
Approximately 10 mL blood will be collected for plasma PD biomarkers and 10 mL blood 
will be collected for serum PD biomarkers from participants per the SoA. Assessments may 
include biomarker endpoints outlined below. In addition, transporter analysis may be 
conducted. These data will be used for internal exploratory purposes and will not be included 
in the CSR. Collection, storage and shipping instructions will be in accordance with the 
laboratory manual.
8.8.5.1. Plasma PD Biomarker Assessments
Plasma samples will be used to assess cytokines of inflammatory response (eg, IL-1B, IL-2, 
IL-4, IL-6, IL-8, IL-10, IL-12p70, IL-13 TNF-α, and IFN-γ) and proteomics. Plasma samples 
will be collected to assess coagulation markers (eg, PT, aPTT, and D-dimer) and fibrinogen
at time points described in the SoA.
Residuals of all samples may be banked for up to 5 years for future research. Collection, 
storage and shipping instructions will be in accordance with the laboratory manual.
8.8.5.2. Serum PD Biomarker Assessments
Serum samples will be used to assess biomarkers of generalized endothelial damage/anemia 
(eg, ferritin), cardiac dysfunction (eg, CK, proBNPII, and troponin), haptoglobin, and general 
markers of sepsis/organ damage (eg, LDH, hsCRP, and cystatin-C), and procalcitonin. In 
addition, host innate responses will be monitored using serological endpoints (anti-SARS 
CoV-2). Residuals of all samples may be banked for up to 5 years for future research.
Collection, storage and shipping instructions will be in accordance with the laboratory 
manual.
8.9. Immunogenicity Assessments
Immunogenicity assessments are not included in this study.
8.10. Health Economics
Health economics/medical resource utilization and health economics parameters are not 
evaluated in this study.
9. STATISTICAL CONSIDERATIONS
Detailed methodology for summary and statistical analyses of the data collected in this study 
is outlined here and further detailed in 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.
CCI


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9.1. Estimands and Statistical Hypotheses
There are no estimands or statistical hypotheses for this study.
9.2. Sample Size Determination
No formal sample size calculation was performed.
The sample size for both Part 1: SAD and Part 2: MAD of approximately 8 participants per 
cohort (6 PF-07304814:2 placebo) has been chosen based on the need to minimize first 
exposure to humans of a new chemical entity and the requirements to provide adequate safety 
and toleration information at each dose level.
Participants who discontinue for reasons other than drug-related safety events during the trial 
may be replaced at the discretion of the Sponsor and Investigator.
9.3. Analysis Sets
For purposes of analysis, the following analysis sets are defined:
Population
Description
Enrolled/Randomly 
assigned to study 
intervention
"Enrolled" means a participant's, or his/her legally authorized
representative’s, agreement to participate in a clinical study 
following completion of the informed consent process.
Potential participants who are screened for the purpose of 
determining eligibility for the study, but do not participate in 
the study, are not considered enrolled, unless otherwise 
specified by the protocol.
Evaluable
All participants randomly assigned to study intervention and 
who take at least 1 dose of study intervention.
Safety
All participants randomly assigned to study intervention and 
who take at least 1 dose of study intervention. Participants 
will be analyzed according to the product they actually 
received.
PK Concentration Set
All participants randomly assigned to study intervention and 
who take at least 1 dose of study intervention and in whom at 
least 1 concentration value is reported for the given part of 
the study (Part 1: SAD or Part 2: MAD).
PK Parameter Set
All participants randomly assigned to study intervention and 
who take at least 1 dose of study intervention and in whom at 
least 1 of the PK parameters of interest are reported for the 
given part of the study (Part 1: SAD or Part 2: MAD).


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Population
Description
Biomarker Analysis Set
All participants randomly assigned to study intervention and 
who take at least 1 dose of study intervention and in whom at 
least 1 of the biomarkers of interest are reported for the given 
part of the study (Part 1: SAD or Part 2: MAD).
9.4. Statistical Analyses
The SAP will be developed and finalized before any analyses are performed and will 
describe the analyses and procedures for accounting for missing, unused, and spurious data.
This section is a summary of the planned statistical analyses of the primary and secondary 
endpoints.
9.4.1. Primary Endpoint: Safety
All safety analyses will be performed on the safety population. No formal analyses are 
planned for safety data.
AEs, ECGs, BP, pulse rate, pulse oximetry/SpO2, clinical laboratory data and infusion site 
reactions 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.
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 may not be required to be 
reported, unless otherwise noted. Demographic data collected at screening will be reported.
9.4.1.1. Electrocardiogram Analyses
Changes from baseline for the ECG parameters QT interval, heart rate, QTcF interval, PR 
interval, and QRS complex will be summarized by treatment and time.
The number (%) of participants with maximum post-dose QTcF values and maximum 
increases from baseline in the following categories will be tabulated by treatment:
Safety QTcF Assessment
Degree of Prolongation
Mild (msec)
Moderate (msec)
Severe (msec)
Absolute value
>450-480
>480-500
>500
Increase from baseline
30-60
>60


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9.4.2. Secondary Endpoint: Pharmacokinetic Analyses
9.4.2.1. Derivation of Pharmacokinetic Parameters
Plasma PK parameters of PF-07304814 and PF-00835231 to be derived (if data permit) from 
the concentration-time data using standard noncompartmental methods following 24h or 
120h infusion are defined in Table 7 and Table 8, respectively. Urine PF-00835231 PK 
parameters following 24h infusion are defined in Table 9.
Actual PK sampling times will be used in the derivation of PK parameters. In the case that 
actual PK sampling times are not available, nominal PK sampling time will be used in the 
derivation of PK parameters.
Table 7.
Plasma PF-07304814 and PF-00835231 PK Parameters Definitions for 
Part 1: SAD (24-h Continuous Infusion)
Parameter
Definition
Method of Determination
C24
Concentration at 24h (end of infusion
in Part 1)
Observed directly from data
C24 (dn)
Dose normalized C24
C24/Dose
Actual PK sampling times will be used in derivation of PK parameters.
Table 8.
Plasma PF-07304814 and PF-00835231 PK Parameters for Part 2: MAD
(120-h Continuous Infusion)
Parameter
Definition
Method of Determination
C120
Concentration at 120h (end of 
infusion) 
Observed directly from data
Cmax
Maximum observed concentration
Observed directly from data
Css
Steady state concentration
Average concentration after achieving steady state
t1/2*
Terminal half-life.
Loge(2)/kel,
where kel is the terminal phase rate constant 
calculated by a linear regression of the loglinear 
concentration-time curve. Only those data points 
judged to describe the terminal loglinear decline 
will be used in the regression.
*If data permit.
Actual PK sampling times will be used in derivation of PK parameters.




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supporting clinical development. Unblinded results will be reviewed by a designated limited
number of sponsor colleagues within the study team.
An independent IRC will assess whether it is safe to proceed to continued dosing after a 
small sentinel cohort of 2 participants within each dose-escalating cohort or if it is safe to 
dose-escalate to the next dose level within Part 1.
9.6. Data Monitoring Committee or Other Independent Oversight Committee
This study will use an independent IRC for Part 1. The IRC is independent of the study team 
and includes Pfizer internal members. Emerging data will be reviewed by the Investigator(s) 
(if available), the study team and the IRC. The IRC charter describes the role of the IRC in 
more detail.
The IRC will be responsible for ongoing monitoring of the safety of participants in the study 
according to the charter. The recommendations made by the IRC to alter the conduct of the 
study will be forwarded to the appropriate Pfizer personnel for final decision. Pfizer will 
forward such decisions, which may include summaries of aggregate analyses of safety data, 
to regulatory authorities, as appropriate. 
The IRC will review the data collected for decision to proceed to dosing of the rest of the 
cohort after the sentinel cohort in each dose-escalating cohort, as well as to proceed to the 
next dose level in Part 1: SAD. The IRC may also be consulted at other times to review 
safety data and in the event of unexpected safety findings in study C4611007.


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


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


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A participant who is rescreened is not required to sign another ICD if the rescreening occurs 
within 7 days from the previous ICD signature date.
Unless prohibited by local requirements or IRB/EC decision, the ICD will contain a separate 
section that addresses the use of samples for optional additional research. The optional 
additional research does not require the collection of any further samples. The investigator or 
authorized designee will explain to each participant the objectives of the additional research.
Participants will be told that they are free to refuse to participate and may withdraw their 
consent at any time and for any reason during the storage period. A separate signature will be 
required to document a participant's agreement to allow specimens to be used for additional
research. Participants who decline to participate in this optional additional research will not 
provide this separate signature.
10.1.4. Data Protection
All parties will comply with all applicable laws, including laws regarding the implementation 
of organizational and technical measures to ensure protection of participant data.
Participants’ personal data will be stored at the study site in encrypted electronic and/or paper 
form and will be password protected or secured in a locked room to ensure that only 
authorized study staff have access. The study site will implement appropriate technical and 
organizational measures to ensure that the personal data can be recovered in the event of 
disaster. In the event of a potential personal data breach, the study site will be responsible for 
determining whether a personal data breach has in fact occurred and, if so, providing breach 
notifications as required by law.
To protect the rights and freedoms of participants with regard to the processing of personal 
data, participants will be assigned a single, participant-specific numerical code. Any 
participant records or data sets that are transferred to the sponsor will contain the numerical 
code; participant names will not be transferred. All other identifiable data transferred to the 
sponsor will be identified by this single, participant-specific code. The study site will 
maintain a confidential list of participants who participated in the study, linking each 
participant’s numerical code to his or her actual identity and medical record identification. In 
case of data transfer, the sponsor will protect the confidentiality of participants’ personal data 
consistent with the clinical study agreement and applicable privacy laws.
10.1.5. 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.


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


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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.
The investigator must maintain accurate documentation (source data) that supports the 
information entered in the CRF.
The investigator must ensure that the CRFs are securely stored at the study site in encrypted 
electronic form and are password protected to prevent access by unauthorized third parties.
The investigator must permit study-related monitoring, audits, IRB/EC review, and 
regulatory agency inspections and provide direct access to source data documents. This 
verification may also occur after study completion. It is important that the investigator(s) and 
their relevant personnel are available during the monitoring visits and possible audits or 
inspections and that sufficient time is devoted to the process.
Monitoring details describing strategy (eg, risk-based initiatives in operations and quality 
such as risk management and mitigation strategies and analytical risk-based monitoring), 
methods, responsibilities, and requirements, including handling of noncompliance issues and 
monitoring techniques (central, remote, or on-site monitoring), are provided in the 
monitoring plan.
The sponsor or designee is responsible for the data management of this study, including 
quality checking of the data.
Study monitors will perform ongoing source data verification to confirm that data entered 
into the CRF by authorized site personnel are accurate, complete, and verifiable from source 
documents; that the safety and rights of participants are being protected; and that the study is 
being conducted in accordance with the currently approved protocol and any other study 
agreements, ICH GCP, and all applicable regulatory requirements.
Records and documents, including signed ICDs, pertaining to the conduct of this study must 
be retained by the investigator for 15 years after study completion unless local regulations or 
institutional policies require a longer retention period. No records may be destroyed during 
the retention period without the written approval of the sponsor. No records may be 
transferred to another location or party without written notification to the sponsor. The 
investigator must ensure that the records continue to be stored securely for as long as they are 
maintained.
When participant data are to be deleted, the investigator will ensure that all copies of such 
data are promptly and irrevocably deleted from all systems.


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The investigator(s) will notify the sponsor or its agents immediately of any regulatory 
inspection notification in relation to the study. Furthermore, the investigator will cooperate 
with the sponsor or its agents to prepare the investigator site for the inspection and will allow 
the sponsor or its agent, whenever feasible, to be present during the inspection. The 
investigator site and investigator will promptly resolve any discrepancies that are identified 
between the study data and the participant's medical records. The investigator will promptly 
provide copies of the inspection findings to the sponsor or its agent. Before response 
submission to the regulatory authorities, the investigator will provide the sponsor or its 
agents with an opportunity to review and comment on responses to any such findings.
10.1.7. 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 can be found in the study monitoring plan.
Description of the use of computerized system is documented in the Data Management Plan.
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.
The investigator may initiate study-site closure at any time upon notification to the sponsor 
or designee/CRO if requested to do so by the responsible IRB/EC or if such termination is 
required to protect the health of study participants.
Reasons for the early closure of a study site by the sponsor may include but are not limited 
to:

Failure of the investigator to comply with the protocol, the requirements of the 
IRB/EC or local health authorities, the sponsor's procedures, or GCP guidelines.


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


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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 SToD system. 
To facilitate access to appropriately qualified medical personnel on study-related medical 
questions or problems, participants are provided with a contact card at the time of informed 
consent. The contact card contains, at a minimum, protocol and study intervention identifiers, 
participant numbers, contact information for the investigator site, and contact details for a 
contact center in the event that the investigator site staff cannot be reached to provide advice 
on a medical question or problem originating from another healthcare professional not 
involved in the participant’s participation in the study. The contact number can also be used 
by investigator staff if they are seeking advice on medical questions or problems; however, it 
should be used only in the event that the established communication pathways between the 
investigator site and the study team are not available. It is therefore intended to augment, but 
not replace, the established communication pathways between the investigator site and the 
study team for advice on medical questions or problems that may arise during the study. The 
contact number is not intended for use by the participant directly, and if a participant calls 
that number, he or she will be directed back to the investigator site.


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10.2. Appendix 2: Clinical Laboratory Tests
The following safety laboratory tests will be performed at times defined in the SoA section of 
this protocol. Additional laboratory results may be reported on these samples as a result of 
the method of analysis or the type of analyzer used by the clinical laboratory, or as derived 
from calculated values. These additional tests would not require additional collection of 
blood. Unscheduled clinical laboratory measurements may be obtained at any time during the 
study to assess any perceived safety issues.
Table 10.
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 
serum creatinine (and 
eGFR using 
Cockcroft-Gault)
Glucose
Calcium
Sodium
Potassium
Chloride
Total 
CO2 (bicarbonate)
AST, ALT
Phosphorus
Total bilirubin
Alkaline phosphatase
Uric acid
Albumin
Total protein
Lipid panel (Part 2 
only)
pH
Glucose (qual)
Protein (qual)
Blood (qual)
Ketones
Nitrites
Leukocyte esterase
Urobilinogen
Urine bilirubin
Microscopya
At screening only:

FSHb

Pregnancy test (-hCG)c
At timepoints in SoA:

Coagulation 

D-dimer

PT/INR

aPTT

Fibrinogen
a.
Only if urine dipstick is positive for blood, protein, nitrites, or leukocyte esterase.
b.
For confirmation of postmenopausal status only.
c.
Local urine testing will be standard for the protocol unless serum testing is required by local regulation 
or IRB/EC. Serum or urine -hCG for female participants of childbearing potential.
Investigators must document their review of each laboratory safety report.






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should be considered serious.
Hospitalization for elective treatment of a preexisting condition that did not worsen from 
baseline is not considered an AE.
d. Results in persistent disability/incapacity

The term disability means a substantial disruption of a person’s ability to conduct 
normal life functions.

This definition is not intended to include experiences of relatively minor medical 
significance such as uncomplicated headache, nausea, vomiting, diarrhea, 
influenza, and accidental trauma (eg, sprained ankle) which may interfere with or 
prevent everyday life functions but do not constitute a substantial disruption.
e.
Is a congenital anomaly/birth defect
f.
Other situations:

Medical or scientific judgment should be exercised in deciding whether SAE 
reporting is appropriate in other situations such as important medical events that 
may not be immediately life-threatening or result in death or hospitalization but 
may jeopardize the participant or may require medical or surgical intervention to 
prevent one of the other outcomes listed in the above definition. These events 
should usually be considered serious.

Examples of such events include invasive or malignant cancers, intensive treatment
in an emergency room or at home for allergic bronchospasm, blood dyscrasias or 
convulsions that do not result in hospitalization, or development of drug 
dependency or drug abuse.

Suspected transmission via a Pfizer product of an infectious agent, pathogenic or 
non-pathogenic, is considered serious. The event may be suspected from clinical 
symptoms or laboratory findings indicating an infection in a patient exposed to a 
Pfizer product. The terms “suspected transmission” and “transmission” are 
considered synonymous. These cases are considered unexpected and handled as 
serious expedited cases by pharmacovigilance personnel. Such cases are also 
considered for reporting as product defects, if appropriate.










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10.4. Appendix 4: Contraceptive Guidance 
10.4.1. Male Participant Reproductive Inclusion Criteria
Male participants are eligible to participate if they agree to the following requirements during 
the intervention period and for at least 3 days after the last dose of study intervention, which
corresponds to the time needed to eliminate reproductive safety risk of the study 
intervention(s):

Refrain from donating sperm.
PLUS either:

Be abstinent from heterosexual intercourse with a female of childbearing potential as 
their preferred and usual lifestyle (abstinent on a long-term and persistent basis) and 
agree to remain abstinent.
OR

Must agree to use a male condom when engaging in any activity that allows for 
passage of ejaculate to another person.
In addition to male condom use, a highly effective method of contraception may be 
considered in WOCBP partners of male participants (refer to the list of highly effective 
methods below in Section 10.4.4).
10.4.2. Female Participant Reproductive Inclusion Criteria
A female participant is eligible to participate if she is not pregnant or breastfeeding, and at 
least 1 of the following conditions applies:

Is not a WOCBP (see definitions below in Section 10.4.3).
OR

Is a WOCBP and using a contraceptive method that is highly effective (with a failure 
rate of <1% per year), 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). If a 
highly effective method that is user dependent is chosen, a second effective method of 
contraception, as described below, must also be used. The investigator should 
evaluate the effectiveness of the contraceptive method in relationship to the first dose 
of study intervention.

The investigator is responsible for review of medical history, menstrual history, and 
recent sexual activity to decrease the risk for inclusion of a woman with an early 
undetected pregnancy.


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10.4.3. Woman of Childbearing Potential
A woman is considered fertile following menarche and until becoming postmenopausal 
unless permanently sterile (see below).
If fertility is unclear (eg, amenorrhea in adolescents or athletes) and a menstrual cycle cannot 
be confirmed before the first dose of study intervention, additional evaluation should be 
considered.
Women in the following categories are not considered WOCBP:

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.

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 of age and not using hormonal 
contraception or HRT. 

Female on HRT and whose menopausal status is in doubt will be required to 
use one of the nonestrogen hormonal highly effective contraception methods 
if they wish to continue their HRT during the study. Otherwise, they must 
discontinue HRT to allow confirmation of postmenopausal status before study 
enrolment.


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Page 112
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. Female 
participants utilizing hormonal contraception, including those with hormonal intrauterine 
devices placed, cannot participate in the study since hormonal contraception is not permitted. 
Highly Effective Methods That Have Low User Dependency
1. Non hormonal intrauterine device
2. Bilateral tubal occlusion.
3. Vasectomized partner:

Vasectomized partner is a highly effective contraceptive method provided that the 
partner is the sole sexual partner of the woman of childbearing potential 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 Have Low User Dependency
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.




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


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






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10.8. Appendix 8: Prohibited Medications 
Use of any medication or substance that are strong inhibitors (Table 11) or inducers 
(Table 12) of CYP3A4 is not permitted. Examples of some common medications that are 
strong inhibitors or inducers CYP3A4 are provided in the tables below. These lists are not 
comprehensive.
Table 11.
Common Medications That Inhibit CYP450 3A4a
Category
Examples
Antiretrovirals
Indinavir, nelfinavir, ritonavir, saquinavir, delavirdine, amprenavir, 
fosamprenavir, atazanavir, cobicistat, lopinavir, danopravir, boceprivir
Antifungal:
Itraconazole, ketoconazole, voriconazole, posaconazole
Anti-infectives
Macrolides: telithromycin, clarithromycin
Antidepressants
Nefazodone
Antineoplastic
Idelalisib
a.
Not a comprehensive list.
Table 12.
Common Medications That Induce CYP450 3A4a
Category
Examples
Anti-infectives
Rifampin
Anti-epileptic
Phenytoin, carbamazepine
Psychoactive drugs
St. John's wort
a.
Not a comprehensive list.
For concomitant medications metabolized primarily via CYP3A, recommendations for dose 
modifications and/or precautions should be implemented according to their labeled drug 
interaction potential with CYP3A inhibitors. 
For concomitant use of drugs that are substrates of P-gp, BCRP, OATP1B1/1B3, OCT1, and 
MATE1/2K transporters, recommendations for dose modifications and/or precautions should 
be implemented according to their labeled drug interaction potential with transporters
inhibitors.


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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
Abs
absolute
ACE
angiotensin converting enzyme
ACE2
angiotensin converting enzyme 2
AE
adverse event
ALT
alanine aminotransferase
aPTT
activated partial thromboplastin time 
ARDS
Acute Respiratory Distress Syndrome
AST
aspartate aminotransferase
AUC
area under the curve
AUC24
area under the curve from time 0 to 24 hours
AUCinf
area under the plasma concentration-time profile from time 0 
extrapolated to infinite time
AUClast
area under the plasma concentration-time profile from time 0 to the time 
of the last quantifiable concentration
AUMCinf
area under the first moment curve from time 0 extrapolated to infinite 
time
AV
atrioventricular
-hCG
beta-human chorionic gonadotropin
BCRP
breast cancer resistance protein
BID
twice daily
BLQ
below limit of quantification
BMI
body mass index
BP
blood pressure
BUN
blood urea nitrogen
C24
concentration at 24 hours
C120
concentration at 120 hours
CC50
50% cytotoxic concentration
Ceff
efficacious concentration
CFR
Code of Federal Regulations
CIOMS
Council for International Organizations of Medical Sciences
CK
creatine kinase
CL
clearance
Clast
last quantifiable concentration
CLp
plasma clearance
Cmin
minimum observed concentration
Cmax
maximum observed concentration
Cmax, free
maximum free observed concentration
CO2
carbon dioxide (bicarbonate)
CONSORT
Consolidated Standards of Reporting Trials


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Abbreviation
Term
CoV
Coronavirus
COVID-19
Coronavirus Disease 2019
CPE
cytopathic effect
CLcr
creatinine clearance
COVID
Corona virus infectious disease
CRF
case report form
CRO
contract research organization
CRU
clinical research unit
CSR
Clinical Study Report
Css
concentration at steady state
CT
Clinical trial
CT Scan
computerized tomography scan
CTG
Cell Titer-Glo (luminescent cell viability assay)
CV
cardiovascular
CYP
Cytochrome P450
DDI
drug-drug interaction
DILI
drug-induced liver injury
dn
Dose normalized
DNA
deoxyribonucleic acid
DOF
duration of IV infusion 
DVT
deep vein thrombosis
EC
ethics committee
EC50
50% effective concentration
EC90
90% effective concentration
ECG
electrocardiogram
ECMO
Extracorporeal membrane oxygenation
eCRF
electronic case report form
EDP
exposure during pregnancy
EGFP
enhanced green fluorescent protein
eGFR
estimated glomerular filtration rate
EI
efflux inhibitor
EMA
European Medicines Agency
EOT
end of treatment
EU
European Union
EUA
Emergency Use Authorization
EudraCT
European Clinical Trials Database
FDA
Food and drug administration
FIP
First in Patient
fm
fraction of metabolism
FOB
functional observation battery
FSH
follicle-stimulating hormone
FU
follow-up


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Abbreviation
Term
GCP
Good Clinical Practice
GGT
gamma-glutamyl transferase
GLP
Good Laboratory Practice
h
hour(s)
HAE
human airway epithelium
HCV
hepatitis C
hERG
human Ether-a-go-go Related Gene
HIPAA
Health Insurance Portability and Accountability Act
HIV
human immunodeficiency virus
HR
heart rate
HRT
hormone replacement therapy
hsCRP
high sensitivity C-Reactive Protein
Huh7
human hepatocellular carcinoma cells-7
HV
healthy volunteer
IB
Investigator’s Brochure
ICD
informed consent document
ICH
International Council for Harmonization
ID
identification
IFN-γ
Interferon gamma
IL
interleukin
IMP
investigational medicinal product
IND
Investigational New Drug
INR
international normalized ratio
IP
investigational product 
IP-10
interferon-inducible protein 10
IPAL
Investigational Product Accountability Log
IRB
Institutional Review Board
IRC
internal review committee
IRT
Interactive Response Technology
IV
intravenous
K3EDTA
dipotassium ethylenediaminetetraacetic acid
Kel
terminal phase rate constant
LBBB
left bundle branch block
LDH
Lactate dehydrogenase
LFT
liver function test
Loge
natural logarithm
MA
mouse-adapted
MAD
multiple ascending dose
MATE
multidrug and toxic compound extrusion transporter
MCH
mean corpuscular hemoglobin
MCHC
mean corpuscular hemoglobin concentration
MCV
mean corpuscular volume


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Abbreviation
Term
MRC-5
Medical Research Council cell strain 5 – human lung fibroblast
msec
millisecond
N/A
not applicable
NIH
National Institute of Health
NIMP
Non-investigational medicinal product
NOAEL
no-observed-adverse-effect level
NYU
New York University
OCT
organic cation transporter
OATP
organic anion transporting polypeptides
PD
pharmacodynamic(s)
PE
Physical exam
P-gp
P-glycoprotein
PK
pharmacokinetic(s)
proBNP
Pro-B-Type Natriuretic Peptide
PT
prothrombin time
PVC
premature ventricular contraction/complex
QRS
Q wave to the end of the S wave corresponding ventricle depolarization
QTc
corrected QT interval
QTcF
corrected QT using Fridericia’s formula
qual
qualitative
RBC
red blood cell
Rega 
Rega Institute
RNA
ribonucleic acid
RT-PCR
Reverse transcription polymerase chain reaction
SAD
single ascending doses
SAE
serious adverse event
SAP
Statistical Analysis Plan
SARS
severe acute respiratory syndrome
SARS-CoV-1
Severe Acute Respiratory Syndrome-Coronavirus-1
SARS-CoV-2
Severe Acute Respiratory Syndrome-Coronavirus-2
SBP
Systolic blood pressure
s.c
subcutaneous
SoA
schedule of activities
SoC
standard of care
SOP
standard operating procedure
SpO2
oxygen saturation
SRI
Southern Research Institute
SRSD
single reference safety document
SToD
study team on demand
SUSAR
Suspected Unexpected Serious Adverse Reaction
t½
terminal half-life
CCI


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Abbreviation
Term
TBD
to be determined
TBili
total bilirubin
TEAE
treatment-emergent adverse event
TI
Therapeutic Index
TNF-α
Tumor Necrosis Factor-α
ULN
upper limit of normal
US
United States
Vss
Steady-state volume of distribution 
WBC
white blood cell
WOCBP
woman of childbearing potential


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11. REFERENCES
1.
WHO Situation Report 51. 11 March 2020 Available from: 
https://www.who.int/emergencies/diseases/novel-coronavirus-2019/situation-reports. 
Accessed: 29 March 2020.
2.
Wu Z, McGoogan JM. Characteristics of and important lessons from the coronavirus 
disease 2019 (COVID-19) outbreak in China: summary of a report of 72 314 cases from
the Chinese Center for Disease Control and Prevention. JAMA 2020;323(13):1239-42.
3.
Richardson S, Hirsch JS, Narasimhan M, et al. Presenting characteristics, comorbidities, 
and outcomes among 5700 patients hospitalized with COVID-19 in the New York City 
area. JAMA 2020;323(20):2052-9.
4.
Docherty AB, Harrison EM, Green CA, et al. Features of 20 133 UK patients in hospital 
with covid-19 using the ISARIC WHO Clinical Characterisation Protocol: prospective 
observational cohort study. BMJ 2020;369:m1985.
5.
Wang D, Hu B, Hu C, et al. Clinical characteristics of 138 hospitalized patients with 
2019 novel coronavirus-infected pneumonia in Wuhan, China. JAMA 
2020;323(11):1061-9.
6.
Cummings MJ, Baldwin MR, Abrams D, et al. Epidemiology, clinical course, and 
outcomes of critically ill adults with COVID-19 in New York City: a prospective cohort 
study. Lancet 2020;395(10239):1763-70.
7.
Chen T, Wu D, Chen H, et al. Clinical characteristics of 113 deceased patients with 
coronavirus disease 2019: retrospective study. BMJ 2020;368:m1091.
8.
Mao L, Jin H, Wang M, et al. Neurologic Manifestations of Hospitalized Patients With 
Coronavirus Disease 2019 in Wuhan, China. JAMA Neurol. 2020;77(6):683-90.
9.
Mehta P, McAuley DF, Brown M, et al. COVID-19: consider cytokine storm 
syndromes and immunosuppression. Lancet 2020;395(10229):1033-4.
10.
Beigel JH, Tomashek KM, Dodd LE et al. Remdesivir for the treatment of 
Covid-19 final report. N Engl J Med. 2020:1-14.
11.
US FDA. Remdesivir letter of EUA. Available from: 
https://www.fda.gov/media/137564/download. Accessed: 14 June 2020.
12.
Summary on compassionate use (Remdesivir). Available from: 
https://www.ema.europa.eu/en/documents/other/summary-compassionate-use-
Remdesivir-gilead_en.pdf. Accessed: 17 June 2020.




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25.
Shen L, Peterson S, Sedaghat AR, et al. Dose-response curve slope sets class-specific 
limits on inhibitory potential of anti-HIV drugs. Nat Med. 2008;14(7):762-6.

SAP_001.pdf: 
Protocol C4611001 (PF-07304814) Statistical Analysis Plan
PFIZER CONFIDENTIAL 
Page 1
TMF Doc ID: 98.03
Protocol C4611001
A PHASE 1B, 2-PART, DOUBLE-BLIND, PLACEBO-
CONTROLLED, SPONSOR-OPEN STUDY, TO EVALUATE 
THE SAFETY, TOLERABILITY AND PHARMACOKINETICS 
OF SINGLE ASCENDING (24-HOUR, PART 1) AND 
MULTIPLE ASCENDING (120-HOUR, PART 2) 
INTRAVENOUS INFUSIONS OF PF-07304814 IN 
HOSPITALIZED PARTICIPANTS WITH COVID-19
Statistical Analysis Plan 
(SAP)
Version:
2.0
Date:
29 Jun 2021  


Protocol C4611001 (PF-07304814) Statistical Analysis Plan
PFIZER CONFIDENTIAL 
Page 2
TMF Doc ID: 98.03
TABLE OF CONTENTS
LIST OF TABLES.....................................................................................................................3
LIST OF FIGURES ...................................................................................................................4
APPENDICES ...........................................................................................................................4
1. VERSION HISTORY............................................................................................................5
2. INTRODUCTION .................................................................................................................6
2.1. Study Objectives, Endpoints, and Estimands............................................................7
2.2. Study Design .............................................................................................................8
3. ENDPOINTS AND BASELINE VARIABLES:  DEFINITIONS AND 
CONVENTIONS ................................................................................................................10
3.1. Primary Endpoint(s) ................................................................................................10
3.1.1. Adverse Events...........................................................................................10
3.1.2. Laboratory Data..........................................................................................11
3.1.3. Vital Signs ..................................................................................................11
3.1.4. ECG ............................................................................................................12
3.1.5. Pulse Oximetry/SpO2 .................................................................................12
3.2. Secondary Endpoint(s) ............................................................................................12
3.3. Other Endpoint(s)....................................................................................................13
3.3.1. SARS-CoV-2 Viral Load............................................................................13
3.3.2. Biomarkers..................................................................................................13
3.4. Baseline Variables...................................................................................................15
3.5. Safety Endpoints .....................................................................................................15
4. ANALYSIS SETS (POPULATIONS FOR ANALYSIS)...................................................15
5. GENERAL METHODOLOGY AND CONVENTIONS....................................................16
5.1. Hypotheses and Decision Rules ..............................................................................16
5.2. General Methods .....................................................................................................16
5.2.1. Analyses for Continuous Endpoints ...........................................................16
5.2.2. Analyses for Categorical Endpoints ...........................................................16
5.3. Methods to Manage Missing Data ..........................................................................16
6. ANALYSES AND SUMMARIES ......................................................................................17
6.1. Primary Endpoint(s) ................................................................................................17
CCI


Protocol C4611001 (PF-07304814) Statistical Analysis Plan
PFIZER CONFIDENTIAL 
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TMF Doc ID: 98.03
6.1.1. Adverse Events...........................................................................................17
6.1.2. Laboratory Data..........................................................................................17
6.1.3. Vital Signs ..................................................................................................17
6.1.4. ECG ............................................................................................................17
6.1.5. Pulse Oximetry/SpO2 .................................................................................18
6.2. Secondary Endpoint(s) ............................................................................................18
6.3. Other Endpoint(s)....................................................................................................20
6.3.1. SARS-CoV-2 Viral Load............................................................................20
6.3.2. Biomarkers..................................................................................................20
6.4. Subset Analyses.......................................................................................................21
6.5. Baseline and Other Summaries and Analyses.........................................................21
6.5.1. Study Conduct and Participant Disposition................................................21
6.5.2. Demographic Data......................................................................................22
6.5.3. Significant Medical History........................................................................22
6.5.4. Study Treatment Exposure .........................................................................22
6.5.5. Concomitant Medications and Nondrug Treatments..................................22
6.6. Safety Summaries and Analyses .............................................................................22
7. INTERIM ANALYSES.......................................................................................................22
7.1. Introduction .............................................................................................................22
7.2. Interim Analyses and Summaries............................................................................22
8. REFERENCES ....................................................................................................................22
APPENDICES .........................................................................................................................23
LIST OF TABLES
Table 1.
Summary of Changes..............................................................................................5
Table 2.
Noncompartmental PK Parameters for Part 1: SAD.............................................13
Table 3.
Noncompartmental PK Parameters for Part 2: MAD ...........................................13
Table 4.
PK Parameters to be Summarized Descriptively for Part 1: SAD........................19
Table 5.
PK Parameters to be Summarized Descriptively for Part 2: MAD.......................19
CCI


Protocol C4611001 (PF-07304814) Statistical Analysis Plan
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Page 4
TMF Doc ID: 98.03
LIST OF FIGURES
Figure 1.
Part 1: SAD (24-h Continuous IV Infusion)...........................................................9
Figure 2.
Part 2: MAD (120-h Continuous IV Infusion)......................................................10
APPENDICES
Appendix 1. Categorical Classes for ECG and Vital Signs of Potential Clinical Concern......23


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TMF Doc ID: 98.03
1. VERSION HISTORY
Table 1.
Summary of Changes
Version/
Date
Associated 
Protocol 
Amendment
Rationale
Specific Changes
1.0
25 Aug 2020
Original 
04 Aug 2020
N/A
N/A
2.0
29 June 2021
PACL 1
17 Sep 2020
Protocol 
Amendment 1 
21 Sep 2020
PACL 2
08 Oct 2020
Protocol 
Amendment 2
16 Oct 2020
Protocol 
Amendment 3
05 Nov 2020
PACL 3
06 Nov 2020
Protocol 
Amendment 4
15 Dec 2020
PACL 4
11 Feb 2021
PACL 5
01 Apr 2021
Ongoing 
data 
review

General – text taken directly from 
protocol made to be consistent with 
changes in protocol amendment 4 since 
the original protocol.

Sections 3.1.3 and 3.1.4 - clarified both 
planned and unplanned measurements 
will be included in the maximum increase 
from baseline.

Section 3.1.4 – clarified baseline 
calculation. Removed wording around 
QTcF to be derived for all participants. 
Only centrally read data used.

Section 3.2 – removed PK parameters to 
be consistent with protocol amendment 4
although original PK parameters can be 
calculated for 500mg (in Cohort 1 as 
more timepoints). Added Tmax for Part 2: 
MAD. Removed reference to urine as 
only collected in Part 1: SAD Cohort 2 
which was not conducted

Section 3.3.2 – added exploratory 
biomarkers from protocol to be included 
in the CSR.

Section 5.2 – added the screening and 
early termination will be included in the 
summaries.

Section 5.3 – added cytokine data for 
BLQ values

Section 6 – placebo in Part 1: SAD will 
be reported separately by Cohort. If doses 
have been repeated, data will be pooled 
unless otherwise specified.

Section 6.1.2 – added listing of the most 
clinical significant laboratory test 
abnormalities.








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and PK with multiple ascending doses of PF-07304814 given as 120-hour IV infusions.  Two 
planned and 2 optional cohorts with 8 participants/cohort will be included in Part 2.
Figure 1.
Part 1: SAD (24-h Continuous IV Infusion)
Precautionary sentinel dosing will be used in each dose-escalating cohort in Part 1.  A small 
cohort of 2 participants (1 receiving PF-07304814 and 1 receiving placebo) will be dosed 
prior to the remainder of the cohort.  
Cohorts of 8 participants each who meet the eligibility criteria will be enrolled. The 2 
sentinel participants will be randomized in a ratio of 1 (PF-07304814): 1 (placebo), while 
the remaining 6 participants will be randomized in a ratio of 5 (PF-07304814):1 (placebo).
All participants will follow the study procedures as outlined in Schedule of Activities (SoA). 
They will be required to stay in hospital from at a minimum, Day 1, pre-dose (at least 2 
hours) through completion of Day 3 evaluations (Follow-up 1). Participants will then return 
for Day 6 (Follow-up 2) activities and a planned final follow-up visit per the SoA on Day 30-
37 (Follow-up 3) for a total of approximately 4-5 weeks study participation from first dose to 
follow-up, excluding screening. 
Participants who discontinue for reasons other than drug-related safety events during the 
trial may be replaced at the discretion of the Sponsor and investigator.
Three optional cohorts may be added to further explore the dose range based on emerging 
safety, tolerability and PK assessments. If dose progression is further explored in Part 1 of 


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the study, the predicted exposures for both PF-00835231 and PF-07304814 will not exceed 
the agreed PK stopping limit with competent regulatory authorities.
Figure 2.
Part 2: MAD (120-h Continuous IV Infusion)
Progression to Part 2 will occur if safety, tolerability, and PK data from the Part 1 24-h
infusion cohorts as well as those from study C4611007 are determined to be supportive and
acceptable by competent regulatory authorities. The dose progression will be based on
emerging PK, safety and tolerability data and will not exceed the exposure limits agreed with
competent authorities.
Cohorts of 8 participants each who meet the eligibility criteria will be enrolled and 
randomized in a ratio of 6 PF-07304814:2 placebo. All participants will follow the study 
procedures as outlined in SoA. They will be required to stay in hospital from at a minimum, 
Day 1, pre-dose through completion of Day 7 evaluations (Follow-up 1). Participants will 
then return for Day 10 (Follow-up 2) and Day 14 (Follow-up 3) activities and a final 
planned follow-up (Follow-up 4) visit per the SoA on Days 34-41 for a total of approximately 
5-6 weeks study participation from the start of dosing to follow-up, excluding screening.
Participants who discontinue for reasons other than drug-related safety events during the 
trial may be replaced at the discretion of the Sponsor and investigator.
3. ENDPOINTS AND BASELINE VARIABLES: DEFINITIONS AND 
CONVENTIONS
3.1. Primary Endpoint(s)
3.1.1. Adverse Events
An adverse event is considered a Treatment-Emergent Adverse Event (TEAE) if the event 
started during the effective duration of treatment. All events that start on or after the first 


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dosing day and time/start time, if collected, but before the end of the study will be flagged as 
TEAEs.  The algorithm will not consider any events that started prior to the first dose date.
A 3-tier approach for summarizing AEs will not be used due to the low number of 
participants planned to be recruited. 
Infusion site reactions are being assessed as part of AEs.
3.1.2. Laboratory Data
Safety laboratory tests will be performed as described in the protocol.
Baseline will be the last pre-dose measurement.
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.
3.1.3. Vital Signs
Single supine blood pressure and pulse measurements will be taken at times detailed in the 
SoA given in the protocol. 
Baseline will be defined as the last pre-dose  measurement.
The following vital signs endpoints will be determined:

Change from baseline in supine systolic and diastolic blood pressure, pulse rate,
temperature and respiratory rate.

The maximum decrease from baseline over all measurements taken post-dose for 
supine systolic and diastolic blood pressures and respiratory rate. 

The maximum increase from baseline over all measurements taken post-dose for 
supine pulse rate and temperature. 
The maximum increase from baseline will be calculated by first subtracting the baseline 
value from each post-dose measurement (both planned and unplanned) to give the change 
from baseline.  The maximum of these values over the respective period will then be 
selected, except in the case where a participant does not show an increase.  In such an 
instance, the minimum decrease should be taken. 
Similarly, the maximum decrease from baseline will be determined by selecting the 
minimum value of the changes from baseline.  In cases where a participant does not show a
decrease, the minimum increase should be taken.


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3.1.4. ECG
Only centrally read ECG data will be used.
A single 12-lead ECG will be obtained on all participants at screening.
12-lead ECGs will be recorded in triplicate on all subjects at times detailed in the SoA given 
in the protocol. The QT, heart rate, QTcF, PR and QRS will be recorded at each assessment 
time.
The average of the triplicate readings collected at each assessment time will be calculated for 
each ECG parameter.  Baseline will be defined as the average (if possible) of the triplicate
pre-dose recordings on Day 1.
The following ECG endpoints will be determined:

Change from baseline in QT interval, heart rate, QTcF interval, PR interval, and QRS 
complex.

The maximum absolute value (post-dose) will be calculated for QTcF, PR and QRS 

The maximum increase from baseline over all measurements taken post-dose will be 
calculated for QTcF.
The maximum increase from baseline will be calculated by first subtracting the baseline value 
from each post-dose measurement (both planned and unplanned) to give the change from 
baseline.  The maximum of these values over the respective period will then be selected, except 
in the case where a participant does not show an increase.  In such an instance, the minimum 
decrease should be taken.
3.1.5. Pulse Oximetry/SpO2
Pulse oximetry/SpO2 will be taken at times detailed in the SoA given in the protocol. 
The following pulse oximetry endpoints will be determined:

Change from baseline in pulse oximetry/SpO2
Baseline will be defined as the last pre-dose measurement.
3.2. Secondary Endpoint(s)
Blood samples for PK analysis of PF-07304814 and PF-00835231 will be taken according to 
the SoA given in the protocol. Urine PK was only planned to be collected in Part 1: SAD 
Cohort 2 and as this was not conducted, has been removed from the SAP.
Plasma PK parameters of PF-07304814 and PF-00835231 will be derived (if data permit) 
from the concentration-time data using standard noncompartmental methods following 24h 
infusion (see Table 2) or 120h (see Table 3) infusions.  .






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3.4. Baseline Variables
N/A.
3.5. Safety Endpoints
See Section 3.1 for details.
4. ANALYSIS SETS (POPULATIONS FOR ANALYSIS)
Data for all participants will be assessed to determine if participants meet the criteria for 
inclusion in each analysis population prior to unblinding and releasing the database and 
classifications will be documented per standard operating procedures.
Population
Description
Enrolled/Randomly 
assigned to study 
intervention 
"Enrolled" means a participant's, or his/her legally authorized 
representative’s, agreement to participate in a clinical study 
following completion of the informed consent process. Potential 
participants who are screened for the purpose of determining 
eligibility for the study, but do not participate in the study, are 
not considered enrolled, unless otherwise specified by the 
protocol.
Evaluable
All participants randomly assigned to study intervention and 
who take at least 1 dose of study intervention for the given part 
of the study (Part 1: SAD or Part 2: MAD).
Safety
All participants randomly assigned to study intervention and 
who take at least 1 dose of study intervention for the given part 
of the study (Part 1: SAD or Part 2: MAD). Participants will 
be analyzed according to the product they actually received.
PK Concentration Set
All participants randomly assigned to study intervention and 
who take at least 1 dose of study intervention and in whom at 
least 1 concentration value is reported for the given part of the 
study (Part 1: SAD or Part 2: MAD).
PK Parameter Set
All participants randomly assigned to study intervention and 
who take at least 1 dose of study intervention and in whom at 
least 1 of the PK parameters of interest are reported for the 
given part of the study (Part 1: SAD or Part 2MAD).
Biomarker Analysis Set
All participants randomly assigned to study intervention and 
who take at least 1 dose of study intervention and in whom at 
least 1 of the biomarkers of interest are reported for the given 
part of the study (Part 1: SAD or Part 2: MAD).
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5. GENERAL METHODOLOGY AND CONVENTIONS
5.1. Hypotheses and Decision Rules
There is no statistical hypothesis testing planned for this study and no statistical decision 
rules will be applied.
5.2. General Methods
Unless otherwise stated, all summaries and plots will be presented by treatment. Screening 
and Early Termination will be included in the summaries.
5.2.1. Analyses for Continuous Endpoints
Continuous variables will be presented using summary statistics: number of observations, 
arithmetic mean, standard deviation, median, minimum and maximum values.
Log transformed continuous variables will be presented using summary statistics: number of 
observations, arithmetic mean, median, cv%, standard deviation, minimum, maximum, 
geometric mean and geometric cv%.
5.2.2. Analyses for Categorical Endpoints
Categorical variables will be presented using summary statistics: number of observations and 
percentages.
5.3. Methods to Manage Missing Data
For the analysis of safety endpoints, the sponsor data standard rules for imputation will be 
applied.
In all PK data presentations (except listings), concentrations below the limit of quantification 
(BLQ) will be set to zero. 
In listings, BLQ values will be reported as “<LLQ”, where LLQ will be replaced with the 
value for the lower limit of quantification (LLQ).
For PK summary tables and plots of mean/median profiles, statistics will be calculated 
having set concentrations to missing if 1 of the following cases is true:
1. A concentration has been collected as ND (ie not done) or NS (ie no sample),
2. A deviation in sampling time is of sufficient concern or a concentration has been 
flagged anomalous by the pharmacokineticist/statistician.
For listing of viral load and cytokine data, BLQ values will be reported as “<LLQ”, where 
LLQ will be replaced with the value for the lower limit of quantification (LLQ). For 
summaries and plots BLQ values will be replaced with the value for the lower limit of 
quantification (LLQ).


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6. ANALYSES AND SUMMARIES
Separate tables will be produced for Part 1: SAD and Part 2: MAD unless otherwise 
specified. Listings will include both Part 1: SAD and Part 2: MAD unless otherwise 
specified. Placebo will be reported separately by Cohort for Part 1: SAD. If doses have been 
repeated, data will be pooled unless otherwise specified.
6.1. Primary Endpoint(s)
6.1.1. Adverse Events
Adverse events will be reported in accordance with the sponsor reporting standards.
6.1.2. Laboratory Data 
Laboratory data will be listed and summarized by treatment in accordance with the sponsor 
reporting standards.  Baseline is as defined in Section 3.1.2.
A listing of the most clinically significant laboratory test abnormalities, by participant will be 
produced. The listing will include the baseline value, most abnormal value and the final 
value.
6.1.3. Vital Signs
Absolute values and changes from baseline in supine systolic and diastolic blood pressure, 
pulse rate, temperature and respiratory rate will be summarized by treatment and time post-
dose, according to sponsor reporting standards.  Tables will be paged by parameter.  Baseline 
is as defined in Section 3.1.3.
Mean changes from baseline for supine systolic and diastolic blood pressure, pulse rate,
temperature and respiratory rate will be plotted against time post-dose.  On each plot there 
will be 1 line for each treatment.  Data from all cohorts will be plotted on the same figure 
usingseparate lines for each placebo for Part 1: SAD and a single line for the pooled placebo 
for Part 2: MAD .  Corresponding individual plots of changes from baseline will also be 
produced for each treatment.
Maximum decrease from baseline for supine systolic and diastolic blood pressures and 
respiratory rate and maximum increase from baseline for supine pulse rate and temperature 
will be summarized by treatment, according to sponsor reporting standards.
Maximum absolute values and changes from baseline for supine vital signs will also be 
summarized descriptively by treatment using categories as defined in Appendix 1.  Numbers 
and percentages of participants meeting the categorical criteria will be provided.  All planned 
and unplanned post-dose timepoints will be counted in these categorical summaries.  
6.1.4. ECG
Absolute values and changes from baseline in QT, heart rate, QTcF, PR and QRS will be 
summarized by treatment and time post-dose using sponsor reporting standards.  Tables will 
be paged by parameter.  Baseline is as defined in Section 3.1.4.


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Mean changes from baseline in QT, heart rate and QTcF will be plotted against time 
postdose.  On each plot there will be 1 line for each treatment. Data from all cohorts will be 
plotted on the same figureusing separate lines for each placebo for Part 1: SAD and a single 
line for the pooled placebo for Part 2: MAD .   Corresponding individual plots of changes 
from baseline will also be produced for each treatment.
Changes from baseline in QTcF will also be plotted separately against drug concentrations
(separate plots for PF-07304814 and PF-00835231).  This will be a scatter plot for all 
observations where QTcF and drug concentration are recorded.  Placebo data will also be 
included (with drug concentration set to zero).  Different symbols will be used for each 
treatment.
Maximum increase from baseline for QTcF will be summarized by treatment, according to 
sponsor reporting standards. 
ECG endpoints and changes from baseline (QTcF, PR and QRS) will also be summarized 
descriptively by treatment using categories as defined in Appendix 1 (for QTcF these 
correspond to the Pfizer Guidance in Section 8).  Numbers and percentages of participants
meeting the categorical criteria will be provided.  All planned and unplanned postdose 
timepoints will be counted in these categorical summaries.  
Listings of participants with any single post-dose value >500msec will also be produced for 
QTcF.
6.1.5. Pulse Oximetry/SpO2
Absolute values and changes from baseline in pulse oximetry/SpO2 will be summarized by 
treatment and time post-dose. Baseline is as defined in Section 3.1.5.
Numbers and percentages of participants meeting the categorical criteria as defined in 
Appendix 1 will be provided. All planned and unplanned post-dose timepoints will be 
counted in these categorical summaries. 
All tables above will have three columns per treatment based on whether the participant is 
receiving oxygen 
 throughout, at 
somepoint during the study or never received. Days 2 to 6 will be used i.e. Days 2, 3 & 6 for 
Part 1: SAD and Days 2, 3, 4, 5 & 6 for Part 2: MAD and any unplanned readings between 
Day 2 and Day 6 will be used (where collected).
6.2. Secondary Endpoint(s)
To assess the pharmacokinetics of PF-07304814 and PF-00835231, the PK parameters detailed 
in Section 3.2 will be listed and summarized for participants in the PK analysis set (as defined in 
Section 4). Missing values will be handled as detailed in Section 5.3. Each PK parameter will be 
summarized byanalyte and dose. Each summary will include the set of summary statistics as 
specified in Table 4 for the Part 1: SAD part and Table 5 for the Part 2: MAD part respectively.
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
a listing of all concentrations sorted by participant ID, dose and nominal time post-dose.  
The concentration listing will also include the actual times.  Deviations from the nominal 
time will be given in a separate listing.

a summary of concentrations by dose and nominal time post-dose, where the set of 
statistics will include n, mean, median, standard deviation, coefficient of variation (cv), 
minimum, maximum and the number of concentrations above the lower limit of 
quantification.

individual concentration-time plots by dose (on both linear and semi-log scales) against 
actual time post-dose (there will be separate spaghetti plots for each dose per scale).

median concentrations-time plots (on both linear and semi-log scales) against nominal 
time post-dose by dose (all doses on the same plot per scale, based on the summary of 
concentrations by dose and time post-dose).

mean concentrations-time plots (on both linear and semi-log scales) against nominal time 
post-dose by dose (all doses on the same plot per scale, based on the summary of 
concentrations by dose and time post-dose).
The scale used for the x-axis (time) of these plots will be decided on review of the data, and 
will depend on how long PF-07304814 and PF-00835231 concentration is quantifiable in the 
matrix.
For summary statistics, median and mean plots by sampling time, the nominal PK sampling 
time will be used, for individual participant plots by time, the actual PK sampling time will be 
used.
6.3. Other Endpoint(s)
6.3.1. SARS-CoV-2 Viral Load
Absolute and changes from baseline in nasopharyngeal swab and saliva viral load will be 
summarized by treatment and time post-dose. Baseline is as defined in Section 3.3.1.
Individual and mean plots will be produced for absolute and changes from baseline in
nasopharyngeal swab and saliva viral load by treatment.
The percentage of participants who have viral load detectable at baseline and undetectable
(<BLQ for both nasopharyngeal swab and saliva) at 24 hours after the end of the infusion 
(i.e. at the FU #1 visit) will be produced by treatment.
6.3.2. Biomarkers
Absolute and changes from baseline in blood hs-CRP, LDH, Ferritin, WBC, Monocytes, 
Haptoglobin, Procalcitonin, Neutrophils and Creatine Kinase will be summarized by 
treatment and time post-dose. Baseline is as defined in Section 3.3.2.
Absolute and changes from baseline in coagulation markers (D-dimer, PT, aPTT) and 
Fibrinogen will be summarized by treatment and time post-dose. Baseline is as defined in 
Section 3.3.2.




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6.5.2. Demographic Data
Demographic data (age, gender, race, ethnicity, weight, body mass index and height) will be 
summarised by treatment and overall (if applicable) in accordance with the sponsor reporting 
standards. 
6.5.3. Significant Medical History
Significant medical history will be summarized by treatment and overall.
6.5.4. Study Treatment Exposure
For Part 2: MAD, a summary table of infusion duration will be presented by treatment and 
overall
6.5.5. Concomitant Medications and Nondrug Treatments
All prior and concomitant medication(s) as well as non-drug treatment(s) will be reported 
according to current sponsor reporting standards. 
6.6. Safety Summaries and Analyses
See Section 6.1 for details.
7. INTERIM ANALYSES
7.1. Introduction
No formal interim analysis will be conducted for this study. However, as this is a sponsor-
open study, the sponsor will conduct unblinded reviews of the safety and PK data during the 
course of the study along with the IRC for the purpose of safety assessment, facilitating dose-
escalation decisions, facilitating PK/PD modeling, and/or supporting clinical development. 
Unblinded results will be reviewed by a designated limited number of sponsor colleagues 
within the study team.
An independent IRC will assess whether it is safe to proceed to continued dosing after a 
small sentinel cohort of 2 participants within each dose-escalating cohort or if it is safe to 
dose-escalate to the next dose level within Part 1.
7.2. Interim Analyses and Summaries
N/A
8. REFERENCES
Pfizer Guidance for Evaluation of QT / QTc Interval Prolongation and Proarrhythmic 
Potential for Non-antiarrhythmic Drugs; Members of the Cardiovascular Safety & Advisory 
Council (CVSAC); January 26, 2018


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APPENDICES
Appendix 1. Categorical Classes for ECG and Vital Signs of Potential Clinical Concern
Categories for QTcF
Absolute value of
QTcF (msec)
450 and 480
>480 and 500
>500
Increase from baseline
in QTcF (msec)
30 and 60
>60
Categories for PR and QRS
PR (ms)
max. ≥300
PR (ms) increase 
from baseline
Baseline >200 
and max. 
≥25% increase
Baseline ≤200 and 
max. ≥50% 
increase
QRS (ms)
max. ≥140
QRS (ms) 
increase from 
baseline
≥50% increase
Categories for Vital Signs & Pulse Oximetry
Systolic BP (mm Hg)
min. <90
Systolic BP (mm Hg) 
change from baseline
max. decrease ≥30
max. increase ≥30
Diastolic BP (mm Hg)
min. <50
Diastolic BP (mm Hg) 
change from baseline
max. decrease ≥20
max. increase ≥20
Supine pulse rate (bpm)
min. <40
max. >120
Standing pulse rate (bpm)
min. <40
max. >140
Pulse oximetry/SpO2 (%)
<94