Clinical trial NCT05654181
Conditions: Healthy
Sponsor: Pfizer
Start date: 2022-10-17; Completion date: 2023-05-03
Enrollment: 20 participants; Allocation: RANDOMIZED; Intervention model: CROSSOVER

Brief summary:
This study is the first clinical study with PF-07328948. The safety, tolerability, and plasma pharmacokinetics and pharmacodynamics of PF-07328948 after administration of escalating, single, oral doses will be evaluated.

Detailed description:

Arms: arm 1: Participants will receive up to 4 dose levels of PF-07328948 single dose and up to 2 single doses of matching placebo. Doses will be administered as oral suspensions and each dose level is to be determined. arm 2: Participants will receive up to 4 dose levels of PF-07328948 single dose and up to 2 single doses of matching placebo. Doses will be administered as oral suspensions and each dose level is to be determined. arm 3: Participants will receive up to 4 dose levels of PF-07328948 single dose and up to 2 single doses of matching placebo. Doses will be administered as oral suspensions and each dose level is to be determined.
Interventions: intervention 1: PF-07328948 intervention 2: Placebo
Intervention descriptions: intervention 1: investigational drug administered orally intervention 2: Placebo matching active drug administered orally

Protocol documents:
Prot_000.pdf: 
PF-07328948 
Protocol C4921001 
Final Protocol Amendment 2, 24 Jan 2023 
PFIZER CONFIDENTIAL 
Page 1 
 
 
 
 
A PHASE 1, RANDOMIZED, DOUBLE-BLIND, SPONSOR-OPEN, 
PLACEBO-CONTROLLED, 4-PERIOD, CROSSOVER, FIRST-IN-HUMAN STUDY 
TO EVALUATE THE SAFETY, TOLERABILITY, PHARMACOKINETICS, AND 
PHARMACODYNAMICS OF SINGLE ASCENDING ORAL DOSES OF 
PF-07328948 ADMINISTERED TO HEALTHY ADULT PARTICIPANTS 
 
Study Intervention Number: 
PF-07328948 
Study Intervention Name: 
NA 
US IND Number: 
CCI 
 
EudraCT Number: 
NA 
ClinicalTrials.gov ID: 
NA 
Pediatric Investigational Plan Number: 
NA 
Protocol Number: 
C4921001 
Phase: 
1 
Brief Title: A Phase 1 Study of Single Ascending Doses of PF-07328948 in Healthy 
Adult Participants 
 
 
 
This document and accompanying materials contain confidential information belonging to Pfizer. Except as 
otherwise agreed to in writing, by accepting or reviewing these documents, you agree to hold this 
information in confidence and not copy or disclose it to others (except where required by applicable law) or 
use it for unauthorized purposes. In the event of any actual or suspected breach of this obligation, Pfizer 
must be promptly notified. 


PF-07328948 
Protocol C4921001 
Final Protocol Amendment 2, 24 Jan 2023 
PFIZER CONFIDENTIAL 
Page 2 
 
 
Document History 
 
Document 
Version Date 
Amendment 2 
24 Jan 2023 
Amendment 1 
29 Sep 2022 
Original protocol 
02 Sep 2022 
 
This amendment incorporates all revisions to date, including amendments made at the 
request of country health authorities and IRBs/ECs and any protocol administrative change 
letter(s). 
Protocol Amendment Summary of Changes Table 
Amendment 2 (24 Jan 2023) 
Overall Rationale for the Amendment: The protocol is being amended to add pre- and 
post-dose neurological examinations to the Schedule of Activities and to extend CRU 
confinement of participants for an additional 24 hours to facilitate PK assessment at 72 hours 
post-dose. These changes are prompted by emerging safety and PK data from Cohort 1. 
 
Section # and 
Name 
Description of Change 
Brief Rationale 
Substantial or 
Nonsubstantial 
Sections 1.1 
(Synopsis), 1.3 
(Schedule of 
Activities), 2.3.1 
(Risk 
Assessment), 
2.3.2 (Benefit 
Assessment), 4.2 
(Scientific 
Rationale for 
Study Design), 
8.3.2 
(Neurological 
Examinations), 
9.3.1 (Safety 
Endpoints) 
Updated to include 
neurological 
examinations pre- and 
post-dose, with relevant 
rationale. 
A SAE of “possible 
seizure” occurred during 
follow-up in 1 
participant in Cohort 1. 
Although not considered 
related to blinded study 
intervention by Pfizer 
safety assessment or 
Risk Management 
Committee, out of an 
abundance of caution, 
participants in this study 
will be monitored 
closely with serial 
physical exams directed 
at identifying any 
neurological signs or 
symptoms. 
Substantial 


PF-07328948 
Protocol C4921001 
Final Protocol Amendment 2, 24 Jan 2023 
PFIZER CONFIDENTIAL 
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Section # and 
Name 
Description of Change 
Brief Rationale 
Substantial or 
Nonsubstantial 
Section 4.1 
(Overall 
Design), 
Section 4.2 
(Scientific 
Rationale for 
Study Design), 
Section 4.3.1 
(Human PK 
Predictions) 
The participants in each 
treatment period will be 
confined in CRU for an 
additional day and 
discharged on Day 4 of 
Cohort 2 and optional 
Cohort 3 (changed from 
discharge on Day 3 in 
Cohort 1) to collect PK 
samples at 72 hours post- 
dose. The preliminary PK 
data emerging from 
Cohort 1 suggested the 
terminal half-life could 
be longer than this 
predicted 4 hours. 
The emerging PK data 
from Cohort 1 suggested 
the terminal t1/2 for PF- 
07328948 is longer than 
the previously predicted 
4 hours based on 
preclinical data. 
Participants will stay in 
CRU for an additional 
day for PK assessment at 
72 hours post-dose. 
Substantial 
Section 1.3 
(Schedule of 
Activities), 
Section 5.3.2 
(Meals and 
Dietary 
Restrictions) 
CRU discharge, 
contraception check, 
physical exam, 
urinalysis, and safety 
laboratory tests removed 
from Day 3, and replaced 
as pre-discharge 
activities on Day 4; 
added “Day 4 (if 
applicable)” for meals 
and dietary resctrictions 
As a result for one 
additional day 
confinement in CRU and 
discharge changed to 
Day 4, some 
assessments scheduled 
on Day 3 are moved to 
prior to discharge on 
Day 4. 
Nonsubstantial 
Section 1.3 
(Schedule of 
Activities) 
PK sample collection at 
16 hours post-dose was 
removed. 
PK sample at 16 hours 
was replaced by PK 
sample at 72 hours post- 
dose so the total blood 
volume withdrawn in 
each participant remains 
same 
Nonsubstantial 


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Protocol C4921001 
Final Protocol Amendment 2, 24 Jan 2023 
PFIZER CONFIDENTIAL 
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TABLE OF CONTENTS 
LIST OF TABLES ..................................................................................................................... 9 
LIST OF FIGURES .................................................................................................................... 9 
1. PROTOCOL SUMMARY ................................................................................................... 10 
1.1. Synopsis ................................................................................................................... 10 
1.2. Schema..................................................................................................................... 16 
1.3. Schedule of Activities .............................................................................................. 17 
2. INTRODUCTION ................................................................................................................ 24 
2.1. Study Rationale ........................................................................................................ 24 
2.2. Background .............................................................................................................. 24 
2.2.1. Nonclinical Pharmacology .......................................................................... 24 
2.2.2. Nonclinical Pharmacokinetics and Metabolism .......................................... 25 
CCI 
 
2.2.4. Nonclinical Safety ....................................................................................... 26 
2.3. Benefit/Risk Assessment ......................................................................................... 27 
2.3.1. Risk Assessment ......................................................................................... 28 
2.3.2. Benefit Assessment ..................................................................................... 30 
2.3.3. Overall Benefit/Risk Conclusion ................................................................ 30 
3. OBJECTIVES AND ENDPOINTS ..................................................................................... 30 
4. STUDY DESIGN ................................................................................................................. 31 
4.1. Overall Design ......................................................................................................... 31 
4.2. Scientific Rationale for Study Design ..................................................................... 32 
4.2.1. Choice of Contraception/Barrier Requirements .......................................... 34 
4.2.2. Collection of Retained Research Samples ................................................... 34 
4.3. Justification for Dose ............................................................................................... 34 
CCI 
 
4.3.2. Predicted Efficacious Concentration and Human Dose .............................. 35 
4.3.3. Human Exposure Stopping Limits .............................................................. 35 
4.3.4. Rationale for Dose Selection ....................................................................... 36 
4.4. End of Study Definition ........................................................................................... 37 
5. STUDY POPULATION ...................................................................................................... 37 


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PFIZER CONFIDENTIAL 
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5.1. Inclusion Criteria .................................................................................................... 38 
5.2. Exclusion Criteria ................................................................................................... 38 
5.3. Lifestyle Considerations ......................................................................................... 41 
5.3.1. Contraception ............................................................................................. 41 
5.3.2. Meals and Dietary Restrictions .................................................................. 41 
5.3.3. Caffeine, Alcohol, and Tobacco ................................................................. 43 
5.3.4. Activity ...................................................................................................... 43 
5.4. Screen Failures ........................................................................................................ 44 
6. STUDY INTERVENTION(S) AND CONCOMITANT THERAPY ................................. 44 
6.1. Study Intervention(s) Administered ........................................................................ 44 
6.1.1. Administration ............................................................................................ 45 
6.2. Preparation, Handling, Storage, and Accountability .............................................. 45 
6.2.1. Preparation and Dispensing ........................................................................ 46 
6.3. Assignment to Study Intervention .......................................................................... 47 
6.4. Blinding .................................................................................................................. 47 
6.4.1. Blinding of Participants .............................................................................. 47 
6.4.2. Blinding of Site Personnel .......................................................................... 47 
6.4.3. Blinding of the Sponsor ............................................................................. 48 
6.4.4. Breaking the Blind ..................................................................................... 48 
6.5. Study Intervention Compliance .............................................................................. 48 
6.6. Dose Modification .................................................................................................. 48 
6.6.1. Dose Escalation and Stopping Rules .......................................................... 49 
6.7. Continued Access to Study Intervention After the End of the Study ..................... 50 
6.8. Treatment of Overdose ........................................................................................... 50 
6.9. Prior and Concomitant Therapy .............................................................................. 51 
6.9.1. Rescue Medicine ........................................................................................ 51 
7. DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL ........................................................................... 51 
7.1. Discontinuation of Study Intervention .................................................................... 51 
7.1.1. ECG Changes ............................................................................................. 52 
7.1.2. Potential Cases of Acute Kidney Injury ..................................................... 52 
7.1.3. COVID-19 .................................................................................................. 53 


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7.2. Participant Discontinuation/Withdrawal From the Study ....................................... 54 
7.2.1. Withdrawal of Consent ............................................................................... 54 
7.3. Lost to Follow-up .................................................................................................... 55 
8. STUDY ASSESSMENTS AND PROCEDURES ............................................................... 55 
8.1. Administrative Procedures ....................................................................................... 55 
8.2. Efficacy Assessments .............................................................................................. 56 
8.3. Safety Assessments .................................................................................................. 56 
8.3.1. Physical Examinations ................................................................................ 57 
8.3.2. Neurological Examinations ......................................................................... 57 
8.3.3. Vital Signs ................................................................................................... 57 
8.3.3.1. Blood Pressure and Pulse Rate .................................................. 57 
8.3.3.2. Respiratory Rate ........................................................................ 58 
8.3.4. Electrocardiograms ...................................................................................... 58 
8.3.4.1. Continuous Cardiac Monitoring by Telemetry .......................... 59 
8.3.5. Clinical Safety Laboratory Assessments ..................................................... 59 
8.4. Adverse Events, Serious Adverse Events, and Other Safety Reporting .................. 60 
8.4.1. Time Period and Frequency for Collecting AE and SAE Information ....... 61 
8.4.1.1. Reporting SAEs to Pfizer Safety ............................................... 61 
8.4.1.2. Recording Nonserious AEs and SAEs on the CRF ................... 61 
8.4.2. Method of Detecting AEs and SAEs ........................................................... 62 
8.4.3. Follow-Up of AEs and SAEs ...................................................................... 62 
8.4.4. Regulatory Reporting Requirements for SAEs ........................................... 62 
8.4.5. Environmental Exposure, Exposure During Pregnancy or 
Breastfeeding, and Occupational Exposure ..................................................... 63 
8.4.5.1. Exposure During Pregnancy ...................................................... 63 
8.4.5.2. Exposure During Breastfeeding ................................................. 65 
8.4.5.3. Occupational Exposure .............................................................. 65 
8.4.6. Cardiovascular and Death Events ................................................................ 65 
8.4.7. Disease-Related Events and/or Disease-Related Outcomes Not 
Qualifying as AEs or SAEs .............................................................................. 65 
8.4.8. Adverse Events of Special Interest ............................................................. 65 
8.4.8.1. Lack of Efficacy ........................................................................ 66 


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PFIZER CONFIDENTIAL 
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8.4.9. Medical Device Deficiencies ...................................................................... 66 
8.4.10. Medication Errors ...................................................................................... 66 
8.5. Pharmacokinetics ..................................................................................................... 67 
8.5.1. Plasma for Analysis of PF-07328948 Concentrations ................................. 67 
8.6. Genetics ................................................................................................................... 68 
8.6.1. Specified Genetics ....................................................................................... 68 
8.6.2. Retained Research Samples for Genetics .................................................... 68 
8.7. Pharmacodynamics .................................................................................................. 68 
8.7.1. Biomarkers .................................................................................................. 68 
8.7.1.1. Specified Gene Expression (RNA) Research ............................ 68 
8.7.1.2. Specified Protein Research ........................................................ 69 
8.7.1.3. Specified Metabolomic Research ............................................... 69 
8.7.1.4. Retained Research Samples for Biomarker ................................ 69 
8.7.2. Pharmacodynamics Assessments ................................................................ 69 
CCI 
 
8.8. Immunogenicity Assessments ................................................................................. 70 
8.9. Health Economics .................................................................................................... 71 
9. STATISTICAL CONSIDERATIONS ................................................................................. 71 
9.1. Statistical Hypothesis .............................................................................................. 71 
9.2. Analysis Sets ............................................................................................................ 71 
9.3. Statistical Analyses .................................................................................................. 72 
9.3.1. Safety Endpoints ......................................................................................... 72 
9.3.1.1. Electrocardiogram Analyses ...................................................... 72 
9.3.2. PK Endpoints .............................................................................................. 73 
9.3.2.1. Derivation of PF-07328948 PK Parameters .............................. 73 
9.3.2.2. Statistical Methods for PK Data ................................................ 74 
9.3.3. Tertiary/Exploratory Endpoint(s) Analysis ................................................. 74 
9.3.4. Other Analyses ............................................................................................ 74 
9.4. Interim Analyses ...................................................................................................... 74 
9.5. Sample Size Determination ..................................................................................... 74 


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PFIZER CONFIDENTIAL 
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10. SUPPORTING  DOCUMENTATION  AND  OPERATIONAL 
CONSIDERATIONS .......................................................................................................... 75 
10.1. Appendix 1: Regulatory, Ethical, and Study Oversight Considerations ............... 75 
10.1.1. Regulatory and Ethical Considerations .................................................... 75 
10.1.1.1. Reporting of Safety Issues and Serious Breaches of the 
Protocol or ICH GCP ........................................................................ 75 
10.1.2. Financial Disclosure ................................................................................. 76 
10.1.3. informed Consent Process ........................................................................ 76 
10.1.4. Data Protection ......................................................................................... 77 
10.1.5. Committees Structure ............................................................................... 77 
10.1.5.1. Data Monitoring Committee ................................................... 77 
10.1.6. Dissemination of Clinical Study Data ...................................................... 77 
10.1.7. Data Quality Assurance ............................................................................ 79 
10.1.8. Source Documents ................................................................................... 80 
10.1.9. Study and Site Start and Closure .............................................................. 80 
10.1.10. Publication Policy .................................................................................. 81 
10.1.11. Sponsor’s Medically Qualified Individual ............................................. 82 
10.2. Appendix 2: Clinical Laboratory Tests ................................................................ 83 
10.3. Appendix 3: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-Up, and Reporting ..................................................................... 85 
10.3.1. Definition of AE ....................................................................................... 85 
10.3.2. Definition of an SAE ................................................................................ 86 
10.3.3. Recording/Reporting and Follow-Up of AEs and/or SAEs During 
the Active Collection Period ........................................................................... 87 
10.3.4. Reporting of SAEs ................................................................................... 91 
10.4. Appendix 4: Contraceptive and Barrier Guidance ................................................ 92 
10.4.1. Male Participant Reproductive Inclusion Criteria ................................... 92 
10.4.2. Female Participant Reproductive Inclusion Criteria ................................ 92 
10.4.3. Woman of Childbearing Potential ............................................................ 92 
10.4.4. Contraception Methods ............................................................................ 93 
10.5. Appendix 5: Genetics ........................................................................................... 95 
10.6. Appendix 6: Liver Safety: Suggested Actions and Follow-Up Assessments ....... 96 
10.7. Appendix 7: Kidney Safety: Monitoring Guidelines ............................................ 98 


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PFIZER CONFIDENTIAL 
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10.7.1. Laboratory Assessment of Change in Kidney Function and 
Detection of Kidney Injury ............................................................................. 98 
10.7.2. Age-Specific Kidney Function Calculation Recommendations ............... 98 
10.7.2.1. Adults (18 Years and Above)—2021 CKD-EPI 
Equations .......................................................................................... 98 
10.7.3. Adverse Event Grading for Kidney Safety Laboratory 
Abnormalities .................................................................................................. 98 
10.8. Appendix 8: ECG Findings of Potential Clinical Concern ................................... 99 
10.9. Appendix 9: Protocol Amendment History ........................................................ 101 
10.10. Appendix 10: Abbreviations ............................................................................. 102 
11. REFERENCES ................................................................................................................ 107 
 
LIST OF TABLES 
Table 1. 
Study Schedule of Assessment ................................................................. 17 
Table 2. 
Schedule of Activities for PK, PD, Vitals, and ECGs on Day 1 (and 
Day -1 if Applicable) ............................................................................... 22 
Table 3. 
Predicted Human Exposures, Pharmacodynamic Effects, and Safety 
Margin at Proposed Single Doses of PF-07328948 ................................. 36 
Table 4. 
Plasma PF-07328948 PK Parameters ....................................................... 73 
Table 5. 
Protocol-Required Safety Laboratory Assessments ................................. 83 
 
 
LIST OF FIGURES 
Figure 1. 
Study Design Schemaa,b,c,d ............................................................................................................. 16 


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PFIZER CONFIDENTIAL 
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1. PROTOCOL SUMMARY 
1.1. Synopsis 
Protocol Title: A Phase 1, Randomized, Double-Blind, Sponsor-Open, Placebo-Controlled, 
4-Period, Crossover, First-in-Human Study to Evaluate the Safety, Tolerability, 
Pharmacokinetics, and Pharmacodynamics of Single Ascending Oral Doses of PF-07328948 
Administered to Healthy Adult Participants 
Brief Title: A Phase 1 Study of Single Ascending Doses of PF-07328948 in Healthy Adult 
Participants 
Regulatory Agency Identification Number(s): 
 
US IND Number: 
CCI  
EudraCT Number: 
NA 
ClinicalTrials.gov ID: 
NA 
Pediatric Investigational Plan Number: 
NA 
Protocol Number: 
C4921001 
Phase: 
1 
Rationale: This study is the first clinical study with PF-07328948. The safety, tolerability, 
and plasma PK and PD of PF-07328948 after administration of escalating, single, oral doses 
will be evaluated. 


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Protocol C4921001 
Final Protocol Amendment 2, 24 Jan 2023 
PFIZER CONFIDENTIAL 
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Objectives and Endpoints: 
 
 
Primary: 
Objectives 
 
Primary: 
Endpoints 
• To evaluate the safety and tolerability of single 
ascending doses of PF-07328948 administered orally to 
healthy adult participants. 
 
Secondary: 
• To evaluate the pharmacokinetics of PF-07328948 
following single doses of PF-07328948 administered 
orally to healthy adult participants. 
Tertiary/Exploratory: 
• To evaluate additional pharmacokinetic parameters of 
PF-07328948 following single doses of PF-07328948 
administered orally to healthy adult participants. 
• 
Assessment of adverse events, clinical safety 
laboratory tests, vital signs, continuous cardiac 
monitoring, 12-lead electrocardiograms, and physical 
examinations. 
Secondary: 
• 
PK parameters derived from plasma PF-07328948 
concentrations: Cmax, Tmax, AUClast, and if data permit, 
AUCinf, and t½. 
Tertiary/Exploratory: 
• 
Additional PK parameters derived from plasma 
PF-07328948 concentrations: Cmax(dn), AUClast(dn) 
and if data permit AUCinf(dn), CL/F and Vz/F. 
• CCI 
 
 
 
 
 
 
 
 
 
 
 
• To evaluate the effect of food (eg, a protein-rich meal 
such as MMTT), if administered, on the plasma PK of 
PF-07328948 following single dose of PF-07328948 
administered orally to healthy adult participants. 
. 
• 
PK parameters derived from plasma PF-07328948 
concentrations after MMTT: Cmax, Tmax, AUClast, and 
if data permit, AUCinf, and t½. 
 
 
Overall Design: 
This is a randomized, investigator- and participant-blind, sponsor-open, placebo-controlled, 
first-in-human study to assess safety, tolerability, PK and PD of single ascending oral doses 
of PF-07328948 administered to healthy adult participants in 2 planned cohorts (Cohort 1 
and Cohort 2). Each cohort will be a 4-period, sequential, crossover, placebo-controlled 
design, with a washout interval of at least 7 days between doses. Precautionary sentinel 
dosing will be used in any period evaluating escalating doses of PF-07328948. Sentinel 
dosing may be omitted for periods when repeating a dose level or administering a lower dose 
level than previously evaluated. Safety and tolerability data through at least 24 hours post- 
dose for the sentinel participants will be reviewed prior to dosing the remaining participants 


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Protocol C4921001 
Final Protocol Amendment 2, 24 Jan 2023 
PFIZER CONFIDENTIAL 
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CCI 
of that period. Participants will be screened for the eligibility criteria as listed in Section 5, 
within 28 days prior to administration of the first dose for each cohort. 
Based on the review of emerging safety, tolerability, and PK, 1 optional cohort of 
8 participants may be enrolled (crossover, placebo-controlled design) to explore additional 
doses, to repeat a dose, to evaluate split dosing, or to investigate food effects on PK and PD 
biomarkers. 
 
Number of Participants: A total of up to approximately 16 (Cohorts 1 and 2) or 24 (with 
optional Cohort 3) healthy adult participants (approximately 8 participants per cohort) will be 
enrolled in the study. 
Note: "Enrolled" means a participant's agreement to participate in a clinical study following 
completion of the informed consent process and randomization to study intervention. A 
participant will be considered enrolled if the informed consent is not withdrawn prior to 
participating in any study activity after screening. Potential participants who are screened for 
the purpose of determining eligibility for the study, but do not participate in the study, are not 
considered enrolled, unless otherwise specified by the protocol. 
Study Population: Key inclusion and exclusion criteria are listed below: 
Inclusion Criteria 
Participants must meet the following key inclusion criteria to be eligible for enrollment into 
the study: 
1. Female participants of non-childbearing potential and males must be 18 to 60 years of 
age, inclusive, at the time of signing the ICD. 
2. Female participants of non-childbearing potential and males who are overtly healthy 
as determined by medical evaluation including medical history, physical examination, 
laboratory tests, and cardiac monitoring. 
3. Participants who are willing and able to comply with all scheduled visits, treatment 
plan, laboratory tests, lifestyle considerations, and other study procedures. 
Exclusion Criteria 
Participants with any of the following characteristics/conditions will be excluded: 
1. Evidence or history of clinically significant hematological, renal, endocrine, 
pulmonary, gastrointestinal, cardiovascular, hepatic, psychiatric, neurological, or 


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PFIZER CONFIDENTIAL 
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allergic disease (including drug allergies, but excluding untreated, asymptomatic, 
seasonal allergies at the time of dosing). 
• 
Any condition possibly affecting drug absorption (eg, gastrectomy, 
cholecystectomy). 
• 
History of HIV infection, hepatitis B, or hepatitis C; positive testing for HIV, 
HBsAg, HBcAb, or HCVAb. Hepatitis B vaccination is allowed. 
2. Other medical or psychiatric condition including recent (within the past year) or 
active suicidal ideation/behavior or laboratory abnormality or other conditions or 
situations related to COVID-19 pandemic that may increase the risk of study 
participation or, in the investigator’s judgment, make the participant inappropriate for 
the study. 
3. Use of prescription or nonprescription drugs and dietary and herbal supplements 
within 7 days or 5 half-lives (whichever is longer) prior to the first dose of study 
intervention. 
4. Receipt of a COVID-19 vaccine within 7 days before screening or within 7 days 
before any visit in which a safety lab is planned. Vaccination with a COVID-19 
vaccine that occurs greater than 7 days from either screening or any visit in which a 
safety lab is planned is permitted. 
5. Previous administration with an investigational product (drug or vaccine) within 
30 days (or as determined by the local requirement) or 5 half-lives preceding the first 
dose of study intervention used in this study (whichever is longer). 
6. Screening supine BP ≥140 mm Hg (systolic) or ≥90 mm Hg (diastolic), following at 
least 5 minutes of supine rest. 
7. Renal impairment as defined by an eGFR <75 mL/min/1.73m2 calculated using 
CKD-EPI SCr formulas. 
8. Standard 12-lead ECG that demonstrates clinically relevant abnormalities that may 
affect participant safety or interpretation of study results (eg, QTcF >450 ms, 
complete LBBB, signs of an acute or indeterminate age myocardial infarction, STT 
interval changes suggestive of myocardial ischemia, second- or third-degree AV 
block, or serious bradyarrhythmias or tachyarrhythmias). If the uncorrected QT 
interval is >450 ms, this interval should be rate corrected using the Fridericia method 
only and the resulting QTcF should be used for decision-making and reporting. 


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9. Participants with ANY of the following abnormalities in clinical laboratory tests at 
screening, as assessed by the study specific laboratory and confirmed by a single 
repeat test, if deemed necessary: 
• AST or ALT level ≥1.25× ULN; 
• Total bilirubin level ≥1.5 × ULN; participants with a history of Gilbert’s 
syndrome may have direct bilirubin measured and would be eligible for this study 
provided the direct bilirubin level is ≤ULN. 
10. History of alcohol abuse or binge drinking and/or any other illicit drug use or 
dependence within 6 months of Screening. Binge drinking is defined as a pattern of 
5 (male) and 4 (female) or more alcoholic drinks in about 2 hours. As a general rule, 
alcohol intake should not exceed 14 units per week (1 unit = 8 ounces (240 mL) beer, 
1 ounce (30 mL) of 40% spirit, or 3 ounces (90 mL) of wine). 
11. Investigator site staff directly involved in the conduct of the study and their family 
members, site staff otherwise supervised by the investigator, and sponsor and sponsor 
delegate employees directly involved in the conduct of the study and their family 
members. 
Study Arms and Duration: 
PF-07328948 and placebo will be provided by Pfizer as bulk powders for extemporaneous 
preparation of oral suspensions at the CRU. 
 
Study Intervention(s) 
Intervention Name 
PF-07328948 
Placebo 
Arm Name 
(group of participants receiving a specific treatment or 
no treatment) 
PF-07328948 
Placebo 
Unit Dose Strength(s) 
10-3000 mg 
0 mg 
Route of Administration 
Oral 
Oral 
Use 
Experimental 
Placebo 
IMP or NIMP/AxMP 
IMP 
IMP 


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Study Arm(s) 
Arm Title 
Cohort 1 
Cohort 2 
Cohort 3 (Optional) 
Arm Type 
Experimental 
Experimental 
Experimental 
Arm Description 
Participants will receive up to 
4 dose levels of PF-07328948 
and up to 2 doses of matching 
placebo. Doses will be 
administered as oral 
suspensions as escalating single 
doses to be determined. 
Participants will receive up to 
4 dose levels of PF-07328948 
and up to 2 doses of matching 
placebo. Doses will be 
administered as oral 
suspensions as escalating 
single doses to be determined. 
Participants will receive up to 
4 dose levels of PF-07328948 
and up to 2 doses of matching 
placebo. Doses will be 
administered as oral 
suspensions as escalating 
single doses to be determined. 
 
Statistical Methods: 
The sample size has been chosen based on the need to minimize first exposure to humans of 
a new chemical entity and the requirement to conduct adequate safety, toleration, PK and PD 
assessments at each dose level. All safety analyses will be performed on the safety analysis 
set, which is defined as all participants randomly assigned to study intervention and who take 
at least 1 dose of study intervention. Participants will be analyzed according to the study 
intervention they actually received. Safety data will be presented in tabular and/or graphical 
format and summarized descriptively, where appropriate. The plasma PK parameters for 
PF‑07328948 following oral dose administration will be derived from the plasma 
concentration‑time profiles. Plasma PK parameters and concentrations of PF-07328948 will 
be descriptively summarized by dose (and fasting condition, if appropriate) and nominal 
time, as appropriate. 
Ethical Considerations: 
The participants in this study are not expected to obtain any specific benefit beyond 
contributing to the process of developing new therapies in an area of unmet need. They will 
receive close monitoring of their safety via study procedures undertaken (eg, physical 
examinations, neurological examinations, 12-lead ECGs, vital signs) which will occur as 
outlined in this protocol. Based on the totality of available nonclinical data, and taking into 
account the measures to minimize risk to study participants, the overall benefit/risk profile 
supports clinical testing of PF-07328948 in this study as part of the clinical development for 
an indication of heart failure. 


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1.2. Schema 
Figure 1. 
Study Design Schemaa,b,c,d 
 
a. Doses shown for each cohort except the starting dose in Cohort 1 are planned doses and may be modified based on 
emerging data from previous cohorts. Similarly, assignment to study intervention may be modified. n represents number of 
participants 
b. Effect of food (eg, a protein-rich meal such as MMTT) may be evaluated in at least 1 period of Cohort 2 (eg, P3) and/or 
Cohort 3 
c. In the first period in each cohort (with red box) and the first period of assessment of food effect in any cohort (eg, P3 in 
Cohort 2 with red box), participants will be admitted on Day -2 and time-matched biomarker assessment will be collected on 
Day -1. 
d. Precautionary sentinel dosing will be used in any period evaluating escalating doses of PF-07328948. For such periods, 2 
participants (1 receiving PF-07328948 and 1 receiving placebo) will be dosed initially before the remaining participants of 
that period are dosed. Safety and tolerability data through at least 24 hours post-dose for the sentinel participants will be 
reviewed prior to dosing the remaining participants of that period. Sentinel dosing may be omitted when repeating a dose 
level or administering a lower dose level than previously evaluated. 


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1.3. Schedule of Activities 
The SoA table provides an overview of the protocol visits and procedures. Refer to the STUDY ASSESSMENTS AND 
PROCEDURES section of the protocol for detailed information on each procedure and assessment required for compliance with the 
protocol. 
The investigator may schedule visits (unplanned visits) in addition to those listed in the SoA table, in order to conduct evaluations or 
assessments required to protect the well-being of the participant. 
 
Table 1. 
Study Schedule of Assessment 
 
Visit Identifier 
Abbreviations used in this 
table may be found in 
Appendix 10. 
Screen 
Period 1 to Period 4 
In-patient 
Follow-Up 
ET 
Notes 
Days Relative to Day 1 
Day -28 to 
Day -3 
Day 
-2 
Day 
-1 
Day 
1 
Day 
2 
Day 
3 
Day 
4 
Visit: 
Day 
8±1 
Contact: 
28-35 
days 
All screening should be done ≤28 days before the first dose. 
Day relative to start of study intervention (Day 1). 
Day 1 activities at time=0 hour are prior to the dose, except 
for study intervention administration. 
On-site follow-up visit occurs on Day 8±1 after 
administration of the final dose of study intervention. 
Follow-up may occur via telephone contact and must occur 
28 to 35 days after administration of the final dose of study 
intervention. 
Hours After Dose 
0 
24 
36 
48 
72 
Informed consent 
X 
Informed consent should be obtained prior to undergoing 
any study-specific procedures. 
See Section 10.1.3 for additional information. 
CRU confinement 
X 
X 
→ 
→ 
→ 
→ 
X 
Admission on Day -2 only in Period 1 for each cohort and in 
the 1st period with assessment of food effect in any cohort, 
if applicable 
Inclusion/exclusion criteria 
X 
X 
Period 1 only. Review any changes from Screening. 
Medical/medication history 
X 
X 
History of alcohol, tobacco, 
and illegal drug use 
X 
X 
Review concomitant 
treatments 
X 
→ 
→ 
→ 
→ 
→ 
→ 
→ 
→ 
X 
X 
See Section 6.9 for additional information. 
Demography 
X 


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Table 1. 
Study Schedule of Assessment 
 
Visit Identifier 
Abbreviations used in this 
table may be found in 
Appendix 10. 
Screen 
Period 1 to Period 4 
In-patient 
Follow-Up 
ET 
Notes 
Days Relative to Day 1 
Day -28 to 
Day -3 
Day 
-2 
Day 
-1 
Day 
1 
Day 
2 
Day 
3 
Day 
4 
Visit: 
Day 
8±1 
Contact: 
28-35 
days 
All screening should be done ≤28 days before the first dose. 
Day relative to start of study intervention (Day 1). 
Day 1 activities at time=0 hour are prior to the dose, except 
for study intervention administration. 
On-site follow-up visit occurs on Day 8±1 after 
administration of the final dose of study intervention. 
Follow-up may occur via telephone contact and must occur 
28 to 35 days after administration of the final dose of study 
intervention. 
Hours After Dose 
0 
24 
36 
48 
72 
Contraception check 
X 
X 
X 
X 
X 
X 
X 
Contraception only required for male study participants. 
Contraceptive guidance is outlined in Appendix 4. 
If performed on Day -2 at admission, assessment is not 
needed on Day -1 
COVID-19 related measures 
X 
X 
X 
X 
X 
X 
X 
X 
Per CRU procedures. 
CRU discharge 
X 
Participants may be asked to remain at the CRU after 
completion of Day 4 activities at the discretion of the 
investigator or if safety, tolerability, or PK data dictate the 
need to prolong inpatient stay at the CRU 
Serious and nonserious AE 
monitoring 
X 
→ 
→ 
→ 
→ 
→ 
→ 
→ 
→ 
X 
X 
See Section 8.4.3 for follow-up AE and SAE assessments. 
Physical exam 
X 
X 
See Table 2 
X 
X 
X 
X 
Complete PE at Screening or upon admission for a 
participant’s first period in the study; at all other time points, 
brief PE performed for findings during previous exam or 
new/open AEs, at investigator discretion. 
Including height and weight only at screening 
See Section 8.3.1 for additional information. 
Neurological examination 
X 
X 
X 
Complete neurological exam for timepoints on Day 1 (see 
Table 2) and 24 hours after dosing on Day 1. At other time 
points, neurological exam at investigator discretion. 
See Section 8.3.2 for additional information. 
Respiratory rate 
X 
X 
X 
X 
X 
Single assessment at all timepoints 
See Section 8.3.3 for additional details. 


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Table 1. 
Study Schedule of Assessment 
Visit Identifier 
Abbreviations used in this 
table may be found in 
Appendix 10. 
Screen 
Period 1 to Period 4 
In-patient 
Follow-Up 
ET 
Notes 
Days Relative to Day 1 
Day -28 to 
Day -3 
Day 
-2 
Day 
-1 
Day 
1 
Day 
2 
Day 
3 
Day 
4 
Visit: 
Day 
8±1 
Contact: 
28-35 
days 
All screening should be done ≤28 days before the first dose. 
Day relative to start of study intervention (Day 1). 
Day 1 activities at time=0 hour are prior to the dose, except 
Hours After Dose 
 
 
 
 
 
Supine blood pressure and 
X 
pulse rate 
 
 
 
12-Lead ECG 
X 
 
 
Continuous cardiac telemetry 
Study intervention 
administration 
Standardized meal/snack 
Blood samples for: 
PF-07328948 plasma 
pharmacokinetics 
CCI 
CCI 
0 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
See Table 2 
24  36 
48 
72 
 
 
 
 
 
X 
X 
X 
X 
 
 
 
 
X 
X 
X 
X 
 
 
 
 
 
X 
X 
 
X 
X 
X 
X 
 
C 
C 
for study intervention administration. 
On-site follow-up visit occurs on Day 8±1 after 
administration of the final dose of study intervention. 
Follow-up may occur via telephone contact and must occur 
28 to 35 days after administration of the final dose of study 
intervention. 
X 
Single assessment at Screening, Day 1 at 0 hour, follow-up 
visit and ET. Triplicate assessments at all other times. 
Triplicate measures are collected approximately 2-4 minutes 
apart. 
See Section 8.3.3 for additional details. 
X 
Single 12-lead ECG at Screening, follow-up visit and ET. 
Triplicate 12-lead ECGs at all other times. See Section 8.3.4 
for additional details. 
 
Dosing under fasted or fed conditions (eg, MMTT) is to 
occur as outlined in Section 5.3.2. 
See Section 5.3.2 for detailed instruction. 
 
X 
See Section 8.5.1 for additional details. 
 
 
Samples on Day 2 and Day 3 (24 and 48-hours post-dose) 
and at follow-up visit (Day 8±1) after the final dose will be 
collected after fast overnight for at least 8 hours. 
See Section 8.7.2 for additional information. 
See Table 2 
See Table 2 


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Table 1. 
Study Schedule of Assessment 
 
Visit Identifier 
Abbreviations used in this 
table may be found in 
Appendix 10. 
Screen 
Period 1 to Period 4 
In-patient 
Follow-Up 
ET 
Notes 
Days Relative to Day 1 
Day -28 to 
Day -3 
Day 
-2 
Day 
-1 
Day 
1 
Day 
2 
Day 
3 
Day 
4 
Visit: 
Day 
8±1 
Contact: 
28-35 
days 
All screening should be done ≤28 days before the first dose. 
Day relative to start of study intervention (Day 1). 
Day 1 activities at time=0 hour are prior to the dose, except 
for study intervention administration. 
On-site follow-up visit occurs on Day 8±1 after 
administration of the final dose of study intervention. 
Follow-up may occur via telephone contact and must occur 
28 to 35 days after administration of the final dose of study 
intervention. 
Hours After Dose 
0 
24 36 
48 
72 
Safety laboratory tests 
X 
X 
X 
X 
X 
X 
X 
Participant should fast for at least 4 hours prior to sample 
collection. 
If performed on Day-2 at admission, safety lab tests are not 
needed on Day -1. Results of any pre-dose safety labs 
should be reviewed and confirmed acceptable prior to 
dosing. 
Retained Research Sample for 
Genetics (Prep D1.5) 
X 
Collected in first period only. If not collected on the 
designated collection day, collect at the next available time 
point when biospecimens are being collected in conjunction 
with a participant visit. See Section 8.6.2 for additional 
details. 
Pfizer Prep B1.5 retained 
research sample 
X 
X 
Samples to be collected as outlined in Section 8.7.1.4. 
Samples will be collected in Period 1 and Period 4 only for 
each cohort 
Pfizer Prep B2.5 retained 
research sample 
X 
X 
HIV, HBsAg, HBsAb, 
HBcAb, HCVAb 
X 
See Appendix 2: Clinical Laboratory Tests. 
FSH 
X 
Only for females who have been amenorrheic for at least 12 
months. 
Urine samples for: 
Urine drug testing 
X 
X 
X 
If performed on Day-2 at admission, urine drug testing is not 
needed on Day -1. Results of any pre-dose testing should be 
reviewed and confirmed acceptable prior to dosing. 
See Appendix 2: Clinical Laboratory Tests 


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Table 1. 
Study Schedule of Assessment 
 
Visit Identifier 
Abbreviations used in this 
table may be found in 
Appendix 10. 
Screen 
Period 1 to Period 4 
In-patient 
Follow-Up 
ET 
Notes 
Days Relative to Day 1 
Day -28 to 
Day -3 
Day 
-2 
Day 
-1 
Day 
1 
Day 
2 
Day 
3 
Day 
4 
Visit: 
Day 
8±1 
Contact: 
28-35 
days 
All screening should be done ≤28 days before the first dose. 
Day relative to start of study intervention (Day 1). 
Day 1 activities at time=0 hour are prior to the dose, except 
for study intervention administration. 
On-site follow-up visit occurs on Day 8±1 after 
administration of the final dose of study intervention. 
Follow-up may occur via telephone contact and must occur 
28 to 35 days after administration of the final dose of study 
intervention. 
Hours After Dose 
0 
24 36 
48 
72 
Urinalysis (with microscopy, 
if needed) 
X 
X 
X 
X 
X 
X 
X 
Participant should fast for at least 4 hours prior to sample 
collection. 
If performed on Day-2 at admission, urinalysis not needed 
on Day -1. Results of any pre-dose testing should be 
reviewed and confirmed acceptable prior to dosing. See 
Appendix 2: Clinical Laboratory Tests 


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Table 2. 
Schedule of Activities for PK, PD, Vitals, and ECGs on Day 1 (and Day -1 if Applicable) 
 
Visit Identifier 
Abbreviations used in this table may 
be found in Appendix 10. 
Notes 
Day 1, Day -1 (if applicable) 
Applies to Day 1 for Periods 1-4, and for Day -1 when admission 
occurs on Day -2 
Hours Relative to Dosing at 0 hour 
-1.0 -0.5 0 
0.5 
1 1.5 
2 
3 
4 
8 
10 
12 Day 1 activities at time = 0 hour are prior to the dose, except for study 
intervention administration. 
Study intervention administration 
(Day 1 only) 
X 
Dosing under fasted or fed conditions (eg, MMTT) is to occur as outlined 
in Section 5.3.2. 
Standardized meal/snack 
X 
X 
See Section 5.3.2 for detailed instruction. 
Participants will be provided the same lunch, dinner and snacks at same 
times on Day -1 when time-matched biomarker assessment is collected 
and on Day 1 of each period. If administered on Day -1, MMTT will be 
administered at the same time as planned for administration on Day 1 (ie, 
20 minutes prior to 0 hour). 
High protein meal (eg, MMTT) 
X 
Administered only in periods where food effect is assessed. See 
Section 5.3.2 for detailed instruction. High protein meal to be provided 
approximately 20 minutes prior to 0 hours, and consumed within 10 
minutes such that study intervention is administer approximately 10 
minutes after completion of meal. 
Continuous cardiac telemetry 
(Day 1 only) 
X 
→ 
→ → 
→ → → 
X 
To establish a baseline, telemetry should be recorded for at least a 2-hour 
interval before dosing in Period 1, either immediately prior to dosing or at 
some 2-hour continuous interval in the 24 hours prior to dosing when the 
participant is awake. See Section 8.3.4.1. 
Assessment on Day 1 initiate at time=0 and continue through 8 hours post 
dose. 
Neurological examination 
X 
X 
Day 1 only. The pre-dose assessment (at time =0 hr) can be completed at 
any time within 24 hours prior to the dose on Day 1 in each period. 
12-Lead ECG (Day 1 only) 
X 
X 
X 
X 
X 
X 
X 
X 
X Triplicate measures are collected approximately 2-4 minutes apart. 
See Section 8.3.4 for additional details. 
Supine BP and pulse rate (Day 1 
only) 
X 
X 
X 
X 
X 
X 
X Single measurement only at 0 hour; triplicate measurement at other 
timepoints. Triplicate measures are collected approximately 2-4 minutes 
apart. 
See Section 8.3.3 for additional details. 
Respiratory rate (Day 1 only) 
X 
X 
X 
X 
X 
X 
X Single assessment at all timepoints 
See Section 8.3.3 for additional details. 


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Table 2. 
Schedule of Activities for PK, PD, Vitals, and ECGs on Day 1 (and Day -1 if Applicable) 
Visit Identifier 
Abbreviations used in this table may 
be found in Appendix 10. 
 
 
 
Day 1, Day -1 (if applicable) 
Notes 
 
 
Applies to Day 1 for Periods 1-4, and for Day -1 when admission 
occurs on Day -2 
Hours Relative to Dosing at 0 hour 
PF-07328948 plasma 
pharmacokinetics (Day 1 only) 
CCI 
CCI 
-1.0 -0.5  0 
X 
0.5 
X 
1  1.5 
2 
3 
4 
X  X 
X  X  X 
8 
10 
X 
Day 1 activities at time = 0 hour are prior to the dose, except for study 
12  intervention administration. 
X  See Section 8.5.1 for additional information. 


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2. INTRODUCTION 
PF-07328948 is a small molecule allosteric inhibitor/degrader of BDK that is currently being 
developed as an oral therapy to treat heart failure. 
2.1. Study Rationale 
This study will be the first time PF-07328948 is administered to humans. The purpose of the 
study is to evaluate the safety, tolerability, plasma PK and PD of PF-07328948 following 
administration of escalating, single, oral doses to healthy adult participants. 
2.2. Background 
Tissue and/or plasma BCAA and/or BCKA levels are elevated in various disease states 
including heart failure, type 2 diabetes mellitus, NAFLD/NASH, and obesity.1,2,3,4 
Furthermore, elevated BCAA levels in HF are associated with a loss of the BCAA catabolic 
machinery,1,2 suggesting that the BCKDH pathway, involved in BCAA and BCKA 
catabolism, is dysregulated in cardiometabolic disease indications. Because inhibitory 
phosphorylation of BCKDH by BDK reduces BCAA catabolism, a BDK inhibitor would 
reduce BCKDH phosphorylation, thereby increasing BCAA and BCKA catabolism and 
reducing the elevated levels of BCAAs and BCKAs associated with several cardiovascular 
and metabolic diseases. 
PF-07328948 is an orally administered, small molecule, potent allosteric BDK inhibitor that 
inhibits BCKDH phosphorylation in vitro and has consistently demonstrated robust, dose- 
and time-dependent BCAA and BCKA lowering in plasma and tissues in mouse, rat and/or 
 
These improvements were concomitant with reduced pBCKDH and BDK levels in heart and 
kidney tissue as well as reduced plasma BCAA and BCKA levels. 
2.2.1. Nonclinical Pharmacology 
PF-07328948 is a potent antagonist of mouse, rat, dog, and human BDK CCI 
 
In human skeletal muscle cells, PF-07328948 treatment 
resulted in inhibition of BDK-dependent phosphorylation of BCKDHA. In HEK293 cells, 
PF-07328948 decreased both BDK protein and the ratio of pBCKDHA/BCKDHA protein. 
CCI 
 
 
. In 
diet-induced obese mice, reductions of plasma BCAAs and BCKAs were observed following 
subchronic and chronic dosing. PF-07328948 reduced liver triglycerides, plasma insulin 
levels, and plasma non-esterified free fatty acids after chronic dosing compared with vehicle- 
dog. In addition, CCI 


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PFIZER CONFIDENTIAL 
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CCI 
treated animals. These metabolic improvements were concomitant with decreases in BDK 
protein levels in gastrocnemius muscle and heart, and decreased phosphorylation of BCKDH 
in muscle, heart, and liver. In the ZSF1 rat model of heart failure-preserved ejection, after 
chronic administration in food, PF-07328948 improved exercise capacity and increased 
systolic cardiac functional parameters, with a trend for reduced left atria hypertrophy 
compared to animals that were administered control chow. These improvements were 
concomitant with reduced pBCKDH and BDK levels in heart and kidney tissue as well as 
reduced plasma BCAA and BCKA levels. 
Details of the nonclinical pharmacology are included in the IB. 
2.2.2. Nonclinical Pharmacokinetics and Metabolism 
PF-07328948 was rapidly absorbed with moderate to high oral bioavailability and had low to 
moderate plasma CL and Vss in rats, dogs, and monkeys. After IV administration of PF- 
07328948, renal excretion of unchanged PF‑07328948 was <1% in rats, dogs, and monkeys 
and biliary excretion of unchanged PF‑07328948 was ~1% in rats. In oral repeat-dose 
toxicity studies in rats and dogs, the systemic exposure increased with increasing dose in a 
less than or approximately dose proportional manner and there were no consistent sex-related 
differences or accumulation observed. 
PF-07328948 was highly bound to plasma proteins in all species evaluated, with binding that 
was concentration dependent and was preferentially distributed into plasma relative to blood 
 
 
 
The DDI potential was further evaluated with a static mechanistic model using the projected 
Cmax for reversible inhibition or Cave for induction in plasma, intestinal lumen, enterocytes, 
liver, and portal inlet. 
cells. CCI 


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Page 26 
 
 
CCI 
 These predictions will be refined 
once human PK data are available for PF-07328948. 
Additional details are included in the IB. 
CCI 
 
 
2.2.4. Nonclinical Safety 
PF-07328948 was administered orally to rats and dogs in toxicity studies up to 1 month in 
 
 
 
 
 
 
 
 
 
 
 
 
Based on a weight of evidence, PF-07328948 does not pose a risk for genotoxicity. 
Based on the UV absorption profile of PF-07328948, there is a potential for phototoxicity. 
Additional details of the nonclinical safety are provided in the IB. 
duration. CCI 
The NOAEL in the 1-month GLP 
repeat-dose toxicity study in rats was 100 mg/kg/day, CCI 
. The 
NOAEL in the 1-month GLP repeat-dose toxicity study in dogs was 100 mg/kg/day, CCI 


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2.3. Benefit/Risk Assessment 
Study C4921001 is the first time that PF-07328948 will be administered to humans and is 
designed primarily to generate safety, tolerability, and PK and PD data for further clinical 
development. PF-07328948 is not expected to provide any clinical benefit to healthy 
participants. The purpose of this study is to provide the basis for further clinical development 
of PF-07328948 as a first-in-class therapy for treatment of patients with heart failure. As of 
the date of final protocol, no specific human risks have been identified; postulated risks 
based on nonclinical studies are summarized in Section 2.3.1. The clinical impact of these 
potential risks will be minimized through the proposed cautious dose-escalation process 
wherein higher doses of PF-07328948 will be administered only after lower doses have been 
found to be well tolerated with an acceptable safety profile. Use of stopping rules for dose- 
escalation, as well as by specific safety monitoring measures, have been incorporated into 
this study, where appropriate, as outlined in the SoA. In addition, this study will use 
precautionary sentinel dosing in periods evaluating escalating doses of PF-07328948, and all 
periods will include standard, intensive, inpatient monitoring of the participants following 
administration of single, oral doses of the study intervention. 
More detailed information about the known and expected benefits and risks and reasonably 
expected AEs of PF-07328948 may be found in the IB, which is the SRSD for this study. 


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2.3.1. Risk Assessment 
All study intervention risks are communicated through the IB. 
 
Potential Risk of Clinical Significance 
Summary of Data/Rationale for Risk 
Mitigation Strategy 
Study Intervention - PF-07328948 
Effects on blood pressure 
Decreased BP was observed after single doses 
(≥ 20 mg/kg) of PF-07328948 in dogs in 
exploratory toxicology studies. No BP changes 
were subsequently noted in GLP toxicology 
studies after single doses of ≤ 100 mg/kg in dogs. 
• 
Participants will be in a closely monitored 
environment while in the CRU during the 
study. 
• 
Inpatient monitoring will include serial 
assessment of blood pressure. 
Skin sensitivity to light; sunburn 
Based on light absorption within the UV range, 
PF-07328948 has a risk for phototoxicity. 
• Participants with a history of phototoxicity or 
photosensitivity are excluded from study. 
• Lifestyle and activity considerations have 
been added advising participant to use 
sunscreen and eye protection, and to avoid 
sunlight and high-intensity UV light exposure. 
Drug-drug interactions resulting in exposure changes 
of background concomitant medications. 
CCI 
• Use of prescription or nonprescription drugs 
and dietary and herbal supplements are 
prohibited within 7 days or 5 half-lives 
(whichever is longer) prior to the first dose of 
study intervention through the last PK 
collection. 
Idiosyncratic drug reaction 
IADR risk CCI 
 
• 
Participants will be in a closely monitored 
environment while in the CRU during the 
study. 
• 
Risk of IADR after single dose of 
PF-07328948 is considered low. 
• 
Laboratory safety tests include serial 
assessment of LFTs and CBCs. 


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Potential Risk of Clinical Significance 
Summary of Data/Rationale for Risk 
Mitigation Strategy 
BCAA deficiency 
BCAAs play a multifaceted role in maintenance 
of health. Prolonged deficiency of ≥ 1 BCAA 
caused by excessive dietary restrictions in 
children associated with neurodevelopmental 
delays-function mutations in BDK gene in 
humans are associated with neurological 
sequelae. 
• Single doses of PF-07328948 are not 
anticipated to result in prolonged lowering of 
BCAAs. 
• Risk of neurological sequelae from magnitude 
and duration of BCAA lowering expected 
following single doses of PF-07328948 is 
considered very low. Neurological 
examination as part of the physical exam will 
be performed pre- and post-dose. 
Other 
The COVID-19 pandemic may pose risks to study 
participation. 
During the pandemic, healthy participants could be 
infected with the SARS-CoV-2 virus through study 
participation, which could lead to increased health 
risks for this participant and others in the study. 
AEs could be confounded. 
• Inclusion of COVID-19 specific assessments 
according to the SoA. 


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2.3.2. Benefit Assessment 
The participants in this study are not expected to obtain any specific benefit beyond 
contributing to the process of developing new therapies in an area of unmet need. They will 
receive close monitoring of their safety via study procedures undertaken (eg, physical 
examinations, including neurological examinations, 12-lead ECGs, vital signs) which will 
occur as outlined in this protocol. 
2.3.3. Overall Benefit/Risk Conclusion 
Based on the totality of available nonclinical data, and taking into account the measures to 
minimize risk to study participants, the overall benefit/risk profile supports clinical testing of 
PF-07328948 in this study as part of the clinical development for an indication of heart 
failure. 
3. OBJECTIVES AND ENDPOINTS 
 
 
Primary: 
Objectives 
 
 
Primary: 
Endpoints 
• To evaluate the safety and tolerability of single 
ascending doses of PF-07328948 administered orally to 
healthy adult participants. 
 
Secondary: 
• To evaluate the pharmacokinetics of PF-07328948 
following single doses of PF-07328948 administered 
orally to healthy adult participants. 
Tertiary/Exploratory: 
• To evaluate additional pharmacokinetic parameters of 
PF-07328948 following single doses of PF-07328948 
administered orally to healthy adult participants. 
• 
Assessment of adverse events, clinical safety 
laboratory tests, vital signs, continuous cardiac 
monitoring, 12-lead electrocardiograms, and physical 
examinations. 
Secondary: 
• 
PK parameters derived from plasma PF-07328948 
concentrations: Cmax, Tmax, AUClast, and if data permit, 
AUCinf, and t½. 
Tertiary/Exploratory: 
• 
Additional PK parameters derived from plasma 
PF-07328948 concentrations: Cmax(dn), AUClast(dn) 
and if data permit AUCinf(dn), CL/F and Vz/F. 
• CCI 
 
 
 
 
 
 
 
 
 
 
 
• To evaluate the effect of food (eg, a protein-rich meal 
such as MMTT), if administered, on the plasma PK of 
PF-07328948 following single dose of PF-07328948 
administered orally to healthy adult participants. 
• 
PK parameters derived from plasma PF-07328948 
concentrations after MMTT: Cmax, Tmax, AUClast, and 
if data permit, AUCinf, and t½. 


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CCI 
4. STUDY DESIGN 
4.1. Overall Design 
This is a randomized, investigator- and participant-blind, sponsor-open, placebo-controlled, 
first-in-human, single ascending oral dose, 4-period, sequential, crossover study of 
PF-07328948 administered to healthy adult participants. Approximately 24 healthy adult 
participants (up to 3 cohorts of approximately 8 participants each) will be enrolled in this 
study. The first 2 cohorts are planned, and the third cohort is optional. In each period, 
participants will be randomized to either PF-07328948 or placebo in a ratio of 3:1. Each 
participant is planned to undergo up to 4 treatment periods receiving up to 4 doses of 
PF-07328948 and up to 2 placebo. 
Precautionary sentinel dosing will be used in any period evaluating escalating doses of PF- 
07328948 and may be omitted for periods when repeating a dose level or administering a 
lower dose level than previously evaluated. For periods with sentinel dosing, 2 participants (1 
receiving PF-07328948 and 1 receiving placebo) will be dosed initially before the remaining 
participants of that period are dosed. Safety and tolerability data through at least 24 hours 
post-dose for the sentinel participants will be reviewed prior to dosing the remaining 
participants of that period. 
Participants confirming eligibility according to Section 5 will be admitted to the CRU on 
Day -2 in Period 1 for each cohort and the 1st food period (if applicable) within a cohort. For 
all other periods (ie, Periods 2-4 except the 1st food period within each cohort), participants 
will be re-admitted to the CRU on Day -1. For each period in this study, on Day 1, following 
≥10-hour overnight fast, participants will receive a single oral dose of PF-07328948 or 
placebo. Participants have been discharged on Day 3 in Cohort 1 and will be discharged on 
Day 4, following completion of all scheduled assessments out to 72 hours post-dose in 
Cohort 2 and optional Cohort 3. Participants may stay in the CRU after completion of Day 4 
activities at the discretion of the investigator. In each cohort, a washout interval of at least 7 
days will be introduced between subsequent doses. During the washout interval, emerging 
24-hour PK and 48-hour safety data will be reviewed and the next dose will be determined. 
An on-site follow-up visit on Day 8±1 after the final dose and a final follow-up within 28-35 
days after the final dose will be scheduled. Final follow-up may be a phone contact or an on- 
site visit at the discretion of the PI. 
Based on the review of emerging safety, tolerability, and PK data (and PD data if available) 
in Cohorts 1 and 2, the optional third cohort may enroll 8 participants (crossover, 
placebo-controlled design) to explore additional doses, to repeat a dose, to evaluate split 
dosing, or to investigate food effects on PK and PD biomarkers. 
Dosing will occur in the fasted state for all periods for dose escalation. The effect of a 
high-protein meal on safety, tolerability, PK exposure, and PD biomarkers CCI 
 
may be assessed in at 
least 1 period within Cohort 2 and/or Cohort 3. 
 


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CCI 
CCI 
 Participants 
should only need to undergo these time-matched assessments of PD biomarkers on Day -1 
once in the fasted state and/or once in the fed state in each cohort, unless there is any 
uncertainty regarding the reliability of the initial Day -1 assessment. In addition, if thought 
necessary to achieve study objectives, study intervention may be administered in the fed state 
(eg, following a high-protein meal) during any of the study periods/cohorts. 
The total duration of participation from the screening visit to the telephone follow-up contact 
will be approximately 14 weeks. 
If a participant drops out before completing all study periods within a cohort, or withdraws 
for a reason unrelated to safety, the participant may be replaced at the discretion of the 
investigator and sponsor. The replacement participant(s) may or may not be required to 
complete all periods of the cohort in which they are participating at the discretion of the 
investigator and sponsor. Of note, replacement participants may be required to undergo time- 
matched assessments of PD biomarkers during Day -1 of their initial period in the study. 
4.2. Scientific Rationale for Study Design 
The population planned for this study will be healthy males and females of non-childbearing 
potential. Female participants will be confirmed not to be of childbearing potential because 
embryo-fetal development toxicity studies with PF-07328948 have not been conducted. In 
male participants, appropriate measures are expected to be followed to minimize potential 
transfer of PF-07328948 via semen to partners (see Appendix 4). 
Because this is the first time PF-07328948 will be administered to humans, an escalating 
single, oral dose, crossover design is planned with careful assessment and ongoing review of 
safety, tolerability, and PK data of PF-07328948. Precautionary sentinel dosing will also be 
utilized in any period evaluating escalating doses of PF-07328948 to ensure that safety and 
tolerability data in a subset of 2 participants within each period supports testing additional 
participants in that period. In each period, approximately 6 participants are planned to receive 
PF-07328948, and approximately 2 participants are planned to receive placebo, with all the 
participants at the end of the study having received up to 4 doses of PF-07328948 and up to 2 
placebo. The crossover design permits both within- and between-participants assessments of 
safety, tolerability, and PK at multiple dose levels and placebo. 
In addition, the highest anticipated Cmax and AUC24 of PF-07328948 will not exceed the 
pre-defined human exposure stopping limits nor exceed the highest feasible total daily dose 
CCI 
. Furthermore, to permit an unbiased assessment of safety, the administration of 
both PF-07328948 and placebo in each period will be double-blinded to both site staff 
(except those involved in preparation of doses) as well as participants. To permit real-time 
review of the safety, tolerability, and PK data, a limited number of sponsor study team 
members will be unblinded. 
 
. As a BDK inhibitor/degrader, 


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PF-07328948 is expected to inhibit BDK-mediated phosphorylation of BCKDH enzyme 
complex, resulting in an increase in BCAA/BCKA catabolism and a decrease in circulating 
BCAA and BCKA levels. As protein intake is known to impact plasma BCAA/BCKA 
levels,5 CCI 
 
. Lunch and dinner will be standardized when participants are 
confined in the CRU; additional efforts will be made to ensure lunch, dinner and snacks are 
as identical as is feasible on Day 1 for each period and on Day -1 where time-matched 
CCI 
assessment is performed (Section 5.3.2). CCI 
 
 
 
 
 
Based on predicted half-life in human (~4 hours), PK samples were collected over 48 hours 
post-dose in Cohort 1. However, the preliminary PK data emerging from Cohort 1 suggested 
the terminal half-life could be longer than the predicted 4 hours therefore, participants in 
remaining Cohort 2 and optional Cohort 3 will be confined in CRU up to Day 4 with PK 
samples collected up to 72 hours post-dose. A washout interval of ≥7 days is proposed 
between doses within an individual participant; this interval should be sufficient based on all 
emergent PK data to date, and the projections that CCI 
 levels return to 
baseline within approximately 72 hours post-dose based on a PK/PD model developed with 
preclinical data and emergent PK/PD data in Cohort 1. In addition, this washout interval 
should offer sufficient opportunity to review safety, tolerability, and PK data after each 
dosing period prior required for decision on the PF-07328948 dose to be evaluated in the 
subsequent period. However, sampling times, duration of sampling, and/or the length of the 
washout period may be modified and/or extended based on emerging PK and/or PD data. 
Participants may be asked to remain at the CRU after completion of Day 4 activities at the 
discretion of the investigator or if safety, tolerability, or PK data dictate the need to prolong 
inpatient stay in the CRU. The planned doses and assignment to study intervention in the 
escalation sequence (see Section 1.2) may be modified or repeated, as guided by emerging 
safety, tolerability, and PK data but will follow the dose-escalation rules defined in Section 
6.6.1. 
Decreased blood pressure was observed after single doses (≥ 20 mg/kg) of PF-07328948 in 
dogs in exploratory toxicology studies; however, no significant blood pressure changes were 
subsequently noted in GLP toxicology studies after single doses of ≤ 100 mg/kg in dogs. 
Serial triplicate assessment of blood pressure will be performed following single dose 
administration as outlined in SoA. Triplicate 12-lead ECGs and continuous cardiac telemetry 
CCI 


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also will be monitored as outlined in SoA. PF-07328948 effects on the respiratory system 
included transiently lower tidal volume and minute volume in rats at 100 mg/kg in the 
GLP-compliant pulmonary assessment study. The relevance of these transient effects of 
PF-07328948 on rat tidal and minute volume to humans is unknown, but respiratory rate will 
be monitored in the clinic. 
One serious adverse event was reported during the follow-up period in 1 participant (out of 9 
participants) in the first cohort of this study. This participant completed 4 periods of the 
study, and received single doses of PF-07328948 in each of 3 periods and a single dose of 
placebo in 1 period per protocol, with at least 7 days between doses. An adverse event of 
“loss of consciousness, possible seizure” was reported in this participant during the follow-up 
period, 7 days following the last dose of blinded study medication (PF-07328948 or placebo) 
administered in Period 4. The participant required assessment in the Emergency Department 
for this adverse event, but spontaneously resolved without intervention and did not require 
hospitalization or any specific treatment. While the Principal Investigator could not exclude 
the possibility that the blinded study medication (PF-07328948 or placebo) may have 
contributed to the adverse event of “loss of consciousness, possible seizure”, this event was 
also reviewed by the Pfizer safety team and by a Pfizer Risk Management Committee, and 
these teams concluded that the event was unrelated to study intervention based on the 
prolonged duration between last dose of blinded study medication and animal data indicating 
that PF-07328948 does not cross the blood-brain barrier. In addition, no seizures were 
observed in any of rat or dog studies described above. Out of an abundance of caution, 
however, participants in this study will be monitored closely with serial physical exams 
directed at identifying any neurological signs or symptoms. 
Based on the UV absorption profile of PF-07328948, there is a potential for phototoxicity 
and so participants will be advised to take necessary precautions to avoid direct sunlight 
exposure or any high intensity UV light exposure from admission in Period 1 through the 
follow-up contact, as described in Section 5.3.4. 
4.2.1. Choice of Contraception/Barrier Requirements 
Human reproductive safety data are not available for PF-07328948. Therefore, the use of a 
highly effective method of contraception is required for male study participants and is 
recommended for partners of male study participants who are WOCBP (see Appendix 4). 
4.2.2. Collection of Retained Research Samples 
Retained Research Samples will be collected and stored for further analyses which may, for 
example, provide greater understanding of the study intervention. 
4.3. Justification for Dose 
The proposed dose levels of PF-07328948 were derived based on cumulative nonclinical 
data, including in vitro, in vivo, PK and PD data, and the completed nonclinical toxicity 
studies. Dose levels beyond the starting dose (in Period 1 of Cohort 1) may be modified 
based on emerging human safety, tolerability, and PK data in the current study. 


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CCI 
 
 
4.3.2. Predicted Efficacious Concentration and Human Dose 
The desired degree of target modulation is based on published human metabolomic data.3,4,7,8 
As BCAAs are elevated ~20% on a population level in patients with cardiometabolic disease 
 
However, due to uncertainty around the degree of target modulation necessary for efficacy in 
patients with heart failure and the first-in-class nature of the mechanism of BDK inhibition, 
higher degrees of target modulation CCI 
 
is desired to be evaluated if permitted by safety data. 
4.3.3. Human Exposure Stopping Limits 
The NOAELs in the pivotal 1-month GLP toxicity studies were 
which correspond to the highest doses tested in 
those respective studies. 
Therefore, the human exposure stopping limits for PF-07328948 are based on unbound 
exposures at the NOAEL CCI 
 observed in the 1-month GLP toxicity study in 
rats which is defined as the most sensitive species. 
• The human PF-07328948 Cmax limit is CCI 
 
• The human PF-07328948 AUC24 limit is CCI 
 
relative to healthy individuals, CCI 
CCI 


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Dose 
(mg) 
Cmax a 
AUC24 a 
(ng/mL) 
(ng.h/mL) 
Total 
Free 
Total 
Free 
10 
461 
1 
30 
1380 
2 
100 
4610 
6 
300 
13800 
20 
750 
34600 
64 
1500 
69200 
173 
2990 
8910 
29000 
81500 
181000 
310000 
4 
11 
37 
C 
C 
C 
112 
C 
286 
C 
595 
C 
CC 
I 
CCI 
4.3.4. Rationale for Dose Selection 
The safety, tolerability, and plasma PK of PF-07328948 after administration of single 
escalating oral doses across a wide dose/exposure range will be evaluated in this study. 
Dosing will occur in the fasted state, except in periods in which dosing may occur in the fed 
state to permit exploratory assessment of the effect of food on PF-07328948 PK and PD. The 
doses presented in Table 3 are projected based on nonclinical data and may be modified 
based on emerging human safety, tolerability, and PK data. Predicted human PK parameter 
estimates, toxicokinetic data, and projected efficacious concentrations were used to establish 
the initial range of planned doses in this study. The projected human exposures account for 
concentration-dependent protein binding within the planned dose range. 
 
Table 3. 
Predicted Human Exposures, Pharmacodynamic Effects, and Safety 
Margin at Proposed Single Doses of PF-07328948 
 
a. 
Human PK profiles were predicted using a 1-compartment model with the projected human PK 
parameters for PF-07328948 outlined in Section 4.3.1. Human plasma fu values were predicted using the 
linear equation (CCI 
 and hepatic 
clearance was projected using the well-stirred model. 
b. Pharmacodynamic effects elucidated with Ile and KMV was simulated based on a PK/PD model 
developed with preclinical data and Ki for human BDK inhibition and human fasting plasma Ile and KMV 
baseline level. Ave reduction was calculated over 24 hours. 
c. 
SM, safety margin for unbound exposure (Cmax,u and AUC24,u) at the proposed doses were calculated 
based on the NOAELs in the 1-month GLP toxicity studies in both rats and dogs. The human exposure 
limits were defined as CCI 
 
observed at NOAEL in rat 1-month GLP toxicity study. 
 
The PF-07328948 starting dose level of 10 mg is planned. The predicted PF-07328948 Cmax,u 
and AUC24,u after single dose of 10 mg are CCI 
, respectively, 
below the exposure limits defined for PF-07328948 dose escalation in Section 4.3.3. The 
maximum reduction for plasma isoleucine and ketoisoleucine are predicted to be 3% and 4%, 
respectively, suggesting little target modulation at this dose. A single dose of 1500 mg (the 
top dose in Table 3) is estimated to provide an exposure margin CCI 
 
 
, respectively, relative to the exposure limits. 


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The dose range to be studied was selected to account for uncertainties in the projected Ceff 
and the projected therapeutic dose, while also bracketing the expected clinically effective 
dose range in humans for clinically relevant pharmacological activity and providing safety 
coverage for a wide range of PF-07328948 doses. 
Assessment of the safety, tolerability, and PK after each single dose level will be conducted 
before escalating to the next dose level. The dose/exposure-escalation increments are planned 
to be up to approximately semi-logarithmic increases in exposure from the previous highest 
dose level that has been evaluated. If exposure exceeds the projected therapeutic range, or if 
changes in safety parameters are observed, smaller dose-escalation steps may be 
implemented. 
The actual dose levels, target exposures, and/or dose level increments may be adjusted 
(higher or lower) during the study based on emerging human safety, tolerability, and PK 
data, but projected exposures will not exceed the predefined human exposure limits. If 
Cmax-related adverse events are observed, split dosing (eg, the total dose will be divided into 
2 or 3 parts on Day 1) may be used to potentially increase AUC without increasing Cmax. 
Dose levels may also be repeated if warranted. 
When the assessment of the effect of food on the PK and PD of PF-07328948 is conducted, 
the dose level will be selected based on emerging safety, tolerability, and PK data from 
previous periods of this study. The actual dose level used will be expected to achieve 
exposures similar to or greater than projected therapeutic exposures (as outlined in 
Section 4.3.2). 
4.4. End of Study Definition 
The end of the study is defined as the date of last scheduled procedure shown in the SoA for 
the last participant in the trial. 
A participant is considered to have completed the study if they have completed all periods of 
the study, including the last scheduled procedure shown in the SoA. 
5. STUDY POPULATION 
This study can fulfill its objectives only if appropriate participants are enrolled, including 
participants across diverse and representative racial and ethnic backgrounds. Use of a 
prescreening tool is utilized for study recruitment purposes, it will include collection of 
information that reflects the enrollment of a diverse participant population including, where 
permitted under local regulations, age, sex, and race, and ethnicity. The following eligibility 
criteria are designed to select participants for whom participation in the study is considered 
appropriate. All relevant medical and nonmedical conditions should be taken into 
consideration when deciding whether a particular participant is suitable for this protocol. 
Prospective approval of protocol deviations to recruitment and enrollment criteria, also 
known as protocol waivers or exemptions, is not permitted. 


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5.1. Inclusion Criteria 
Participants are eligible to be included in the study only if all of the following criteria apply: 
Age and Sex: 
1. Female participants of non-child bearing potential and males must be 18 to 60 years 
of age, inclusive, at the time of signing the ICD. 
Refer to Appendix 4 for reproductive criteria for male (Section 10.4.1) and female 
(Section 10.4.2) participants. 
2. Female participants of non-child bearing potential and males who are overtly healthy 
as determined by medical evaluation including medical history, physical examination, 
laboratory tests, and cardiac monitoring. 
Other Inclusion Criteria: 
3. BMI of 17.5 to 30.5 kg/m2; and a total body weight >50 kg (110 lb). 
4. Participants who are willing and able to comply with all scheduled visits, treatment 
plan, laboratory tests, lifestyle considerations, and other study procedures. 
5. Capable of giving signed informed consent as described in Appendix 1, which 
includes compliance with the requirements and restrictions listed in the ICD and in 
this protocol. 
5.2. Exclusion Criteria 
Participants are excluded from the study if any of the following criteria apply: 
Medical Conditions: 
1. Evidence or history of clinically significant hematological, renal, endocrine, 
pulmonary, gastrointestinal, cardiovascular, hepatic, psychiatric, neurological, or 
allergic disease (including drug allergies, but excluding untreated, asymptomatic, 
seasonal allergies at the time of dosing). 
• Any condition possibly affecting drug absorption (eg, gastrectomy, 
cholecystectomy). 
• History of HIV infection, hepatitis B, or hepatitis C; positive testing for HIV, 
HBsAg, HBcAb, or HCVAb. Hepatitis B vaccination is allowed. 
• History of phototoxicity or photosensitivity. 


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2. Other medical or psychiatric condition including recent (within the past year) or 
active suicidal ideation/behavior or laboratory abnormality or other conditions or 
situations related to COVID-19 pandemic that may increase the risk of study 
participation or, in the investigator’s judgment, make the participant inappropriate for 
the study. 
Prior/Concomitant Therapy: 
3. Use of prescription or nonprescription drugs and dietary and herbal supplements 
within 7 days or 5 half-lives (whichever is longer) prior to the first dose of study 
intervention through the last PK collection, with the exception of moderate/strong 
CYP3A inducers or time-dependent inhibitors which are prohibited within 14 days 
plus 5 half-lives prior to the first dose of study intervention. (Refer to Section 6.9 
Prior and Concomitant Therapy for additional details). 
4. Receipt of a COVID-19 vaccine within 7 days before screening or within 7 days 
before any visit in which a safety lab is planned. Vaccination with a COVID-19 
vaccine that occurs greater than 7 days from either screening or any visit in which a 
safety lab is planned is permitted. 
Prior/Concurrent Clinical Study Experience: 
5. Previous administration with an investigational product (drug or vaccine) within 
30 days (or as determined by the local requirement) or 5 half-lives preceding the first 
dose of study intervention used in this study (whichever is longer). 
Diagnostic Assessments: 
6. A positive urine drug test. 
7. Screening supine BP ≥140 mm Hg (systolic) or ≥90 mm Hg (diastolic), following at 
least 5 minutes of supine rest. If BP is ≥140 mm Hg (systolic) or ≥90 mm Hg 
(diastolic), the BP should be repeated 2 more times and the average of the 3 BP 
values should be used to determine the participant’s eligibility. 
8. Renal impairment as defined by an eGFR 75 mL/min/1.73m2 (based on serum 
creatinine). Based upon participant age at screening, eGFR is calculated from serum 
creatinine using the recommended CKD-EPI SCr formulas in Section 10.7.2 to 
determine eligibility and to provide a baseline to quantify any subsequent kidney 
safety events. 
9. Standard 12-lead ECG that demonstrates clinically relevant abnormalities that may 
affect participant safety or interpretation of study results (eg, QTcF 450 ms, 
complete LBBB, signs of an acute or indeterminate- age myocardial infarction, ST-T 
interval changes suggestive of myocardial ischemia, second- or third-degree AV 
block, or serious bradyarrhythmias or tachyarrhythmias). If the uncorrected QT 


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interval is 450 ms, this interval should be rate-corrected using the Fridericia method 
only and the resulting QTcF should be used for decision making and reporting. If 
QTcF exceeds 450 ms, or QRS exceeds 120 ms, the ECG should be repeated twice 
and the average of the 3 QTcF or QRS values used to determine the participant’s 
eligibility. Computer-interpreted ECGs should be overread by a physician 
experienced in reading ECGs before excluding a participant. 
10. Participants with ANY of the following abnormalities in clinical laboratory tests at 
screening, as assessed by the study-specific laboratory and confirmed by a single 
repeat test, if deemed necessary: 
• AST or ALT level ≥1.25 × ULN; 
• Total bilirubin level ≥1.5 × ULN; participants with a history of Gilbert’s 
syndrome may have direct bilirubin measured and would be eligible for this study 
provided the direct bilirubin level is ≤ ULN. 
Other Exclusion Criteria: 
11. History of alcohol abuse or binge drinking and/or any other illicit drug use or 
dependence within 6 months of Screening. Binge drinking is defined as a pattern of 
5 (male) and 4 (female) or more alcoholic drinks in about 2 hours. As a general rule, 
alcohol intake should not exceed 14 units per week (1 unit = 8 ounces (240 mL) beer, 
1 ounce (30 mL) of 40% spirit, or 3 ounces (90 mL) of wine). 
12. Blood donation (excluding plasma donations) of approximately 1 pint (500 mL) or 
more within 60 days prior to dosing. 
13. History of sensitivity to heparin or heparin-induced thrombocytopenia. 
14. Use of tobacco or nicotine-containing products in excess of the equivalent of 
5 cigarettes/day or 2 chews of tobacco/day. 
15. Unwilling or unable to comply with the criteria in the Lifestyle Considerations 
section of this protocol. 
16. Investigator site staff directly involved in the conduct of the study and their family 
members, site staff otherwise supervised by the investigator, and sponsor and sponsor 
delegate employees directly involved in the conduct of the study and their family 
members. 


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5.3. Lifestyle Considerations 
The following guidelines are provided: 
5.3.1. Contraception 
The investigator or their designee, in consultation with the participant, will confirm that the 
participant is utilizing an appropriate method of contraception for the individual participant 
and their partner(s) from the permitted list of contraception methods (see Appendix 4, 
Section 10.4.4) and will confirm that the participant has been instructed in its consistent and 
correct use. At timepoints indicated in SoA, the investigator or designee will inform the 
participant of the need to use highly effective contraception consistently and correctly and 
document the conversation and the participant’s affirmation in the participant’s chart. 
Participants need to affirm their consistent and correct use of at least 1 of the selected 
methods of contraception, considering that their risk for pregnancy may have changed since 
the last visit. 
In addition, the investigator or designee will instruct the participant to call immediately if the 
selected contraception method is discontinued and document the requirement to use an 
alternate protocol-specified method, including if the participant will no longer use abstinence 
as the selected contraception method, or if pregnancy is known or suspected in the participant 
or partner. 
5.3.2. Meals and Dietary Restrictions 
• Participants must abstain from all food and drink (except water) at least 4 hours prior 
to any safety laboratory evaluations, and at least 10 hours prior to the collection of the 
pre-dose PK and PD biomarker samples on Day 1 (and on Day -1 if relevant for that 
period), and at least 8 hours prior to PD biomarker collection on Day 2, Day 3, Day 4 
(if applicable) and Day 8 ±1 visit (following final dose of study intervention). 
• Noncaffeinated drinks (except grapefruit or grapefruit-related citrus fruit juices-see 
below) may be consumed with meals and the evening snack. 
• Dosing under fasted conditions: 
• Following an overnight fast of at least 10 hours, participants will receive study 
intervention. 
• Water is permitted until 1 hour prior to study intervention administration. Water 
may be consumed without restriction beginning 1 hour after dosing. 
• No food or drink (other than water) is permitted until lunch approximately 4 hours 
after dosing and after the 4-hour post-dose blood collection samples have been 
completed. 


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• Dosing when an effect of a protein-rich meal (eg, MMTT) is investigated, if 
performed: 
• Following an overnight fast of at least 10 hours, participants will be provided a 
protein-rich meal as 16 ounces of Ensure Plus® breakfast approximately 20 
minutes prior to administration of study intervention. The entire Ensure Plus® 
meal is to be consumed within 10 minutes with study intervention administered 
approximately 10 minutes after completion of the meal at 0 hour. There are no 
water restrictions prior to dosing for participants dosed under fed conditions. 
Water may be consumed without restriction beginning 1 hour after dosing. 
• MMTT on Day -1, if administered: 
• Following an overnight fast of at least 10 hours, participants will be provided a 
protein-rich meal as 16 ounces of Ensure Plus® breakfast; the timing of 
administration of the protein-rich meal on Day -1 will be at approximately the 
same time as planned for administration on Day 1. 
• Lunch will be provided approximately 4 hours after dosing and after the 4-hour 
postdose samples (or time-match sample on Day -1 if applicable) have been collected. 
• Dinner will be provided approximately 10 hours after dosing and after the 10-hour 
postdose samples (or time-matched sample on Day -1 if applicable) have been 
collected. 
• An evening snack may be permitted. Participants will receive the same evening snack 
at approximately the same time (± 30 minutes) on Day -1 and Day 1, as well as on 
any Day -2 if applicable. 
• Participants will be provided the same lunch, dinner and snacks on Day -1 when time- 
matched biomarker assessment is collected and on Day 1 of each period (with or 
without a MMTT) to strive for as similar food intake as is feasible on these days 
across periods. 
• Participants will be encouraged to consume their entire meals on Day 1 during all 
periods. In addition, participants will be encouraged to consume their entire evening 
snack (if applicable) on Day -2 and entire meals on Day -1 if a MMTT is planned for 
Day -1; if participants do not consume their entire meal on Day -1 where a MMTT is 
performed, they will be instructed to consume the same amount of food (±10%, with 
similar uptake of optional snacks) on following Day 1 that they ate on Day -1. The 
approximate percentage of food consumed for these meals should be recorded in the 
CRF based on visual assessment by the site staff. Participants will not be required to 
consume all provided food during standard meals on other study days. 


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• Participants will refrain from consuming red wine, grapefruit, or grapefruit-related 
citrus fruits (eg, Seville oranges, pomelos, fruit juices) from 7 days prior to the first 
dose of study intervention until collection of the final PK blood sample. 
• While participants are confined, their total daily nutritional composition should be 
approximately 55% carbohydrate, 30% fat, and 15% protein. The daily caloric intake 
per participant should not exceed approximately 3200 kcal. However, these 
guidelines may be adapted to facilitate meal and dietary restrictions required for Day 
1 in each period and for Day -1 when time-matched biomarker assessment is 
collected with or without a MMTT. 
5.3.3. Caffeine, Alcohol, and Tobacco 
• Participants will abstain from caffeine -containing products for 24 hours prior to the 
start of dosing until collection of the final PK sample of each study period. 
• Participants will abstain from alcohol for 24 hours prior (or as specified above for red 
wine) to admission to the CRU and continue abstaining from alcohol until collection 
of the final PK sample of each study period. Participants may undergo an alcohol 
breath test or blood alcohol test at the discretion of the investigator. 
• Participants will abstain from the use of tobacco- or nicotine-containing products for 
24 hours prior to dosing and during confinement in the CRU. 
5.3.4. Activity 
• Participants will abstain from strenuous exercise (eg, heavy lifting, weight training, 
calisthenics, aerobics) for at least 48 hours prior to each blood collection for clinical 
laboratory tests. Walking at a normal pace will be permitted. 
• In order to standardize the conditions on PK sampling days, participants will be 
required to refrain from lying down (except when required for BP, pulse rate, and 
ECG measurements), eating, and drinking beverages, other than water, during the 
first 4 hours after dosing. 
• Participants will be confined to the procedure room for the first 4 hours after dosing 
on Day 1 during continuous cardiac monitoring, except to use the bathroom. After 
this, if the equipment setup allows, participants may be ambulatory during the ECG 
monitoring period, but should not engage in strenuous activities. If equipment does 
not allow ambulation, appropriate accommodations will be made by the investigator 
site to facilitate continuous monitoring (eg, bedside urinals should be provided to 
accommodate participants’ excretory needs). 
• Participants will be advised to avoid direct sunlight exposure or any high intensity 
UV light exposure, from admission in Period 1 through the follow-up contact. In 
addition, participants will be instructed to apply sun cream/lotion with an SPF of ≥50, 
and wear eye-protective sunglasses as appropriate. 


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5.4. Screen Failures 
Screen failures are defined as participants who consent to participate in the clinical study but 
are not subsequently enrolled in the study. Screen failure data are collected and remain as 
source and are not reported on the CRF. 
Individuals who do not meet the criteria for participation in this study (screen failure) may be 
rescreened. 
6. STUDY INTERVENTION(S) AND CONCOMITANT THERAPY 
Study interventions are all prespecified investigational and noninvestigational medicinal 
products/auxiliary medicinal products, medical devices, and other interventions (eg, surgical 
and behavioral) intended to be administered to the study participants during the study 
conduct. 
For the purposes of this protocol, study intervention refers to: 
• PF-07328948; 
• Placebo for PF-07328948. 
6.1. Study Intervention(s) Administered 
 
Study Intervention(s) 
Intervention Name 
PF-07328948 
Placebo 
Arm Name 
(group of participants receiving a 
specific treatment or no 
treatment) 
PF-07328948 
Placebo 
Type 
Drug 
Drug 
Dose Formulation 
Bulk powder for extemporaneous 
preparation of oral suspensions 
Bulk powder for extemporaneous 
preparation of oral suspensions 
Unit Dose Strength(s) 
10-3000 mg 
0 mg 
Dosage Level(s) 
Single ascending doses 10-3000 mg 
0 mg 
Route of Administration 
Oral 
Oral 
Use 
Experimental 
Placebo 
IMP or NIMP/AxMP 
IMP 
IMP 
Sourcing 
Provided by the sponsor 
Provided by the sponsor 
Packaging and Labeling 
Study intervention will be provided as 
bulk powder for extemporaneous 
preparation of oral suspensions. 
Study intervention will be provided 
as bulk powder for 
extemporaneous preparation of oral 
suspensions. 


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Study Arm(s) 
Arm Title 
Cohort 1 
Cohort 2 
Cohort 3 (Optional) 
Arm Type 
Experimental 
Experimental 
Experimental 
Arm Description 
Participants will receive 
up to 4 dose levels of 
PF-07328948 and up to 
2 matching placebo. 
Doses will be 
administered as oral 
suspensions as 
escalating single doses 
to be determined 
Participants will receive 
up to 4 dose levels of 
PF-07328948 and up to 
2 matching placebo. 
Doses will be 
administered as oral 
suspensions as 
escalating single doses 
to be determined 
Participants will receive 
up to 4 dose levels of PF- 
07328948 and up to 2 
matching placebo. Doses 
will be administered as 
oral suspensions as 
escalating single doses to 
be determined 
Associated Intervention 
Labels 
PF-07328948; Placebo 
PF-07328948; Placebo 
PF-07328948; Placebo 
PF-07328948 and placebo will be provided by Pfizer as bulk powders for extemporaneous 
preparation of oral suspensions at the CRU. 
PF-07328948 and placebo will be presented to the participants in individual dosing 
containers. 
6.1.1. Administration 
For fasted period(s): 
• Following an overnight fast of at least 10 hours, participants will receive study 
intervention at approximately 0800 hours (plus or minus 2 hours) without breakfast 
on Day 1. 
For period(s) when an effect of protein-rich meal (ie, MMTT) is investigated: 
• Following an overnight fast of at least 10 hours, participants will be provided a 
protein-rich meal as 16 ounces of Ensure Plus® breakfast approximately 20 minutes 
prior to administration of study intervention. The entire Ensure Plus® meal is to be 
consumed within 10 minutes with study intervention administered approximately 
10 minutes after completion of the meal at 0 hour on Day 1 (Section 5.3.2.) 
For all periods, investigator site personnel will administer a single oral dose of study 
intervention on Day 1 of each period with ambient temperature water to a total volume of 
approximately 240 mL. Administer study intervention according to the EDR. 
6.2. Preparation, Handling, Storage, and Accountability 
1. The investigator or designee must confirm that appropriate conditions (eg, 
temperature) have been maintained during transit for all study interventions received 
and any discrepancies are reported and resolved before use of the study intervention. 


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2. Only participants enrolled in the study may receive study intervention and only 
authorized site staff may supply, prepare, and/or administer study intervention. 
3. All study interventions must be stored in a secure, environmentally controlled, and 
monitored (manual or automated recording) area in accordance with the labeled 
storage conditions with access limited to the investigator and authorized site staff. At 
a minimum, daily minimum and maximum temperatures for all site storage locations 
must be documented and available upon request. Data for nonworking days must 
indicate the minimum and maximum temperatures since previously documented upon 
return to business. 
4. Any excursions from the study intervention label storage conditions should be 
reported to Pfizer upon discovery along with actions taken. The site should actively 
pursue options for returning the study intervention to the labeled storage conditions, 
as soon as possible. Once an excursion is identified, the study intervention must be 
quarantined and not used until Pfizer provides permission to use the study 
intervention. Specific details regarding the excursion definition and information to 
report for each excursion will be provided to the site in the PCRU site procedures. 
5. Any storage conditions stated in the SRSD will be superseded by the storage 
conditions stated on the label. 
6. Study interventions should be stored in their original containers. 
7. The investigator, institution, head of the medical institution (where applicable), or 
authorized site staff is responsible for study intervention accountability, 
reconciliation, and record maintenance (ie, receipt, reconciliation, and final 
disposition records), such as the IPAL or sponsor-approved equivalent. All study 
interventions will be accounted for using a study intervention accountability 
form/record. 
8. Further guidance and information for the final disposition of unused study 
interventions are provided in the PCRU’s site procedures. All destruction must be 
adequately documented. If destruction is authorized to take place at the investigator 
site, the investigator must ensure that the materials are destroyed in compliance with 
applicable environmental regulations, institutional policy, and any special instructions 
provided by Pfizer. 
Upon identification of a product complaint, notify the sponsor within 1 business day of 
discovery. 
6.2.1. Preparation and Dispensing 
Within this protocol, preparation refers to the investigator site activities performed to make 
the study intervention ready for administration or dispensing to the participant by qualified 
staff. Dispensing is defined as the provision of study intervention, concomitant treatments, 
and accompanying information by qualified staff member(s) to a healthcare provider, 


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participant, in accordance with this protocol. Local health authority regulations or 
investigator site guidelines may use alternative terms for these activities. 
PF-07328948 and placebo oral dosing suspensions will be prepared in the CRU by 
2 operators, 1 of whom is a pharmacist. Details of dose preparation will be given in a 
separate EDR. Prepared doses will be provided in unit dose containers and labeled in 
accordance with Pfizer regulations and the investigator site’s labeling requirements. 
PF-07328948 and placebo will be prepared by qualified unblinded site personnel according 
to the EDR. Blinded study intervention will be administered in a blinded fashion to the 
participant. 
6.3. Assignment to Study Intervention 
The investigator will assign participant numbers to the participants as they are screened for 
the study. Pfizer will provide a randomization schedule to the investigator and, in accordance 
with the randomization numbers, the participant will receive the study treatment regimen 
assigned to the corresponding randomization number. 
6.4. Blinding 
This is a double-blind (sponsor-unblinded) study. 
6.4.1. Blinding of Participants 
Participants will be blinded to their assigned study intervention. 
6.4.2. Blinding of Site Personnel 
Investigators and other site staff will be blinded to participants’ assigned study intervention. 
Participants will be assigned to receive study intervention according to the assigned treatment 
group from the 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 or 
dispensing. 
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. 
PCRU Pharmacy staff responsible for preparing all study intervention will be unblinded. 
PCRU site staff providing technical system support to the Pharmacy staff, and supporting 
blinded laboratory data processes will be unblinded. These site staff providing system 
support are not involved in any data collection or clinic floor activities. 


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6.4.3. Blinding of the Sponsor 
As this is a sponsor-open study, a limited number of the sponsor’s team members (excluding 
site staff) may conduct unblinded reviews of the data during the course of the study for the 
purpose of safety and tolerability assessment, facilitating doseescalation 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. 
6.4.4. Breaking the Blind 
The method for breaking the blind in this study will be manual. In case of an emergency, the 
investigator has the sole responsibility for determining if unblinding of a participant’s 
treatment assignment is warranted. Participant safety must always be the first consideration 
in making such a determination. If the investigator decides that unblinding is warranted, the 
investigator should make every effort to contact the study medical monitor prior to 
unblinding a participant’s treatment assignment unless this could delay further management 
of the participant. If a participant’s treatment assignment is unblinded, the sponsor must be 
notified within 24 hours after breaking the blind. When the blinding code is broken, the 
reason must be fully documented in a CRF. 
Blood specimens will be obtained from all participants for PK analysis to maintain the study 
blind at the investigator site. Only the investigator site staff will be blinded to study 
treatment. Other Pfizer personnel will be unblinded to participant treatments in order to 
permit real-time interpretation of the safety and PK data; and provide information necessary 
to potentially alter the dose-escalation sequence. The blinded study monitor, if assigned, will 
remain blinded to treatment until all monitoring for the study has been completed. Specimens 
from participants randomized to placebo will not be routinely analyzed. To minimize the 
potential for bias, treatment randomization information will be kept confidential by Pfizer 
unblinded personnel and will not be released to the blinded investigator or blinded 
investigator site personnel until the study database has been locked or the investigator 
requests unblinding for safety reasons. 
6.5. Study Intervention Compliance 
When the individual dose for a participant is prepared from a bulk supply, the preparation of 
the dose will be confirmed by a second qualified member of the study site staff. 
When participants are dosed at the site, they will receive study intervention directly from the 
investigator or designee, under medical supervision. The date and time of each dose 
administered in the clinic will be recorded in the source documents and recorded in the CRF. 
Study site personnel will examine each participant’s mouth to ensure that the study 
intervention was ingested. 
6.6. Dose Modification 
The decision to proceed to the next dose level of PF-07328948 (either an increase or a 
decrease) will be made by the study team and the investigator based on safety, tolerability, 
and preliminary PK data obtained in at least 6 participants (including at least 1 placebo 


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participant) at the prior dose level. Safety data and PK data through at least 48 hours and 
24 hours post-dose, respectively, will be reviewed. 
The dosing schedule may also be adjusted to expand a dosing cohort to further evaluate 
safety, tolerability, PK, and/or PD findings at a given dose level or to add cohorts to evaluate 
additional dose levels or repeat dose levels. The study procedures for these additional 
participant(s)/cohort(s) will be the same as that described for other study participants/cohorts. 
6.6.1. Dose Escalation and Stopping Rules 
Precautionary sentinel dosing will be used in periods where escalating doses of PF-07328948 
will be evaluated and may be omitted when repeating a dose level or administering a lower 
dose level than previously evaluated. Two participants (1 receiving PF-07328948 and 1 
receiving placebo) within a period will be dosed initially before the remaining participants of 
that period are dosed. Safety and tolerability data through at least 24 hours post-dose for the 
sentinel participants will be reviewed prior to dosing the remaining participants of that 
period. 
Dose escalation stopping rules will be used to determine whether the maximal tolerated dose 
has been attained. Dose escalation may be stopped if it is determined that the limits of safety 
and/or tolerability have been reached. This decision will be made after a discussion takes 
place between the sponsor study team and the investigator. The sponsor study team may not 
overrule the investigator’s decision to stop dose escalation. If dose escalation is stopped 
because of any of these criteria, additional cohorts may receive the same or lower doses of 
the study intervention. 
The dose escalation will be terminated based on the following criteria: 
• If 50% or more of the participants receiving active drug at a given dose level (but not 
participants receiving placebo) develop similar clinically significant laboratory, ECG, 
or vital sign abnormalities, in the same organ class, indicating dose-limiting 
intolerance. 
• Severe nonserious AEs, considered as, at least, possibly related to study intervention 
administration, in 2 participants at a given dose level (but not participants receiving 
placebo), independent of within or not within the same system organ class, indicating 
dose-limiting intolerance. 
• Dosing will be paused for any SAE that occurs in a participant receiving active 
treatment until causality is fully assessed by the PI and sponsor. Dosing may resume 
if the SAE is determined to be not drug-related by the PI and sponsor. If the SAE is 
determined to be either drug-related or unknown, either dosing will cease or the SAE 
will be evaluated by the sponsor’s protocol review committee (or similar review 
group), which is independent of the study team and investigators. If the protocol 
review committee determines that dosing may resume, a plan that mitigates risks to 
participants with the resumption of dosing will be implemented. Such a plan could 


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include a revision of inclusion/exclusion criteria, repeating or reducing the dose, or 
adding appropriate safety monitoring. 
• It is determined that the limit of safety and/or tolerability has been reached. This 
decision will be made following discussions between the study team and the 
investigator. 
• Other findings that, at the discretion of the study team and investigator, indicate that 
dose escalation should be halted. 
• If, at any dose level, the average exposure reaches or exceeds the PK stopping limits: 
Unbound Cmax of 285 ng/mL; or unbound AUC24 of 3250 ng•h/mL. 
• If, based on the observed data, the group mean Cmax,u or AUC24,u of the next planned 
dose is projected to exceed the escalation limits, that dose will not be explored. 
Modified doses may be explored if they are not expected to exceed PK stopping 
criteria. 
Progression to the next dose level will occur if the last dose level is well tolerated and after 
satisfactory review of the available safety and PK data. 
6.7. Continued Access to Study Intervention After the End of the Study 
No study intervention will be provided to participants at the end of their study participation. 
It is expected that participants will be treated as required with standard-of-care treatments, as 
advised by their usual care physician. 
6.8. Treatment of Overdose 
For this study, any dose of PF-07328948 greater than 3000 mg within a 24-hour time period 
will be considered an overdose. 
There is no specific treatment for an overdose. 
In the event of an overdose, the investigator or treating physician should: 
1. Contact the study medical monitor within 24 hours. 
2. Closely monitor the participant for any AEs/SAEs and laboratory abnormalities as 
medically appropriate and at least until the next scheduled follow-up. 
3. Document the quantity of the excess dose as well as the duration of the overdose in 
the CRF. 
4. Overdose is reportable to Pfizer Safety only when associated with an SAE. 


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5. Obtain a blood sample for PK analysis within 3 days from the date of the last dose of 
study intervention if requested by the study 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 study medical monitor as needed based on the clinical evaluation of the 
participant. 
6.9. Prior and Concomitant Therapy 
Use of prescription or nonprescription drugs and dietary and herbal supplements are 
prohibited within 7 days or 5 half-lives (whichever is longer) prior to the first dose of study 
intervention through the last PK collection, with the exception of moderate/strong CYP3A 
inducers or time-dependent inhibitors which are prohibited within 14 days plus 5 half-lives 
prior to the first dose of study intervention. Limited use of nonprescription medications that 
are not believed to affect participant safety or the overall results of the study may be 
permitted on a case-by-case basis following approval by the sponsor. 
Acetaminophen/paracetamol may be used at doses of ≤1 g/day. 
Females taking hormone replacement therapy may be eligible to participate in this study if 
they are willing to discontinue therapy at least 28 days prior to the first dose of study 
treatment and remain off hormonal therapy for the duration of the study. 
All concomitant treatments taken during the study must be recorded with indication, daily 
dose, and start and stop dates of administration. All participants will be questioned about 
concomitant treatment at each clinic visit. 
Treatments taken within 28 days before the first dose of study intervention will be 
documented as a prior treatment. Treatments taken after the first dose of study intervention 
will be documented as concomitant treatments. 
6.9.1. Rescue Medicine 
There is no rescue therapy to reverse the AEs observed with PF-07328948; standard medical 
supportive care must be provided to manage the AEs. 
7. DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL 
7.1. Discontinuation of Study Intervention 
It may be necessary for a participant to permanently discontinue study intervention. Reasons 
for permanent discontinuation of study intervention include the following: adverse events, or 
some other (administrative) reasons. 
Note that discontinuation of study intervention does not represent withdrawal from the study. 
If study intervention is permanently discontinued, the participant should remain in the study 
to be evaluated for ongoing AEs. See the SoA for data to be collected at the time of 


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discontinuation of study intervention and follow-up for any further evaluations that need to 
be completed. 
In the event of discontinuation of study intervention, it must be documented on the 
appropriate CRF/in the medical records whether the participant is discontinuing further 
receipt of study intervention or also from study procedures, posttreatment study follow-up, 
and/or future collection of additional information. 
7.1.1. ECG Changes 
A participant who meets either of the following bulleted criteria based on the average of 
triplicate ECG readings will be withdrawn from the study intervention. 
• QTcF 500 ms. 
• Change from baseline: QTcF 60 ms. 
If a clinically significant finding is identified (including, but not limited to, changes from 
baseline in QTcF after enrollment), the investigator or qualified designee will determine if 
the participant can continue in the study and if any change in participant management is 
needed. This review of the ECG printed at the time of collection must be documented. Any 
new clinically relevant finding should be reported as an AE. 
7.1.2. Potential Cases of Acute Kidney Injury 
Participants exposed to study intervention demonstrating transient or sustained increase in 
SCr (with decrease in SCr-based eGFR or eCrCL) require expedited evaluation to 
differentiate AKI from DICI. DICI is defined as transporter-mediated effect related to altered 
renal tubular creatinine handling without histological injury. 
Differentiating Acute Kidney Injury from Drug-Induced Creatinine Increase: 
Both AKI and DICI are associated with 
• confirmed Scr increase ≥0.3 mg/dL (≥26.5 µmol/L) within 48 hours 
OR 
• confirmed Scr increase ≥1.5 times baseline (known or suspected to have occurred 
within the prior 7 days). 
AKI is associated with 
• simultaneous, confirmed SCys increase and confirmed Scr increase AND decrease in 
Scr-based eGFR and combined Scr-Scys-based eGFR (where applicable), 
OR 


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• confirmed albuminuria increase 
OR 
• urine volume <0.5mL/kg/h for 6 consecutive hours. 
DICI is associated with 
• confirmed Scr increase without confirmed increase in reflex SCys 
AND 
• confirmed Scr-based eGFR decrease without confirmed combined Scr-Scys-based 
eGFR decrease (where applicable). 
Confirmed post-baseline decrease in kidney function should be assessed individually based 
on clinical judgment. Cases wherein uncertainty remains, the investigator can review the case 
with the sponsor. Consult the Kidney Safety Council if such a situation occurs during the 
study for support if needed. 
The participant should return to the site for evaluation as soon as possible, preferably within 
48 hours of awareness of the abnormal results. Evaluation should include physical 
examination, laboratory tests, detailed medical and surgical history, review of all medications 
(including recreational drugs and supplements [herbal]), family history, sexual history, travel 
history, blood transfusion, and potential occupational exposure to chemicals. If appropriate, 
nephrology consultation may be recommended to facilitate differentiation of renal 
parenchymal disease, pre-renal azotemia, and post-renal obstruction. All confirmed cases of 
clinically relevant decrease in kidney function should be considered potential cases of DIKI 
if no other reason for the kidney function abnormalities has been found. 
If ≥2 healthy participants in a given period/treatment arm are noted to have confirmed AKI, 
an assessment of whether the finding may be considered an adverse drug reaction should be 
undertaken. 
7.1.3. COVID-19 
If a participant has COVID-19 during the study, this should be reported as an AE or SAE (as 
appropriate) and appropriate medical intervention provided. Study treatment may continue 
unless the investigator/treating physician is concerned about the safety of the participant, in 
which case temporary or permanent discontinuation may be required. 
It is recommended that the investigator discuss temporary or permanent discontinuation of 
study intervention with the study medical monitor. 


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7.2. Participant Discontinuation/Withdrawal From the Study 
A participant may withdraw from the study at any time at their own request. Reasons for 
discontinuation from the study include the following: 
• Refused further study procedure; 
• Lost to follow-up; 
• Death; 
• Study terminated by sponsor; 
• Discretion of the investigator or sponsor for safety or behavioral reasons, or the 
inability of the participant to comply with the protocol required schedule of study 
visits or procedures. 
At the time of discontinuing from the study, if possible, an early discontinuation visit should 
be conducted. See the SoA for assessments to be collected at the time of study 
discontinuation and follow-up and for any further evaluations that need to be completed. 
The early discontinuation visit applies only to participants who are enrolled/randomized and 
then are prematurely withdrawn from the study. Participants should be questioned regarding 
their reason for withdrawal. 
The participant will be permanently discontinued from the study intervention and the study at 
that time. 
If a participant withdraws from the study, they 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 will be performed and no 
additional data will be collected. The sponsor may retain and continue to use any data 
collected before such withdrawal of consent. 
7.2.1. Withdrawal of Consent 
Participants who request to discontinue receipt of study intervention will remain in the study 
and must continue to be followed for protocol-specified follow-up procedures. The only 
exception to this is when a participant specifically withdraws consent for any further contact 
with them or persons previously authorized by the participant to provide this information. 
Participants should notify the investigator in writing of the decision to withdraw consent 
from future follow-up, whenever possible. The withdrawal of consent should be explained in 
detail in the medical records by the investigator, as to whether the withdrawal is only from 
further receipt of study intervention or also from study procedures and/or posttreatment study 


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


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shipment), then participants do not require rescreening if the laboratory results obtained prior 
to first dose administration meet eligibility criteria. 
A participant who qualified for this protocol but did not enroll from an earlier cohort/group 
may be used in a subsequent cohort/group without rescreening, provided laboratory results 
obtained prior to the first dose administration meet eligibility criteria for this study. In 
addition, other clinical assessments or specimen collections, eg, retained research samples, 
may be used without repeat collection, as appropriate. 
Every effort should be made to ensure that protocol-required tests and procedures are 
completed as described. However, it is anticipated that from time to time there may be 
circumstances outside the control of the investigator that 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 they have 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. 
Any safety, laboratory, or analyte results that have been collected for the purposes of this 
study and could unblind the study will not be reported to investigative sites or other blinded 
personnel until the study has been unblinded. 
If an IV catheter is utilized for blood sample collections, ECGs and vital sign assessments 
(pulse rate and BP) should be collected prior to the insertion of the catheter. 
For samples being collected and shipped, detailed collection, processing, storage, and 
shipment instructions and contact information will be provided to the investigator site prior 
to initiation of the study. 
The total blood sampling volume for individual participants in this study is approximately 
515-550 mL. The actual collection times of blood sampling may change. Additional blood 
samples may be taken for safety assessments at times specified by Pfizer, provided the total 
volume taken during the study does not exceed 550 mL during any period of 56 consecutive 
days. 
To prepare for study participation, participants will be instructed on the information in the 
Lifestyle Considerations and Prior and Concomitant Therapy sections of the protocol. 
8.2. Efficacy Assessments 
No efficacy assessments are being conducted in this study. 
8.3. Safety Assessments 
Planned time points for all safety assessments are provided in the SoA. Unscheduled safety 
measurements may be obtained at any time during the study to assess any perceived safety 
issues. 


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8.3.1. Physical Examinations 
Physical examinations are to be performed at the nominal timepoints specified in the SoA. 
Additional physical examinations will be permitted, as necessary, to ensure appropriate 
collection of safety data. 
A complete physical examination will include, at a minimum, head, ears, eyes, nose, mouth, 
skin, heart and lung examinations (including lung auscultation), lymph nodes, and 
gastrointestinal, musculoskeletal, and neurological systems. 
A brief physical examination will include, at a minimum, assessments of general appearance, 
the respiratory (including lung auscultation) and cardiovascular systems, and 
participant-reported symptoms. 
Physical examinations may be conducted by a physician, trained physician’s assistant, or 
nurse practitioner as acceptable according to local regulation. 
Height and weight will also be measured and recorded as per the SoA. For measuring weight, 
a scale with appropriate range and resolution is used and must be placed on a stable, flat 
surface. Participants must remove shoes, bulky layers of clothing, and jackets so that only 
light clothing remains. They must also remove the contents of their pockets and remain still 
during measurement of weight. 
Physical examination findings collected during the study will be considered source data and 
will not be required to be reported, unless otherwise noted. Any untoward physical 
examination findings that are identified during the active collection period and meet the 
definition of an AE or SAE (Appendix 3) must be reported according to the processes in 
Sections 8.4.1 to 8.4.3. 
8.3.2. Neurological Examinations 
Neurological examinations as part of the physical exam may be conducted by a physician, 
trained physician's assistant, or nurse practitioner as acceptable according to local regulation. 
The neurological exam will consist of assessment of higher cortical function, the cranial 
nerves, motor function, deep tendon reflexes, sensory exam, and coordination and gait. The 
exam should be done to the extent needed to assess the participant for any potential changes 
in neurological status, as determined by the investigator (or designee). 
8.3.3. Vital Signs 
8.3.3.1. Blood Pressure and Pulse Rate 
Supine BP will be measured with the participant’s arm supported at the level of the heart, and 
recorded to the nearest mm Hg after approximately 5 minutes of rest. The same arm 
(preferably the dominant arm) will be used throughout the study. Participants should be 
instructed not to speak during measurements. When triplicate measurements of supine BP or 
pulse rate are required per SoA, measurements should be collected 2-4 minutes apart. 


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The same properly sized and calibrated BP cuff will be used to measure BP each time. The 
use of an automated device for measuring BP and pulse rate is acceptable; however, when 
done manually, pulse rate will be measured in the brachial/radial artery for at least 
30 seconds. When the timing of these measurements coincides with a blood collection, BP 
and pulse rate should be obtained prior to the nominal time of the blood collection. 
8.3.3.2. Respiratory Rate 
Respiratory rate will be measured after approximately 5 minutes rest in supine position by 
observing and counting the respirations of the participant for 30 seconds and multiplied by 2. 
When blood pressure is to be taken at the same time, respiration measurement will be done 
during the 5 minutes of rest and before blood pressure measurement. 
Additional collection times, or changes to collection times, of vital signs will be permitted, as 
necessary, to ensure appropriate collection of safety data. 
Any untoward vital sign findings that are identified during the active collection period and 
meet the definition of an AE or SAE (Appendix 3) must be reported according to the 
processes in Sections 8.4.1 to 8.4.3. 
8.3.4. Electrocardiograms 
Standard 12-lead ECGs utilizing limb leads (with a 10-second rhythm strip) should be 
collected at times specified in the SoA section of this protocol using an ECG machine that 
automatically calculates the HR and measures PR interval, QT interval, QTcF, and QRS 
complex. Alternative lead placement methodology using torso leads (eg, Mason-Likar) 
should not be used given the potential risk of discrepancies with ECGs acquired using 
standard limb lead placement. All scheduled ECGs should be performed after the participant 
has rested quietly for at least 5 minutes in a supine position. 
Triplicate 12-lead ECGs will be obtained approximately 2-4 minutes apart; the average of the 
triplicate ECG measurements collected at -1.0, -0.5, and 0 hours pre-dose on Day 1 of each 
period will serve as each participant’s baseline QTcF value for that period. 
To ensure safety of the participants, a qualified individual at the investigator site will make 
comparisons to baseline measurements. Additional ECG monitoring will occur if a) the mean 
value from the triplicate measurements for any postdose QTcF interval is increased by 
≥60 ms from the baseline and is >450 ms; or b) an absolute QT value is ≥500 ms for any 
scheduled ECG. If either of these conditions occurs, then a single ECG measurement must be 
repeated at least hourly until QTcF values from 2 successive ECGs fall below the threshold 
value that triggered the repeat measurement. 
For single ECG collections, additional ECG monitoring will occur if a) a postdose QTcF 
interval is increased by ≥60 ms from the baseline and is >450 ms; or b) an absolute QT value 
is ≥500 ms for any scheduled ECG. If either of these conditions occurs, then 2 additional 
ECGs will be collected approximately 2 -4 minutes apart to confirm the original 
measurement. If the QTcF values from these repeated ECGs remain above the threshold 


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value, then a single ECG must be repeated at least hourly until QTc values from 2 successive 
ECGs fall below the threshold value that triggered the repeat measurement. 
If a) a postdose QTcF interval remains ≥60 ms from the baseline and is >450 ms; or b) an 
absolute QT value is ≥500 ms for any scheduled ECG for greater than 4 hours (or sooner, at 
the discretion of the investigator); or c) QTcF value get progressively longer, the participant 
should undergo continuous ECG monitoring. A cardiologist should be consulted if QTcF 
values do not return to less than the criteria listed above after 8 hours of monitoring (or 
sooner, at the discretion of the investigator). 
In some cases, it may be appropriate to repeat abnormal ECGs to rule out improper lead 
placement as contributing to the ECG abnormality. It is important that leads be placed in the 
same positions each time in order to achieve precise ECG recordings. If a machine-read 
QTcF value is prolonged, as defined above, repeat measurements may not be necessary if a 
qualified medical provider’s interpretation determines that the QTcF values are in the 
acceptable range. 
ECG values of potential clinical concern are listed in Appendix 8. 
8.3.4.1. 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. 
Telemetry should be collected using a centralized system that also allows for the storage and 
advanced analysis of all recorded data in order to preserve important events for future 
evaluations. Holter monitoring should not be used in parallel with continuous telemetry, 
unless it is the only means of data storage available at the investigator site, or verifiable 
arrhythmia quantification is required. To establish a baseline, telemetry should be recorded 
for at least a 2-hour interval before dosing in Period 1. This may be done immediately prior 
to dosing or at some 2-hour continuous interval in the 24 hours prior to dosing, as long as the 
recording is performed when the participant is awake. Telemetry may be stopped within a 
reasonably short period of time prior to dosing, in order to avoid interference with study 
operations conducted immediately before dosing. However, it is expected that the telemetry 
leads will be in place and the system connected prior to dosing. 
8.3.5. Clinical Safety Laboratory Assessments 
See Appendix 2 for the list of clinical safety laboratory tests to be performed and the SoA for 
the timing and frequency. All protocol-required laboratory assessments, as defined in 
Appendix 2, must be conducted in accordance with the laboratory manual and the SoA. 
Unscheduled clinical laboratory measurements may be obtained at any time during the study 
to assess any perceived safety issues. 


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The investigator must review the laboratory report, document this review, and record any 
clinically significant changes occurring during the study in the AE section of the CRF. 
Clinically significant abnormal laboratory test findings are those that are not associated with 
the underlying disease, unless judged by the investigator to be more severe than expected for 
the participant’s condition. 
All laboratory tests with values considered clinically significant and abnormal during 
participation in the study or within 28 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 study medical monitor. 
If such values do not return to normal/baseline within a period of time judged reasonable by 
the investigator, the etiology should be identified and the sponsor notified. 
See Appendix 6 for suggested actions and follow-up assessments in the event of potential 
DILI. 
See Appendix 7 for instructions for laboratory testing to monitor kidney function and 
reporting laboratory test abnormalities. 
Participants may undergo random urine drug testing at the discretion of the investigator. 
Drug testing conducted prior to dosing must be negative for participants to receive study 
intervention. 
8.4. Adverse Events, Serious Adverse Events, and Other Safety Reporting 
The definitions of an AE and an SAE can be found in Appendix 3. 
AEs may arise from symptoms or other complaints reported to the investigator by the 
participant (or, when appropriate, by a caregiver, surrogate, or the participant’s legally 
authorized representative), or they may arise from clinical findings of the investigator or 
other healthcare providers (clinical signs, test results, etc). 
The investigator and any qualified designees are responsible for detecting, documenting, and 
recording events that meet the definition of an AE or SAE and remain responsible to pursue 
and obtain adequate information both to determine the outcome and to assess whether the 
event meets the criteria for classification as an SAE or caused the participant to discontinue 
the study intervention (see Section 7.1). 
During the active collection period as described in Section 8.4.1, each participant will be 
questioned about the occurrence of AEs in a nonleading manner. 
In addition, the investigator may be requested by Pfizer Safety to obtain specific follow-up 
information in an expedited fashion. 


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8.4.1. Time Period and Frequency for Collecting AE and SAE Information 
The time period for actively eliciting and collecting AEs and SAEs (“active collection 
period”) for each participant begins from the time the participant provides informed consent, 
which is obtained before undergoing any study-related procedure and/or receiving study 
intervention), through and including a minimum of 28 calendar days, except as indicated 
below, after the last administration of the study intervention. 
Follow-up by the investigator continues throughout the active collection period and until the 
AE or SAE or its sequelae resolve or stabilize at a level acceptable to the investigator. 
When a clinically important AE remains ongoing at the end of the active collection period, 
follow-up by the investigator continues until the AE or SAE or its sequelae resolve or 
stabilize at a level acceptable to the investigator and Pfizer concurs with that assessment. 
For participants who are screen failures, the active collection period ends when screen failure 
status is determined. 
If the participant withdraws from the study and also withdraws consent for the collection of 
future information, the active collection period ends when consent is withdrawn. 
If a participant permanently discontinues or temporarily discontinues study intervention 
because of an AE or SAE, the AE or SAE must be recorded on the CRF and the SAE 
reported using the CT SAE Report Form. 
Investigators are not obligated to actively seek information on AEs or SAEs after the 
participant has concluded study participation. However, if the investigator learns of any SAE, 
including a death, at any time after a participant has completed the study, and they consider 
the event to be reasonably related to the study intervention, the investigator must promptly 
report the SAE to Pfizer using the CT SAE Report Form. 
8.4.1.1. Reporting SAEs to Pfizer Safety 
All SAEs occurring in a participant during the active collection period as described in 
Section 8.4.1 are reported to Pfizer Safety on the CT SAE Report Form immediately upon 
awareness and under no circumstance should this exceed 24 hours, as indicated in 
Appendix 3. The investigator will submit any updated SAE data to the sponsor within 
24 hours of its being available. 
8.4.1.2. Recording Nonserious AEs and SAEs on the CRF 
All nonserious AEs and SAEs occurring in a participant during the active collection period, 
which begins after obtaining informed consent as described in Section 8.4.1, will be recorded 
on the AE section of the CRF. 
The investigator is to record on the CRF all directly observed and all spontaneously reported 
AEs and SAEs reported by the participant. 


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As part of ongoing safety reviews conducted by the sponsor, any nonserious AE that is 
determined by the sponsor to be serious will be reported by the sponsor as an SAE. To assist 
in the determination of case seriousness, further information may be requested from the 
investigator to provide clarity and understanding of the event in the context of the clinical 
study. 
Reporting of AEs and SAEs for participants who fail screening are subject to the CRF 
requirements as described in Section 5.4. 
8.4.2. Method of Detecting AEs and SAEs 
The method of recording, evaluating, and assessing causality of AEs and SAEs and the 
procedures for completing and transmitting SAE reports are provided in Appendix 3. 
Care will be taken not to introduce bias when detecting AEs and/or SAEs. Open-ended and 
nonleading verbal questioning of the participant is the preferred method to inquire about 
AE occurrences. 
8.4.3. Follow-Up of AEs and SAEs 
After the initial AE or SAE report, the investigator is required to proactively follow each 
participant at subsequent visits/contacts. For each event, the investigator must pursue and 
obtain adequate information until resolution, stabilization, the event is otherwise explained, 
or the participant is lost to follow-up (as defined in Section 7.3). 
In general, follow-up information will include a description of the event in sufficient detail to 
allow for a complete medical assessment of the case and independent determination of 
possible causality. Any information relevant to the event, such as concomitant medications 
and illnesses, must be provided. In the case of a participant death, a summary of available 
autopsy findings must be submitted as soon as possible to Pfizer Safety. 
Further information on follow-up procedures is provided in Appendix 3. 
8.4.4. Regulatory Reporting Requirements for SAEs 
Prompt notification by the investigator to the sponsor of an SAE is essential so that legal 
obligations and ethical responsibilities toward the safety of participants and the safety of a 
study intervention under clinical investigation are met. 
The sponsor has a legal responsibility to notify both the local regulatory authority and other 
regulatory agencies about the safety of a study intervention under clinical investigation. The 
sponsor will comply with country-specific regulatory requirements relating to safety 
reporting to the regulatory authority, IRBs/ECs, and investigators. 
Investigator safety reports must be prepared for SUSARs according to local regulatory 
requirements and sponsor policy and forwarded to investigators as necessary. 


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An investigator who receives SUSARs or other specific safety information (eg, summary or 
listing of SAEs) from the sponsor will review and then file it along with the SRSD(s) for the 
study and will notify the IRB/EC, if appropriate according to local requirements. 
8.4.5. Environmental Exposure, Exposure During Pregnancy or Breastfeeding, and 
Occupational Exposure 
Environmental exposure, occurs when a person not enrolled in the study as a participant 
receives unplanned direct contact with or exposure to the study intervention. Such exposure 
may or may not lead to the occurrence of an AE or SAE. Persons at risk for environmental 
exposure include healthcare providers, family members, and others who may be exposed. An 
environmental exposure may include EDP, EDB, and occupational exposure. 
Any such exposures to the study intervention under study are reportable to Pfizer Safety 
within 24 hours of investigator awareness. 
8.4.5.1. Exposure During Pregnancy 
An EDP occurs if: 
• A female participant is found to be pregnant while receiving or after discontinuing 
study intervention. 
• A male participant who is receiving or has discontinued study intervention 
inseminates a female partner. 
• A female nonparticipant is found to be pregnant while being exposed or having been 
exposed to study intervention because of environmental exposure. Below are 
examples of environmental EDP: 
• A female family member or healthcare provider reports that she is pregnant after 
having been exposed to the study intervention by ingestion, inhalation, or skin 
contact. 
• A male family member or healthcare provider who has been exposed to the study 
intervention by ingestion, inhalation, or skin contact then inseminates his female 
partner prior to or around the time of conception. 
The investigator must report EDP to Pfizer Safety within 24 hours of the investigator’s 
awareness, irrespective of whether an SAE has occurred. The initial information submitted 
should include the anticipated date of delivery (see below for information related to 
termination of pregnancy). 
• If EDP occurs in a participant 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 


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


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


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8.4.8.1. Lack of Efficacy 
This section is not applicable because efficacy is not expected in this study population. 
8.4.9. Medical Device Deficiencies 
Not applicable. 
8.4.10. Medication Errors 
Medication errors may result from the administration or consumption of the study 
intervention by the wrong participant, or at the wrong time, or at the wrong dosage strength. 
Medication errors are recorded and reported as follows: 
 
Recorded on the 
Medication Error Page 
of the CRF 
Recorded on the 
Adverse Event Page 
of the CRF 
Reported on the CT SAE 
Report Form to Pfizer 
Safety Within 24 Hours of 
Awareness 
All (regardless of whether 
associated with an AE) 
Any AE or SAE associated 
with the medication error 
Only if associated with an 
SAE 
Medication errors include: 
• Medication errors involving participant exposure to the study intervention; 
• Potential medication errors or uses outside of what is foreseen in the protocol that do 
or do not involve the study participant; 
• The administration of expired study intervention; 
• The administration of an incorrect study intervention; 
• The administration of an incorrect dosage; 
• The administration of study intervention that has undergone temperature excursion 
from the specified storage range, unless it is determined by the sponsor that the study 
intervention under question is acceptable for use. 
Such medication errors occurring to a study participant are to be captured on the medication 
error page of the CRF, which is a specific version of the AE page. 
Whether or not the medication error is accompanied by an AE, as determined by the 
investigator, the medication error is recorded on the medication error page of the CRF and, if 
applicable, any associated AE(s), serious and nonserious, are recorded on the AE page of the 
CRF. 


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In the event of a medication dosing error, the sponsor should be notified within 24 hours. 
Medication errors should be reported to Pfizer Safety within 24 hours on a CT SAE Report 
Form only when associated with an SAE. 
8.5. Pharmacokinetics 
8.5.1. Plasma for Analysis of PF-07328948 Concentrations 
Blood samples of approximately 3 mL, to provide approximately 1.2 mL of plasma, will be 
collected for measurement of plasma concentrations of PF-07328948 into appropriately 
labeled tubes containing K2EDTA as specified in the SoA. Instructions for the collection 
including any potential additive information, processing, aliquoting, handling, storage, and 
shipment of biological samples will be provided in the laboratory manual or by the sponsor. 
The actual date and time (24-hour clock time) of each sample will be recorded. 
The actual times may change, but the number of samples will remain the same. All efforts 
will be made to obtain the samples at the exact nominal time relative to dosing. Collection of 
samples up to and including 10 hours after dose administration that are obtained within 
10% of the nominal time relative to dosing (eg, within 6 minutes of a 60-minute sample) will 
not be captured as a protocol deviation, as long as the exact time of the collection is noted on 
the source document and the CRF. Collection of samples more than 10 hours after dose 
administration that are obtained ≤1 hour away from the nominal time relative to dosing will 
not be captured as a protocol deviation, as long as the exact time of the collection is noted on 
the source document and the CRF. This protocol deviation window does not apply to samples 
to be collected more than 10 hours after dose administration at outpatient/follow-up visits 
with visit windows. 
Samples will be used to evaluate the PK of PF-07328948. Samples collected for analyses of 
PF-07328948 plasma concentrations may also be used to evaluate safety aspect related to 
concerns arising during or after the study, for metabolite identification, and/or evaluation of 
the bioanalytical method, or for other internal exploratory purposes. 
 
Samples collected for measurement of plasma concentrations of PF-07328948 will be 
analyzed using a validated analytical method in compliance with applicable SOPs. Potential 
metabolites may be analyzed with either validated or exploratory methods. 
The PK samples must be processed and shipped as indicated in the instructions provided to 
the investigator site to maintain sample integrity. Any deviations from the PK sample 
handling procedure (eg, sample collection and processing steps, interim storage or shipping 
conditions), including any actions taken, must be documented and reported to the sponsor. 
On a case-by-case basis, the sponsor may make a determination as to whether sample 
integrity has been compromised. 


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Drug concentration information that may unblind the study will not be reported to 
investigator sites or blinded personnel until the study has been unblinded. 
Any changes in the timing or addition of time points for any planned study assessments must 
be documented and approved by the relevant study team member and then archived in the 
sponsor and site study files, but will not constitute a protocol amendment. The IRB/EC will 
be informed of any safety issues that require alteration of the safety monitoring scheme or 
amendment of the ICD. 
8.6. Genetics 
8.6.1. Specified Genetics 
Specified genetic analyses are not evaluated in this study. 
8.6.2. Retained Research Samples for Genetics 
A 2-mL blood sample optimized for DNA isolation Prep D1.5 will be collected according to 
the SoA, as local regulations and IRBs/ECs allow. 
Retained Research Samples may be used for research related to the study intervention(s). 
Genes and other analytes (eg, proteins, RNA, nondrug metabolites) may be studied using the 
retained samples. 
See Appendix 5 for information regarding genetic research. Details on processes for 
collection and shipment of these samples can be found in the lab manual and other 
supporting documentation. 
8.7. Pharmacodynamics 
Collection of samples for pharmacodynamics research is also part of this study. 
The following samples for pharmacodynamics research are required and will be collected 
from all participants in this study as specified in the SoA. 
• Retained Prep B1.5 research sample (Period 1 and Period 4 only); 
• Retained Prep B2.5 research sample (Period 1 and Period 4 only); 
• 
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8.7.1. Biomarkers 
8.7.1.1. Specified Gene Expression (RNA) Research 
Specified gene expression (RNA) research is not included in this study. 


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8.7.1.2. Specified Protein Research 
Specified protein research is not included in this study. 
8.7.1.3. Specified Metabolomic Research 
Specified metabolomic research is not included in this study. 
8.7.1.4. Retained Research Samples for Biomarker 
These Retained Research Samples will be collected in this study: 
• 2 mL whole blood Prep B1.5 optimized for plasma (at each sampling time as outlined 
in the SoA); 
• 2 mL whole blood Prep B2.5 optimized for serum (at each sampling time as outlined 
in the SoA). 
Retained Research Samples will be collected as local regulations and IRB/ECs allow 
according to the SoA. 
Retained Research Samples may be used for research related to the study intervention(s). 
Genes and other analytes (eg, proteins, RNA, nondrug metabolites) may be studied using the 
retained samples. 
See Appendix 5 for information regarding genetic research. Details on processes for 
collection and shipment of these samples can be found in the lab manual and other 
supporting documentation. 
8.7.2. Pharmacodynamics Assessments 
 
Instructions for the collection, processing, handling, storage, and shipping of biological 
samples will be provided in the laboratory manual or by the sponsor. The actual date and 
time (24-hour clock time) of each sample will be recorded. 
The actual times may change, but the number of samples will remain the same. All efforts 
will be made to obtain the samples at the exact nominal time relative to dosing. Collection of 
samples up to and including 10 hours after dose administration that are obtained within 
10% of the nominal time relative to dosing (eg, within 6 minutes of a 60-minute sample) will 
not be captured as a protocol deviation, as long as the exact time of the collection is noted on 
the source document and the CRF. Collection of samples more than 10 hours after dose 
administration that are obtained ≤1 hour away from the nominal time relative to dosing will 
not be captured as a protocol deviation, as long as the exact time of the collection is noted on 
the source document and the CRF. This protocol deviation window does not apply to samples 


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Samples collected for analyses of PD may be used to evaluate safety aspect related to 
concerns arising during or after the study, for metabolite identification and/or evaluation of 
bioanalytical method, or for other internal exploratory purposes. 
Genetic analyses will not be performed on these plasma unless consent for this was included 
in the informed consent. Participant confidentiality will be maintained. 
 
The PD samples must be processed and shipped as indicated in the instructions provided to 
the investigator site to maintain sample integrity. Any deviations from the PD sample 
handling procedures (eg, sample collection and processing steps, interim storage, or shipping 
conditions), including any actions taken, must be documented and reported to the sponsor. 
On a case-by-case basis, the sponsor may make a determination as to whether sample 
integrity has been compromised. 
PD concentration information that may unblind the study will not be reported to investigator 
sites or blinded personnel until the study has been unblinded. 
Any changes in the timing or addition of time points for any planned study assessments must 
be documented and approved by the relevant study team members and then archived in the 
sponsor and site study files, but will not constitute a protocol amendment. The IRB/EC will 
be informed of any safety issues that require alteration of the safety monitoring scheme or 
amendment of the ICD. 
 
 
 
8.8. Immunogenicity Assessments 
Immunogenicity assessments are not included in this study. 
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8.9. Health Economics 
Health economics/medical resource utilization and health economics parameters are not 
evaluated in this study. 
9. STATISTICAL CONSIDERATIONS 
Detailed methodology for summary and statistical analyses of the data collected in this study 
is outlined here and further detailed in the SAP, which will be maintained by the sponsor. 
The SAP may modify what is outlined in the protocol where appropriate; however, any major 
modifications of the primary endpoint definitions or their analyses will also be reflected in a 
protocol amendment. 
9.1. Statistical Hypothesis 
No formal statistical hypothesis testing will be performed in this study. 
9.2. Analysis Sets 
For purposes of analysis, the following analysis sets are defined: 
 
Participant Analysis 
Set 
Description 
Enrolled 
“Enrolled” means a participant’s agreement to participate in a 
clinical study following completion of the informed consent 
process and randomization to study intervention. A participant 
will be considered enrolled if the informed consent is not 
withdrawn prior to participating in any study activity after 
screening. Potential participants who are screened for the 
purpose of determining eligibility for the study, but do not 
participate in the study, are not considered enrolled, unless 
otherwise specified by the protocol. 
Safety analysis set 
All participants randomly assigned to study intervention and 
who take at least 1 dose of study intervention. Participants will 
be analyzed according to the study intervention they actually 
received. 
PK Concentration Set 
All participants randomly assigned to study intervention and 
who receive at least 1 dose of study intervention and in whom 
at least 1 plasma concentration value is reported. 
PK Parameter Set 
All participants randomly assigned to study intervention and 
who receive at least 1 dose of study intervention and have at 
least 1 of the PK parameters of interest calculated. 
PD analysis set 
All participants randomly assigned to study intervention and 
who receive at least 1 dose of study intervention and in whom 
at least 1 concentration value is reported for any PD endpoint. 


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9.3. Statistical Analyses 
The SAP will be developed and finalized before any analyses are performed and will 
describe the analyses and procedures for accounting for missing, unused, and spurious data. 
This section is a summary of the planned statistical analyses of the primary, secondary and 
tertiary/exploratory endpoints. 
9.3.1. Safety Endpoints 
All safety analyses will be performed on the safety analysis set. 
AEs, ECGs, BP, pulse rate, respiratory rate, continuous cardiac monitoring, and safety 
laboratory data will be reviewed and summarized on an ongoing basis during the study to 
evaluate the safety of participants. Any clinical laboratory, ECG, BP, pulse rate, and 
respiratory rate abnormalities of potential clinical concern will be described. Safety data will 
be presented in tabular and/or graphical format and summarized descriptively, where 
appropriate. 
Medical history and physical examination (including neurological examinations) as 
applicable, collected during the course of the study will be considered source data and will 
not be required to be reported, unless otherwise noted. However, any untoward findings 
identified on physical and/or neurological examinations conducted during the active 
collection period will be captured as AEs, if those findings meet the definition of an AE. 
Data collected at screening that are used for inclusion/exclusion criteria, such as laboratory 
data, ECGs, and vital signs, will be considered source data, and will not be required to be 
reported, unless otherwise noted. Demographic data collected at screening will be reported. 
9.3.1.1. Electrocardiogram Analyses 
Changes from baseline for the ECG parameters (ie, QT interval, heart rate, QTcF interval, PR 
interval, and QRS complex) will be summarized by treatment and time. 
The number (%) of participants with maximum postdose QTcF values and maximum 
increases from baseline in the following categories will be tabulated by treatment: 
 
Safety QTcF Assessment 
 
Degree of Prolongation 
Mild (ms) 
Moderate (ms) 
Severe (ms) 
Absolute value 
>450-480 
>480-500 
>500 
Increase from baseline 
30-60 
>60 
If more than 1 ECG is collected at a nominal time after dose administration (for example, 
triplicate ECGs), the mean of the replicate measurements will be used to represent a single 
observation at that time point. If any of the 3 individual ECG tracings has a QTcF value 
>500 ms, but the mean of the triplicates is not >500 ms, the data from the participant’s 
individual tracing will be described in a safety section of the CSR in order to place the 
>500-ms value in appropriate clinical context. However, values from individual tracings 
within triplicate measurements that are >500 ms will not be included in the categorical 


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analysis unless the average from the triplicate measurements is also >500 ms. Changes from 
baseline will be defined as the change between the postdose QTcF value and the average of 
the pre-dose triplicate values at -1.0, -0.5, 0 hours pre-dose on Day 1. 
In addition, an attempt will be made to explore and characterize the relationship between 
plasma concentration and QT interval length using a PK/PD modeling approach. If a PK/PD 
relationship is found, the impact of participant factors (covariates) on the relationship will be 
examined. The results of such analyses may not be included in the CSR. 
9.3.2. PK Endpoints 
The PK concentration and parameter populations are defined in Section 9.2. 
9.3.2.1. Derivation of PF-07328948 PK Parameters 
The plasma PK parameters for PF-07328948, following oral dose administration, will be 
derived from the plasma concentration-time profiles as detailed in Table 4, as data permit. In 
all cases, actual PK sampling times will be used in the derivation of PK parameters. 
 
Table 4. 
Plasma PF-07328948 PK Parameters 
 
Parameter 
Definition 
Method of Determination 
AUClast 
Area under the plasma 
concentration-time curve from 
time 0 to the time of the Clast 
Linear/Log trapezoidal method 
AUCinf* 
Area under the plasma 
concentration-time curve from 
time 0 extrapolated to infinite time 
AUClast + (Clast*/kel), where Clast* is the predicted 
plasma concentration at the last quantifiable 
timepoint estimated from the log-linear 
regression analysis 
Cmax 
Maximum plasma concentration 
Observed directly from data 
Tmax 
Time for Cmax 
Observed directly from data as time of first 
occurrence 
t½ * 
Terminal elimination half-life 
Loge(2)/kel, where kel is the terminal phase rate 
constant calculated by a linear regression of the 
log-linear concentration-time curve. Only those 
data points judged to describe the terminal 
log-linear decline will be used in the regression. 
CL/F* 
Apparent clearance 
Dose/AUCinf 
Vz/F* 
Apparent volume of distribution 
Dose/(AUCinf∙kel) 
AUClast(dn) 
Dose-normalized AUClast 
AUClast/Dose 
AUCinf(dn)* 
Dose-normalized AUCinf 
AUCinf/Dose 
Cmax(dn) 
Dose-normalized Cmax 
Cmax/Dose 
*As data permits. 


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9.3.2.2. Statistical Methods for PK Data 
Plasma concentrations of PF-07328948 will be summarized descriptively by dose (and 
fasting condition, if appropriate) and nominal PK sampling time. Individual participant and 
median profiles of the plasma concentration-time data will be plotted by dose (and fasting 
condition, if appropriate) using actual (for individual) and nominal (for median) times 
respectively. Median profiles will be presented on both linear and log scales. 
The plasma PK parameters will be summarized descriptively by dose (and fasting condition, 
if appropriate) as applicable. Dose-normalized AUCinf, AUClast, and Cmax will be plotted 
against dose (and fasting condition, if appropriate) using a logarithmic scale, and will include 
individual participant values and the geometric means for each dose. These plots will be used 
to understand the relationship between the PK parameters and dose (and fasting condition, if 
appropriate). 
If the food effect is assessed, a mixed effects ANOVA will be performed separately on the 
natural log transformed AUCinf, AUClast, and Cmax (dose-normalized prior to analysis, if 
appropriate) with fasting condition included as a fixed effect and participant as a random 
effect. Further details of this analysis will be provided in the SAP. 
Additional PK analyses may be performed if deemed appropriate, and may not be included in 
the CSR. 
9.3.3. Tertiary/Exploratory Endpoint(s) Analysis 
The analysis of tertiary/exploratory endpoints will be detailed in the SAP. 
9.3.4. Other Analyses 
Pharmacogenomic or biomarker data from Retained Research Samples may be collected 
during or after the trial and retained for future analyses; the results of such analyses are not 
planned to be included in the CSR. 
9.4. Interim Analyses 
No formal interim analysis will be conducted for this study. However, as this is a 
sponsor-open study, the sponsor will conduct unblinded reviews of the data during the course 
of the study for the purpose of safety and tolerability assessment, facilitating dose-escalation 
decisions, facilitating PK/PD modeling, and/or supporting clinical development. 
9.5. Sample Size Determination 
A sample size of approximately 24 healthy adult participants (up to 3 cohorts of 
approximately 8 participants each) has been chosen based on the need to minimize first 
exposure to humans of a new chemical entity and the requirement to provide adequate safety, 
tolerability, PK and PD assessment at each dose level. At each dose level, approximately 
6 participants are planned to receive PF-07328948 and approximately 2 participants are 
planned to receive placebo with all participants at the end of the study having received up to 
4 doses of PF-07328948 and up to 2 doses of placebo. 


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


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


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Participants who are rescreened are required to sign a new ICD. 
10.1.4. Data Protection 
All parties will comply with all applicable laws, including laws regarding the implementation 
of organizational and technical measures to ensure protection of participant data. 
Participants’ personal data will be stored at the study site in encrypted electronic and/or paper 
form and will be password-protected or secured in a locked room to ensure that only 
authorized study staff have access. The study site will implement appropriate technical and 
organizational measures to ensure that the personal data can be recovered in the event of 
disaster. In the event of a potential personal data breach, the study site will be responsible for 
determining whether a personal data breach has in fact occurred and, if so, providing breach 
notifications as required by law. 
To protect the rights and freedoms of participants with regard to the processing of personal 
data, participants will be assigned a single, participant-specific numerical code. Any 
participant records or data sets that are transferred to the sponsor will contain the numerical 
code; participant names will not be transferred. All other identifiable data transferred to the 
sponsor will be identified by this single, participant-specific code. The study site will 
maintain a confidential list of participants who participated in the study, linking each 
participant’s numerical code to their actual identity and medical record ID. In case of data 
transfer, the sponsor will protect the confidentiality of participants’ personal data consistent 
with the clinical study agreement and applicable privacy laws. 
Information technology systems used to collect, process, and store study-related data are 
secured by technical and organizational security measures designed to protect such data 
against accidental or unlawful loss, alteration, or unauthorized disclosure or access. 
The sponsor maintains standard operating procedures on how to respond in the event of 
unauthorized access, use, or disclosure of sponsor information or systems. 
10.1.5. Committees Structure 
10.1.5.1. Data Monitoring Committee 
This study will not use an E-DMC. 
10.1.6. Dissemination of Clinical Study Data 
Pfizer fulfills its commitment to publicly disclose clinical study results through posting the 
results of studies on www.clinicaltrials.gov (ClinicalTrials.gov), the EudraCT/CTIS, and/or 
www.pfizer.com, and other public registries and websites in accordance with applicable local 
laws/regulations. In addition, Pfizer reports study results outside of the requirements of local 
laws/regulations pursuant to its SOPs. 


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In all cases, study results are reported by Pfizer in an objective, accurate, balanced, and 
complete manner and are reported regardless of the outcome of the study or the country in 
which the study was conducted. 
www.clinicaltrials.gov 
Pfizer posts clinical trial results on www.clinicaltrials.gov for Pfizer-sponsored interventional 
studies (conducted in patients) that evaluate the safety and/or efficacy of a product, 
regardless of the geographical location in which the study is conducted. These results are 
submitted for posting in accordance with the format and timelines set forth by US law. 
EudraCT/CTIS 
Pfizer posts clinical trial results on EudraCT/CTIS for Pfizer-sponsored interventional studies 
in accordance with the format and timelines set forth by EU requirements. 
www.pfizer.com 
Pfizer posts CSR synopses and plain-language study results summaries on www.pfizer.com 
for Pfizer-sponsored interventional studies at the same time the corresponding study results 
are posted to www.clinicaltrials.gov. CSR synopses will have personally identifiable 
information anonymized. 
Documents within marketing applications 
Pfizer complies with applicable local laws/regulations to publish clinical documents included 
in marketing applications. Clinical documents include summary documents and CSRs 
including the protocol and protocol amendments, sample CRFs, and SAPs. Clinical 
documents will have personally identifiable information anonymized. 
Data sharing 
Pfizer provides researchers secure access to participant-level data or full CSRs for the 
purposes of “bona-fide scientific research” that contributes to the scientific understanding of 
the disease, target, or compound class. Pfizer will make data from these trials available 
24 months after study completion. Participant-level data will be anonymized in accordance 
with applicable privacy laws and regulations. CSRs will have personally identifiable 
information anonymized. 
Data requests are considered from qualified researchers with the appropriate competencies to 
perform the proposed analyses. Research teams must include a biostatistician. Data will not 
be provided to applicants with significant conflicts of interest, including individuals 
requesting access for commercial/competitive or legal purposes. 


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


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provide copies of the inspection findings to the sponsor or its agent. Before response 
submission to the regulatory authorities, the investigator will provide the sponsor or its 
agents with an opportunity to review and comment on responses to any such findings. 
10.1.8. Source Documents 
Source documents provide evidence for the existence of the participant and substantiate the 
integrity of the data collected. Source documents are filed at the investigator site. 
Data reported on the CRF or entered in the eCRF that are from source documents must be 
consistent with the source documents or the discrepancies must be explained. The 
investigator may need to request previous medical records or transfer records, depending on 
the study. Also, current medical records must be available. 
Definition of what constitutes source data and its origin can be found in the Source 
Document Locator, which is maintained by the sponsor’s designee (Pfizer CRU). 
Description of the use of the computerized system is documented in the Data Management 
Plan, which is maintained by the sponsor’s designee (Pfizer CRU). 
The investigator must maintain accurate documentation (source data) that supports the 
information entered in the CRF. 
The sponsor or designee will perform monitoring to confirm that data entered into the CRF 
by authorized site personnel are accurate, complete, and verifiable from source documents; 
that the safety and rights of participants are being protected; and that the study is being 
conducted in accordance with the currently approved protocol and any other study 
agreements, ICH GCP guidelines, and all applicable regulatory requirements. 
10.1.9. Study and Site Start and Closure 
The study start date is the date on which the clinical study will be open for recruitment of 
participants. 
The first act of recruitment is the date of the first participant’s first visit and will be the study 
start date. 
The sponsor designee reserves the right to close the study site or terminate the study at any 
time for any reason at the sole discretion of the sponsor, including (but not limited to) 
regulatory authority decision, change in opinion of the IRB/EC, or change in benefit-risk 
assessment. Study sites will be closed upon study completion. A study site is considered 
closed when all required documents and study supplies have been collected and a study-site 
closure visit has been performed. 
The investigator may initiate study-site closure at any time upon notification to the sponsor if 
requested to do so by the responsible IRB/EC or if such termination is required to protect the 
health of study participants. 


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Reasons for the early closure of a study site by the sponsor may include but are not limited 
to: 
• Failure of the investigator to comply with the protocol, the requirements of the 
IRB/EC or local health authorities, the sponsor’s procedures, or the ICH GCP 
guidelines; 
• Inadequate recruitment of participants by the investigator; 
• Discontinuation of further study intervention development. 
If the study is prematurely terminated or suspended, the sponsor shall promptly inform the 
investigators, the ECs/IRBs, the regulatory authorities, and any CRO(s) used in the study of 
the reason for termination or suspension, as specified by the applicable regulatory 
requirements. The investigator shall promptly inform the participant and should assure 
appropriate participant therapy and/or follow-up. 
Study termination is also provided for in the clinical study agreement. If there is any conflict 
between the contract and this protocol, the contract will control as to termination rights. 
10.1.10. Publication Policy 
The investigator agrees to refer to the primary publication in any subsequent publications. 
Pfizer will not provide any financial compensation for the investigator’s participation in the 
preparation of the primary congress abstract, poster, presentation, or primary manuscript for 
the study. 
Investigators are free to publish individual center results that they deem to be clinically 
meaningful after publication of the overall results of the study or 12 months after primary 
completion date or study completion at all sites, whichever occurs first, subject to the other 
requirements described in this section. 
The investigator will provide Pfizer an opportunity to review any proposed publication or 
any other type of disclosure of the study results (collectively, “publication”) before it is 
submitted or otherwise disclosed and will submit all publications to Pfizer 30 days before 
submission. If any patent action is required to protect intellectual property rights, the 
investigator agrees to delay the disclosure for a period not to exceed an additional 60 days 
upon request from Pfizer. This allows Pfizer to protect proprietary information and to provide 
comments, and the investigator will, on request, remove any previously undisclosed 
confidential information before disclosure, except for any study-intervention or Pfizer-related 
information necessary for the appropriate scientific presentation or understanding of the 
study results. For joint publications, should there be disagreement regarding interpretation 
and/or presentation of specific analysis results, resolution of, and responsibility for, such 
disagreements will be the collective responsibility of all authors of the publication. 


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For all publications relating to the study, the investigator and Pfizer will comply with 
recognized ethical standards concerning publications and authorship, including those 
established by the International Committee of Medical Journal Editors. The investigator will 
disclose any relationship with Pfizer and any relevant potential conflicts of interest, including 
any financial or personal relationship with Pfizer, in any publications. All authors will have 
access to the relevant statistical tables, figures, and reports (in their original format) required 
to develop the publication. 
10.1.11. Sponsor’s Medically Qualified Individual 
The contact information for the sponsor’s MQI for the study is documented in the study 
contact list located in the clinical trial management system. 
To facilitate access to their investigator and the sponsor’s MQI for study-related medical 
questions or problems from nonstudy healthcare professionals, participants are provided with 
an ECC at the time of informed consent. The ECC contains, at a minimum, (a) protocol and 
study intervention identifiers, (b) participant’s study identification number, and (c) site 
emergency phone number active 24 hours/day, 7 days per week. 
The ECC is intended to augment, not replace, the established communication pathways 
between the participant and their investigator and site staff, and between the investigator and 
sponsor study team. The ECC is only to be used by healthcare professionals not involved in 
the research study, as a means of reaching the investigator or site staff related to the care of a 
participant. 


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10.2. Appendix 2: Clinical Laboratory Tests 
The following safety laboratory tests will be performed at times defined in the SoA section of 
this protocol. Additional laboratory results may be reported on these samples as a result of 
the method of analysis or the type of analyzer used by the clinical laboratory, or as derived 
from calculated values. These additional tests would not require additional collection of 
blood. Unscheduled clinical laboratory measurements may be obtained at any time during the 
study to assess any perceived safety issues. 
 
Table 5. 
Protocol-Required Safety Laboratory Assessments 
 
Hematology 
Chemistry 
Urinalysis 
Other 
Hemoglobin 
Hematocrit 
RBC count 
Platelet count 
WBC count 
Total neutrophils (Abs) 
Eosinophils (Abs) 
Monocytes (Abs) 
Basophils (Abs) 
Lymphocytes (Abs) 
Urea and creatinine 
eGFR (SCr) 
Glucose (fasting) 
Calcium 
Sodium 
Potassium 
Chloride 
Total CO2 (bicarbonate) 
AST, ALT 
Total bilirubin 
Alkaline phosphatase 
Uric acid 
Albumin 
Total protein 
SCysf 
Local dipstick: 
pHa 
Glucose (qual) 
Protein (qual) 
Blood (qual) 
Ketones 
Nitrites 
Leukocyte esterase 
Laboratory: 
Microscopy and 
cultured 
Urine drug screeningb 
COVID-19 testing (per 
CRU procedures) 
At screening only: 
• FSHc 
• Hepatitis B surface 
antigen 
• Hepatitis B surface 
antibodye 
• Hepatitis B core antibody 
• Hepatitis C antibody 
• Human 
immunodeficiency virus 
If Hb/RBC abnormal: 
MCV, MCH, MCHC 
Neutrophils (%) 
Eosinophils (%) 
Basophils (%) 
Lymphocytes (%) 
Monocytes (%) 
RBC morphology 
RBC distribution width 
For suspected DILI: 
AST/ALT 
Total bilirubin, direct and 
indirect bilirubin 
Alkaline phosphatase 
Total bile acids, GGT 
Total protein, albumin 
CK 
PT, INR 
Acetaminophen/paracetamol 
or 
protein adduct levels 
Hepatitis serology (even if 
screening negative) 
For suspected DICI/DIKI: 
Creatinine (SCr) 
CystatinC (SCys) 
eGFR (SCr only and 
combined SCr+SCys) 
Spot (dipstick) UACR 


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Table 5. 
Protocol-Required Safety Laboratory Assessments 
 
a. 
Can be performed on dipstick or pH-meter device. 
b. The minimum requirement for drug screening includes cocaine, THC, opiates/opioids, benzodiazepines, 
and amphetamines (others are site- and study-specific). 
c. 
For confirmation of postmenopausal status only. 
d. Urinary culture only if deemed appropriate by the investigator (eg, if UTI is suspected and/or urine 
dipstick is positive for nitrites or leukocyte esterase or both). 
e. 
HBsAb will be tested if HBsAg and/or HBcAb is positive 
f. 
Baseline (pre-dose) only 
 
The investigator must review the laboratory report, document this review, and record any 
clinically relevant changes occurring during the study in the AE section of the CRF. 
Laboratory/analyte results that could unblind the study and have been collected for the 
purpose of the study will not be reported to investigator sites or other blinded personnel until 
the study has been unblinded. 
Any remaining serum/plasma from samples collected for clinical safety laboratory 
measurements at baseline and at all times after dose administration may be retained and 
stored for the duration of the study. Upon completion of the study, these retained safety 
samples may be used for the assessment of exploratory safety biomarkers or unexpected 
safety findings. These data will not be included in the CSR. Samples to be used for this 
purpose will be shipped to either a Pfizer-approved BBS facility or other designated 
laboratory and retained for up to 1 year following the completion of the study. 


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10.3. Appendix 3: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-Up, and Reporting 
10.3.1. Definition of AE 
 
AE Definition 
• An AE is any untoward medical occurrence in a patient or clinical study 
participant, temporally associated with the use of study intervention, whether or not 
considered related to the study intervention. 
• Note: An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease (new or exacerbated) 
temporally associated with the use of study intervention. 
 
 
Events Meeting the AE Definition 
• Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) 
or other safety assessments (eg, ECG, radiological scans, vital sign measurements), 
including those that worsen from baseline, considered clinically significant in the 
medical and scientific judgment of the investigator. Any abnormal laboratory test 
results that meet any of the conditions below must be recorded as an AE: 
• Is associated with accompanying symptoms; 
• Requires additional diagnostic testing or medical/surgical intervention; 
• Leads to a change in study dosing (outside of any protocol-specified dose 
adjustments) or discontinuation from the study, significant additional 
concomitant drug treatment, or other therapy. 
• Exacerbation of a chronic or intermittent preexisting condition, including an 
increase in either frequency and/or intensity of the condition. 
• New condition detected or diagnosed after study intervention administration, even 
though it may have been present before the start of the study. 
• Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction. 
• Signs, symptoms, or the clinical sequelae of a suspected overdose of either study 
intervention or a concomitant medication. Overdose per se will not be reported as 
an AE or SAE unless it is an intentional overdose taken with possible 
suicidal/self-harming intent. Such overdoses should be reported regardless of 
sequelae. 


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


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


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


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• It is not acceptable for the investigator to send photocopies of the participant’s 
medical records to Pfizer Safety in lieu of completion of the CT SAE Report 
Form/AE or SAE CRF page. 
• There may be instances when copies of medical records for certain cases are 
requested by Pfizer Safety. In this case, all participant identifiers, with the 
exception of the participant number, will be redacted on the copies of the medical 
records before submission to Pfizer Safety. 
• The investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information. Whenever possible, the diagnosis (not 
the individual signs/symptoms) will be documented as the AE or SAE. 
Assessment of Intensity 
The investigator will make an assessment of intensity for each AE and SAE reported 
during the study and assign it to 1 of the following categories: 
• Mild: A type of AE that is usually transient and may require only minimal 
treatment or therapeutic intervention. The event does not generally interfere with 
usual ADL. 
• Moderate: A type of AE that is usually alleviated with additional specific 
therapeutic intervention. The event interferes with usual ADL, causing discomfort, 
but poses no significant or permanent risk of harm to the research participant. 
• Severe: A type of AE that interrupts usual ADL, or significantly affects clinical 
status, or may require intensive therapeutic intervention. 
An event is defined as “serious” when it meets at least 1 of the predefined outcomes as 
described in the definition of an SAE, NOT when it is rated as severe. 
 
 
Assessment of Causality 
• The investigator is obligated to assess the relationship between study intervention 
and each occurrence of each AE or SAE. The investigator will use clinical 
judgment to determine the relationship. 
• A “reasonable possibility” of a relationship conveys that there are facts, evidence, 
and/or arguments to suggest a causal relationship, rather than a relationship cannot 
be ruled out. 


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• Alternative causes, such as underlying disease(s), concomitant therapy, and other 
risk factors, as well as the temporal relationship of the event to study intervention 
administration, will be considered and investigated. 
• The investigator will also consult the IB and/or product information, for marketed 
products, in their assessment. 
• For each AE or SAE, the investigator must document in the medical notes that they 
have reviewed the AE or SAE and have provided an assessment of causality. 
• There may be situations in which an SAE has occurred and the investigator has 
minimal information to include in the initial report to the sponsor. However, it is 
very important that the investigator always make an assessment of causality 
for every event before the initial transmission of the SAE data to the sponsor. 
• The investigator may change their opinion of causality in light of follow-up 
information and send an SAE follow-up report with the updated causality 
assessment. 
• The causality assessment is one of the criteria used when determining regulatory 
reporting requirements. 
• If the investigator does not know whether or not the study intervention caused the 
event, then the event will be handled as “related to study intervention” for reporting 
purposes, as defined by the sponsor. In addition, if the investigator determines that 
an SAE is associated with study procedures, the investigator must record this 
causal relationship in the source documents and CRF, and report such an 
assessment in the dedicated section of the CT SAE Report Form and in accordance 
with the SAE reporting requirements. 
 
 
Follow-Up of AEs and SAEs 
• The investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations, as medically indicated or as requested by the 
sponsor, to elucidate the nature and/or causality of the AE or SAE as fully as 
possible. This may include additional laboratory tests or investigations, 
histopathological examinations, or consultation with other healthcare providers. 
• If a participant dies during participation in the study or during a recognized 
follow-up period, the investigator will provide Pfizer Safety with a copy of any 
postmortem findings, including histopathology. 


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• New or updated information will be recorded in the originally submitted 
documents. 
• The investigator will submit any updated SAE data to the sponsor within 24 hours 
of receipt of the information. 
10.3.4. Reporting of SAEs 
 
SAE Reporting to Pfizer Safety via an Electronic DCT 
• The primary mechanism for reporting an SAE to Pfizer Safety will be the 
electronic DCT. 
• If the electronic system is unavailable, then the site will use the paper SAE DCT 
(see next section) to report the event within 24 hours. 
• The site will enter the SAE data into the electronic DCT (eg, eSAE or PSSA) or 
paper form (as applicable) as soon as the data become available. 
• After the study is completed at a given site, the electronic DCT will be taken 
off-line to prevent the entry of new data or changes to existing data. 
• If a site receives a report of a new SAE from a study participant or receives updated 
data on a previously reported SAE after the electronic DCT has been taken off-line, 
then the site can report this information on a paper SAE form (see next section) or 
to Pfizer Safety by telephone. 
 
 
SAE Reporting to Pfizer Safety via the CT SAE Report Form 
• Facsimile transmission of the CT SAE Report Form is the preferred method to 
transmit this information to Pfizer Safety. 
• In circumstances when the facsimile is not working, an alternative method should 
be used, eg, secured (Transport Layer Security) or password-protected email. If 
none of these methods can be used, notification by telephone is acceptable with a 
copy of the CT SAE Report Form sent by overnight mail or courier service. 
• Initial notification via telephone does not replace the need for the investigator to 
complete and sign the CT SAE Report Form pages within the designated reporting 
time frames. 


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10.4. Appendix 4: Contraceptive and Barrier Guidance 
10.4.1. Male Participant Reproductive Inclusion Criteria 
Male participants are eligible to participate if they agree to the following requirements during 
the intervention period and for at least 28 days after the last dose of study intervention, which 
corresponds to the time needed to eliminate reproductive safety risk of the study 
intervention(s): 
• Refrain from donating sperm. 
PLUS either: 
• Be abstinent from heterosexual intercourse as their preferred and usual lifestyle 
(abstinent on a long-term and persistent basis) and agree to remain abstinent. 
OR 
• Must agree to use contraception/barrier as detailed below: 
• Agree to use a male condom, and should also be advised of the benefit for a 
female partner to use a highly effective method of contraception, as a condom 
may break or leak, when having sexual intercourse with a WOCBP who is not 
currently pregnant. 
• In addition to male condom use, a highly effective method of contraception may be 
considered in WOCBP partners of male participants (refer to the list of highly 
effective methods below in Section 10.4.4). 
10.4.2. Female Participant Reproductive Inclusion Criteria 
The criteria below are part of inclusion criterion 1 (Age and Sex; Section 5.1) and specify the 
reproductive requirements for including female participants. Refer to Section 10.4.4 for a 
complete list of contraceptive methods permitted in the study. 
A female participant is eligible to participate if she is not pregnant or breastfeeding and is not 
a WOCBP (see definition in Section 10.4.3). 
The investigator is responsible for review of medical history, menstrual history, and recent 
sexual activity to decrease the risk for inclusion of a woman with an early undetected 
pregnancy. 
10.4.3. Woman of Childbearing Potential 
A woman is considered fertile following menarche and until becoming postmenopausal 
unless permanently sterile (see below). 


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If fertility is unclear (eg, amenorrhea in adolescents or athletes) and a menstrual cycle cannot 
be confirmed before the first dose of study intervention, additional evaluation should be 
considered. 
Women in the following categories are not considered WOCBP: 
1. Premenopausal female with 1 of the following: 
• Documented hysterectomy; 
• Documented bilateral salpingectomy; 
• Documented bilateral oophorectomy. 
For individuals with permanent infertility due to a medical cause other than the above 
(eg, mullerian agenesis, androgen insensitivity), investigator discretion should be applied 
to determining study entry. 
Note: Documentation for any of the above categories can come from the site personnel’s 
review of the participant’s medical records, medical examination, or medical history 
interview. The method of documentation should be recorded in the participant’s medical 
record for the study. 
2. Postmenopausal female. 
• A postmenopausal state is defined as no menses for 12 months without an 
alternative medical cause. In addition: 
• A high FSH level in the postmenopausal range must be used to confirm a 
postmenopausal state in women under 60 years old and not using hormonal 
contraception or HRT. 
• A female on HRT and whose menopausal status is in doubt must discontinue 
HRT to allow confirmation of postmenopausal status before study enrollment. 
10.4.4. Contraception Methods 
Contraceptive use by men or women should be consistent with local availability/regulations 
regarding the use of contraceptive methods for those participating in clinical trials. 
The following contractive methods are appropriate for this study: 
Highly Effective Methods That Have Low User Dependency (for WOCBP partners of male 
participants) 
1. Implantable progestogen-only hormone contraception associated with inhibition of 
ovulation. 


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2. Intrauterine device. 
3. Intrauterine hormone-releasing system. 
4. Bilateral tubal occlusion. 
5. Vasectomized partner: 
• Vasectomized partner is a highly effective contraceptive method provided that the 
partner is the sole sexual partner of the WOCBP and the absence of sperm has 
been confirmed. If not, an additional highly effective method of contraception 
should be used. The spermatogenesis cycle is approximately 90 days. 
Highly Effective Methods That Are User Dependent (for WOCBP partners of male 
participants) 
6. Combined (estrogen- and progestogen-containing) hormonal contraception associated 
with inhibition of ovulation: 
• Oral; 
• Intravaginal; 
• Transdermal. 
7. Progestogen-only hormone contraception associated with inhibition of ovulation: 
• Oral; 
• Injectable. 
Sexual Abstinence 
8. Sexual abstinence is considered a highly effective method only if defined as 
refraining from heterosexual intercourse during the entire period of risk associated 
with the study intervention. The reliability of sexual abstinence needs to be evaluated 
in relation to the duration of the study and the preferred and usual lifestyle of the 
participant. 


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10.5. Appendix 5: Genetics 
Use/Analysis of DNA 
• Genetic variation may impact a participant’s response to study intervention, 
susceptibility to, and severity and progression of disease. Therefore, where local 
regulations and IRBs/ECs allow, a blood sample will be collected for DNA analysis. 
• The scope of the genetic research may be narrow (eg, 1 or more candidate genes) or 
broad (eg, the entire genome), as appropriate to the scientific question under 
investigation. 
• The samples may be analyzed as part of a multistudy assessment of genetic factors 
involved in the response to study intervention or study interventions of this class to 
understand treatments for the disease(s) under study or the disease(s) themselves. 
• The results of genetic analyses may be reported in the CSR or in a separate study 
summary, or may be used for internal decision making without being included in a 
study report. 
• The sponsor will store the DNA samples in a secure storage space with adequate 
measures to protect confidentiality. 
• The samples will be retained as indicated: 
• Retained samples will be stored indefinitely or for another period as per local 
requirements. 
• Participants may withdraw their consent for the storage and/or use of their Retained 
Research Samples at any time by making a request to the investigator; in this case, 
any remaining material will be destroyed. Data already generated from the samples 
will be retained to protect the integrity of existing analyses. 
• Samples for genetic research will be labeled with a code. The key between the code 
and the participant’s personally identifying information (eg, name, address) will be 
held securely at the study site. 


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10.6. Appendix 6: Liver Safety: Suggested Actions and Follow-Up Assessments 
Potential Cases of Drug-Induced Liver Injury 
Humans exposed to a drug who show no sign of liver injury (as determined by elevations in 
transaminases) are termed “tolerators,” while those who show transient liver injury but adapt 
are termed “adaptors.” In some participants, transaminase elevations are a harbinger of a 
more serious potential outcome. These participants fail to adapt and therefore are 
“susceptible” to progressive and serious liver injury, commonly referred to as DILI. 
Participants who experience a transaminase elevation above 3 × ULN should be monitored 
more frequently to determine if they are “adaptors” or are “susceptible.” 
In the majority of DILI cases, elevations in AST and/or ALT precede T bili elevations 
(>2 × ULN) by several days or weeks. The increase in T bili typically occurs while 
AST/ALT is/are still elevated above 3 × ULN (ie, AST/ALT and T bili values will be 
elevated within the same laboratory sample). In rare instances, by the time T bili 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 T bili 
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 T bili baseline values within the normal range who 
subsequently present with AST OR ALT values ≥3 × ULN AND a T bili value 
≥2 × ULN with no evidence of hemolysis and an alkaline phosphatase value 
<2 × ULN or not available. 
• For participants with baseline AST OR ALT OR T bili values above the ULN, the 
following threshold values are used in the definition mentioned above, as needed, 
depending on which values are above the ULN at baseline: 
• Preexisting AST or ALT baseline values above the normal range: AST or ALT 
values ≥2 times the baseline values AND ≥3 × ULN; or ≥8 × ULN (whichever is 
smaller). 
• Preexisting values of T bili above the normal range: T bili level increased from 
baseline value by an amount of ≥1 × ULN or if the value reaches ≥3 × ULN 
(whichever is smaller). 


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Rises in AST/ALT and T bili 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 T bili for suspected Hy’s law 
cases, additional laboratory tests should include albumin, CK, direct and indirect bilirubin, 
GGT, PT/INR, total bile acids, and alkaline phosphatase. Consideration should also be given 
to drawing a separate tube of clotted blood and an anticoagulated tube of blood for further 
testing, as needed, for further contemporaneous analyses at the time of the recognized initial 
abnormalities to determine etiology. A detailed history, including relevant information, such 
as review of ethanol, acetaminophen/paracetamol (either by itself or as a coformulated 
product in prescription or over-the-counter medications), recreational drug, or supplement 
(herbal) use and consumption, family history, sexual history, travel history, history of contact 
with a jaundiced person, surgery, blood transfusion, history of liver or allergic disease, and 
potential occupational exposure to chemicals, should be collected. Further testing for acute 
hepatitis A, B, C, D, and E infection, liver imaging (eg, biliary tract), and collection of serum 
samples for acetaminophen/paracetamol drug and/or protein adduct levels may be warranted. 
All cases demonstrated on repeat testing as meeting the laboratory criteria of AST/ALT and 
T bili elevation defined above should be considered potential DILI (Hy’s law) cases if no 
other reason for the LFT abnormalities has yet been found. Such potential DILI (Hy’s law) 
cases are to be reported as SAEs, irrespective of availability of all the results of the 
investigations performed to determine etiology of the LFT abnormalities. 
A potential DILI (Hy’s law) case becomes a confirmed case only after all results of 
reasonable investigations have been received and have excluded an alternative etiology. 


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10.7. Appendix 7: Kidney Safety: Monitoring Guidelines 
10.7.1. Laboratory Assessment of Change in Kidney Function and Detection of Kidney 
Injury 
Standard kidney safety monitoring requires assessment of baseline and postbaseline serum 
creatinine (SCr measurement to estimate glomerular filtration rate [SCr-based eGFR] or 
eCrCl]. Baseline and postbaseline serum SCys makes it feasible to distinguish AKI from 
other causes of SCr increase. If SCr increase is confirmed after baseline, then reflex 
measurement of SCys is indicated to estimate the combined SCr-SCys eGFR calculation (for 
adults only). 
Regardless of whether kidney function monitoring tests are required as a routine safety 
monitoring procedure in the study, if the investigator or sponsor deems it necessary to further 
assess kidney safety and quantify kidney function, then these test results should be managed 
and followed per standard of care. 
10.7.2. Age-Specific Kidney Function Calculation Recommendations 
10.7.2.1. Adults (18 Years and Above)—2021 CKD-EPI Equations 
 
2021 CKD-EPI 
SCr Only 
SCr 
(mg/dL) 
SCys 
(mg/L) 
Recommended eGFR Equation 
Female 
if ≤0.7 
NA 
eGFR = 143 × (SCr/0.7)-0.241 × (0.9938)Age 
Female 
if >0.7 
NA 
eGFR = 143 × (SCr/0.7)-1.200 × (0.9938)Age 
Male 
if ≤0.9 
NA 
eGFR = 142 × (SCr/0.9)-0.302 × (0.9938)Age 
Male 
if >0.9 
NA 
eGFR = 142 × (SCr/0.9)-1.200 × (0.9938)Age 
2021 CKD-EPI 
SCr-SCys 
Combined 
SCr 
(mg/dL) 
SCys 
(mg/L) 
Recommended eGFR Equation 
Female 
if ≤0.7 
if ≤0.8 
eGFR = 130 × (SCr/0.7)-0.219 × (SCys/0.8)-0.323 × (0.9961)Age 
Female 
if ≤0.7 
if >0.8 
eGFR = 130 × (SCr/0.7)-0.219 × (SCys/0.8)-0.778 × (0.9961)Age 
Female 
if >0.7 
if ≤0.8 
eGFR = 130 × (SCr/0.7)-0.544 × (SCys/0.8)-0.323 × (0.9961)Age 
Female 
if >0.7 
if >0.8 
eGFR = 130 × (SCr/0.7)-0.544 × (SCys/0.8)-0.778 × (0.9961)Age 
Male 
if ≤0.9 
if ≤0.8 
eGFR = 135 × (SCr/0.9)-0.144 × (SCys/0.8)-0.323 × (0.9961)Age 
Male 
if ≤0.9 
if >0.8 
eGFR = 135 × (SCr/0.9)-0.144 × (SCys/0.8)-0.778 × (0.9961)Age 
Male 
if >0.9 
if ≤0.8 
eGFR = 135 × (SCr/0.9)-0.544 × (SCys/0.8)-0.323 × (0.9961)Age 
Male 
if >0.9 
if >0.8 
eGFR = 135 × (SCr/0.9)-0.544 × (SCys/0.8)-0.778 × (0.9961)Age 
Source:9 
10.7.3. Adverse Event Grading for Kidney Safety Laboratory Abnormalities 
AE grading for decline in kidney function (ie, eGFR or eCrCl) will be according to KDIGO 
criteria.10 


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10.8. Appendix 8: ECG Findings of Potential Clinical Concern 
 
ECG Findings That May Qualify as AEs 
• Marked sinus bradycardia (rate <40 bpm) lasting minutes. 
• New PR interval prolongation >280 ms. 
• New prolongation of QTcF to >480 ms (absolute) or by ≥60 ms from baseline. 
• New-onset atrial flutter or fibrillation, with controlled ventricular response rate: ie, 
rate <120 bpm. 
• New-onset type I second-degree (Wenckebach) AV block of >30 seconds’ 
duration. 
• Frequent PVCs, triplets, or short intervals (<30 seconds) of consecutive ventricular 
complexes. 
ECG Findings That May Qualify as SAEs 
• QTcF prolongation >500 ms. 
• New ST-T changes suggestive of myocardial ischemia. 
• New-onset LBBB (QRS complex>120 ms). 
• New-onset right bundle branch block (QRS complex>120 ms). 
• Symptomatic bradycardia. 
• Asystole: 
• In awake, symptom-free participants in sinus rhythm, with documented periods 
of asystole ≥3.0 seconds or any escape rate <40 bpm, or with an escape rhythm 
that is below the AV node. 
• In awake, symptom-free participants with atrial fibrillation and bradycardia 
with 1 or more pauses of at least 5 seconds or longer. 
• Atrial flutter or fibrillation, with rapid ventricular response rate: rapid = rate 
>120 bpm. 
• Sustained supraventricular tachycardia (rate >120 bpm) (“sustained” = short 
duration with relevant symptoms or lasting >1 minute). 


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


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10.9. Appendix 9: Protocol Amendment History 
The protocol amendment summary of changes table for the current amendment is located 
directly before the TOC. The protocol amendment summary of changes tables for past 
amendment(s) can be found below: 
Amendment 1 (29 September 2022) 
Overall Rationale for the Amendment: use precautionary sentinel dosing in dose 
escalation to mitigate potential unpredicted risks in FIH study 
 
Section # and Name 
Description of Change 
Brief Rationale 
Substantial or 
Nonsubstantial 
Section 1.1 (Synopsis), 
Section 1.2 (Schema), 
Section 4.1 (Overall 
Design), Section 6.6.1 
(Dose Escalation and 
Stopping Rules) 
Added description 
wording of 
precautionary sentinel 
dosing in Overall 
Design of synopsis, 
Schema and Overall 
Design. 
To describe 
sentinel dosing 
Substantial 
Section 2.3 
(Benefit/Risk 
Assessment), 
Mentioned the use of 
precautionary sentinel 
dosing. 
To describe 
sentinel dosing 
Substantial 
Section 4.2 (Scientific 
Rationale for Study 
Design) 
Added the scientific 
rationale for 
precautionary sentinel 
dosing. 
To provide 
rationale for 
precautionary 
sentinel dosing 
Substantial 
Title page and 
Section 1.1 (Synopsis) 
Added US IND number 
To provide the 
US IND number 
Nonsubstantial 


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10.10. Appendix 10: Abbreviations 
The following is a list of abbreviations that may be used in the protocol. 
 
Abbreviation 
Term 
Abs 
absolute 
ADL 
activity/activities of daily living 
AE 
adverse event 
AKI 
acute kidney injury 
ALT 
alanine aminotransferase 
ANOVA 
analysis of variance 
AST 
aspartate aminotransferase 
AUC 
area under the plasma concentration-time curve 
AUC24,u 
unbound AUC over 24 hours 
AUEC 
area under the effect curve 
AV 
atrioventricular 
Ave 
average 
AxMP 
auxiliary medicinal product 
BBS 
Biospecimen Banking System 
BCAA 
branched-chain amino acid 
BCKA 
branched-chain ketoacid 
BCKDH 
branched-chain ketoacid dehydrogenase 
BCKDHA 
branched-chain ketoacid dehydrogenase E1 subunit alpha 
BCRP 
breast cancer resistance protein 
BDK 
branched chain ketoacid dehydrogenase kinase 
BID 
twice a day 
BMI 
body mass index 
BP 
blood pressure 
bpm 
beats per minute 
BUN 
blood urea nitrogen 
Cave 
average concentration 
CBC 
complete blood count 
Ceff 
efficacious concentration 
CFR 
code of Federal Regulations 
CIOMS 
council for International Organizations of Medical Sciences 
CK 
creatine kinase 
CKD-EPI 
chronic kidney disease epidemiology 
CL 
clearance 
Clast 
last quantifiable concentration 
Cmax 
maximum concentration 
Cmax,u 
unbound Cmax 
CO2 
carbon dioxide (bicarbonate) 
COVID-19 
coronavirus disease 2019 
Cp 
total concentration 


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Abbreviation 
Term 
CRF 
case report form 
CRO 
contract research organization 
CRU 
clinical research unit 
CSR 
Clinical Study Report 
CT 
clinical trial 
CTIS 
Clinical Trial Information System 
CYP 
cytochrome P450 
DCT 
data collection tool 
DDI 
drug-drug interaction 
DICI 
drug-induced cholestatic injury 
DIKI 
drug-induced kidney injury 
DILI 
drug-induced liver injury 
C 
CDINA 
deoxyribonucleic acid 
EC 
ethics committee 
ECC 
emergency contact card 
ECCS 
extended clearance classification system 
ECG 
electrocardiogram or electrocardiography 
FDA 
Food and Drug Administration 
eCrCl 
estimated creatinine clearance 
eCRF 
electronic case report form 
EDB 
exposure during breastfeeding 
E-DMC 
external data monitoring committee 
EDP 
exposure during pregnancy 
EDR 
extemporaneous dispensing record 
eGFR 
estimated glomerular filtration rate 
EMA 
European Medicines Agency 
EP 
extemporaneously prepared 
eSAE 
electronic serious adverse event 
ET 
early termination 
EU 
European Union 
EudraCT 
European Union Drug Regulating Authorities Clinical Trials 
(European Clinical Trials Database) 
F 
bioavailability 
fa 
fraction absorbed 
fg 
fraction escaping intestinal metabolism 
FSH 
follicle-stimulating hormone 
fu 
fraction unbound 
GCP 
Good Clinical Practice 
GGT 
gamma-glutamyl transferase 
GLP 
Good Laboratory Practice 
Hb 
hemoglobin 


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Abbreviation 
Term 
HBcAb 
hepatitis B core antibody 
HBsAb 
hepatitis B surface antibody 
HBsAg 
hepatitis B surface antigen 
HCVAb 
hepatitis C antibody 
HF 
heart failure 
HIV 
human immunodeficiency virus 
HR 
heart rate 
HRT 
hormone replacement therapy 
IADR 
idiosyncratic drug reaction 
IB 
Investigator’s Brochure 
IC50 
half maximal inhibitory concentration 
ICD 
informed consent document 
ICH 
International Council for Harmonisation of Technical 
Requirements for Pharmaceuticals for Human Use 
ID 
identification 
Ile 
isoleucine 
IMP 
investigational medicinal product 
IND 
Investigational New Drug 
INR 
international normalized ratio 
IPAL 
Investigational Product Accountability Log 
IRB 
Institutional Review Board 
IV 
intravenous(ly) 
K 
Proportionality constant for Bedside and Modified Schwartz 
Equations (kidney function) 
K2EDTA 
K2 dipotassium ethylenediaminetetraacetic acid 
KDIGO 
Kidney Disease Improving Global Outcomes 
KIC 
ketoleucine 
KIV 
ketovaline 
KMV 
ketoisoleucine 
LBBB 
left bundle branch block 
Leu 
namely leucine 
LFT 
liver function test 
LVSP 
peak left ventricular systolic pressure 
MCH 
mean corpuscular hemoglobin 
MCHC 
mean corpuscular hemoglobin concentration 
MCV 
mean corpuscular volume 
MMTT 
mixed meal tolerance test 
MQI 
medically qualified individual 
NA 
not applicable 
NAFLD 
non-alcoholic fatty liver disease 
NASH 
non-alcoholic steatohepatitis 
NHP 
nonhuman primate 


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Abbreviation 
Term 
NIMP 
noninvestigational medicinal product 
NOAEL 
no observed adverse effect level 
NOEL 
no observed effect level 
OATP 
organic-anion-transporting polypeptides 
CCI 
PBPK 
physiologically based pharmacokinetic 
PCRU 
Pfizer Clinical Research Unit 
PD 
pharmacodynamic(s) 
PE 
physical examination 
PI 
principal investigator 
PK 
pharmacokinetic(s) 
PO 
by mouth 
PR 
pulse rate 
PSSA 
Pfizer's Serious Adverse Event Submission Assistant 
PT 
prothrombin time 
PVC 
premature ventricular contraction/complex 
QTc 
corrected QT interval 
QTcF 
QTc corrected using Fridericia’s formula 
qual 
qualitative 
RBC 
red blood cell 
RNA 
ribonucleic acid 
RRCK 
Ralph Russ canine kidney 
SAD 
single ascending dose 
SAE 
serious adverse event 
SAP 
Statistical Analysis Plan 
SARS-CoV-2 
severe acute respiratory syndrome coronavirus 2 
SBP 
systolic blood pressure 
SCr 
serum creatinine 
SCys 
serum cystatin C 
SM 
safety margin 
SoA 
schedule of activities 
SOP 
standard operating procedure 
SPF 
sun protection factor 
SRSD 
single reference safety document 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
t½ 
terminal elimination half-life 
T bili 
total bilirubin 
THC 
tetrahydrocannabinol 
UACR 
urine albumin/creatinine ratio 
UGT 
uridine 5'-diphospho-glucuronosyltransferase 
ULN 
upper limit of normal 
US 
United States 


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Abbreviation 
Term 
UTI 
urinary tract infection 
UV 
ultraviolet 
Val 
valine 
Vss 
volume of distribution at steady state 
WBC 
white blood cell 
WOCBP 
woman/women of childbearing potential 


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11. REFERENCES 
 
 
 
1 
Sun H, Olson KC, Gao C, et al. Catabolic Defect of Branched-Chain Amino Acids 
Promotes Heart Failure. Circulation. 2016;133(21):2038-2049. 
2 
Uddin GM, Zhang L, Shah S, et al. Impaired branched chain amino acid oxidation 
contributes to cardiac insulin resistance in heart failure. Cardiovasc Diabetol. 
2019;18(1):86. Published 2019 Jul 5. 
3 
Wang J, Li Z, Chen J, et al. Metabolomic identification of diagnostic plasma biomarkers 
in humans with chronic heart failure. Mol Biosyst. 2013;9(11):2618-2626. 
4 
Newgard CB, An J, Bain JR, et al. A branched-chain amino acid-related metabolic 
signature that differentiates obese and lean humans and contributes to insulin resistance. 
Cell Metab 2009;9(4):311-326. 
5 
Burke LM, Winter JA, Cameron-Smith D, et al. Effect of intake of different dietary 
protein sources on plasma amino acid profiles at rest and after exercise. Int J Sport Nutr 
Exerc Metab. 2012;22(6):452-462. 
6 
Varma MV, Steyn SJ, Allerton C, et al. Predicting Clearance Mechanism in Drug 
Discovery: Extended Clearance Classification System (ECCS). Pharm Res. 
2015;32(12):3785-3802. 
7 
Muscelli E, Frascerra S, Casolaro A, et al. The amino acid response to a mixed meal in 
patients with type 2 diabetes: effect of sitagliptin treatment. Diabetes Obes Metab. 
2014;16(11):1140-1147. 
8 
Gaggini M, Carli F, Rosso C, et al. Altered amino acid concentrations in NAFLD: 
Impact of obesity and insulin resistance. Hepatology. 2018;67(1):145-158. 
9 
Inker LA, Eneanya ND, Coresh J, et al. New Creatinine- and Cystatin C-Based 
Equations to Estimate GFR without Race. N Engl J Med. 2021;385(19):1737-1749. 
10 
KDIGO guidelines. KDIGO website. Available from: https://kdigo.org/guidelines/. 
Accessed: 29 Aug 2022. 

SAP_001.pdf: 
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Page 1 of 27 
 
 
 
 
 
 
 
 
 
 
 
Protocol C4921001 
 
 
 
 
A PHASE 1, RANDOMIZED, DOUBLE-BLIND, SPONSOR-OPEN, 
PLACEBO-CONTROLLED, 4-PERIOD, CROSSOVER, FIRST-IN-HUMAN STUDY 
TO EVALUATE THE SAFETY, TOLERABILITY, PHARMACOKINETICS, AND 
PHARMACODYNAMICS OF SINGLE ASCENDING ORAL DOSES OF 
PF-07328948 ADMINISTERED TO HEALTHY ADULT PARTICIPANTS 
 
 
 
Statistical Analysis Plan 
(SAP) 
 
 
 
 
 
 
 
Version: 
2.0 
 
Date: 
09 May 2023 


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CCI 
TABLE OF CONTENTS 
LIST OF TABLES ..................................................................................................................... 4 
LIST OF FIGURES .................................................................................................................... 4 
APPENDICES ............................................................................................................................ 4 
1. VERSION HISTORY ............................................................................................................ 5 
2. INTRODUCTION .................................................................................................................. 6 
2.1. Modifications to the Analysis Plan Described in the Protocol .................................. 6 
2.2. Study Objectives, Endpoints, and Estimands ............................................................ 7 
2.3. Study Design .............................................................................................................. 8 
3. ENDPOINTS AND BASELINE VARIABLES: DEFINITIONS AND 
CONVENTIONS ................................................................................................................... 9 
3.1. Primary Endpoint(s) ................................................................................................... 9 
3.2. Secondary Endpoint(s) ............................................................................................... 9 
3.3. Other Endpoint(s) ...................................................................................................... 9 
3.3.1. PK Endpoints ................................................................................................ 9 
 
 
 
 
 
3.4. Baseline Variables .................................................................................................. 12 
3.5. Safety Endpoints ...................................................................................................... 12 
3.5.1. Adverse Events ........................................................................................... 12 
3.5.2. Laboratory Data .......................................................................................... 12 
3.5.3. Vital Signs ................................................................................................... 12 
3.5.4. Electrocardiograms ...................................................................................... 13 
3.5.5. Continuous Cardiac Monitoring .................................................................. 14 


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3.5.6. Physical Exam ............................................................................................. 14 
4. ANALYSIS SETS (POPULATIONS FOR ANALYSIS).................................................... 14 
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 
5.2.3. Mixed Model for Repeated Measurements (MMRM) ................................ 16 
5.2.4. Mixed Effects Analysis of Variance (ANOVA) ......................................... 17 
5.2.5. Mixed Effects ANCOVA ............................................................................ 17 
5.3. Methods to Manage Missing Data ........................................................................... 18 
5.3.1. Missing Safety Data .................................................................................... 18 
5.3.2. Missing Pharmacokinetic (PK) Data ........................................................... 18 
6. ANALYSES AND SUMMARIES ....................................................................................... 18 
6.1. Primary Endpoint(s) ................................................................................................. 18 
6.2. Secondary Endpoint(s) ............................................................................................. 18 
CCI 
 
6.3.1. PK Endpoints .............................................................................................. 19 
CCI 
 
6.4. Subset Analyses ....................................................................................................... 21 
6.5. Baseline and Other Summaries and Analyses .......................................................... 21 
6.5.1. Baseline Summaries .................................................................................... 21 
6.5.2. Study Conduct and Participant Disposition ................................................ 22 
6.5.3. Concomitant Medications and Nondrug Treatments .................................. 22 
6.6. Safety Summaries and Analyses .............................................................................. 22 
6.6.1. Adverse Events ........................................................................................... 22 
6.6.2. Laboratory Data .......................................................................................... 22 
6.6.3. Vital Signs ................................................................................................... 22 
6.6.4. Electrocardiograms ...................................................................................... 23 
6.6.5. Continuous Cardiac Monitoring .................................................................. 23 


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6.6.6. Physical Examination .................................................................................. 23 
7. INTERIM ANALYSES ....................................................................................................... 24 
7.1. Introduction .............................................................................................................. 24 
7.2. Interim Analyses and Summaries ............................................................................ 24 
8. REFERENCES ..................................................................................................................... 24 
APPENDICES .......................................................................................................................... 25 
 
LIST OF TABLES 
Table 1. 
Summary of Changes ................................................................................. 5 
Table 2. 
Plasma PF-07328948 PK Parameters ....................................................... 10 
Table 3. 
Analysis Sets ............................................................................................ 15 
Table 4. 
PK Parameters to be Summarized Descriptively ...................................... 19 
 
 
LIST OF FIGURES 
Figure 1. 
Study Design Schemaa,b,c .................................................................................................................... 9 
APPENDICES 
Appendix 1. Categorical Classes for ECG and Vital Signs of Potential Clinical Concern ...... 25 
Appendix 2. Example SAS Code for Statistical Analyses........................................................ 26 
Appendix 3. List of Abbreviations ........................................................................................... 27 


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1. VERSION HISTORY 
Table 1. 
Summary of Changes 
 
Version/ 
Date 
Associated 
Protocol 
Amendment 
Rationale 
Specific Changes 
1 
07 Nov 2022 
Original: 
02Sep2022 
Amendment 1 
29 Sept 2022 
N/A 
N/A 
CCI 
 
 
 
 
 
 
 


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2. INTRODUCTION 
PF-07328948 is a small molecule allosteric inhibitor/degrader of BDK that is currently being 
developed as an oral therapy to treat heart failure. 
Tissue and/or plasma BCAA and/or BCKA levels are elevated in various disease states 
including heart failure, type 2 diabetes mellitus, NAFLD/NASH, and obesity. Furthermore, 
elevated BCAA levels in HF are associated with a loss of the BCAA catabolic machinery, 
suggesting that the BCKDH pathway, involved in BCAA and BCKA catabolism, is 
dysregulated in cardiometabolic disease indications. Because inhibitory phosphorylation of 
BCKDH by BDK reduces BCAA catabolism, a BDK inhibitor would reduce BCKDH 
phosphorylation, thereby increasing BCAA and BCKA catabolism and reducing the elevated 
levels of BCAAs and BCKAs associated with several cardiovascular and metabolic diseases. 
PF-07328948 is an orally administered, small molecule, potent allosteric BDK inhibitor that 
inhibits BCKDH phosphorylation in vitro and has consistently demonstrated robust, dose- and 
 
 
 
 
 
 
 
These improvements were concomitant with reduced pBCKDH and BDK levels in heart and 
kidney CCI  as well as reduced plasma BCAA and BCKA levels. 
This study will be the first time PF-07328948 is administered to humans. The purpose of the 
study is to evaluate the safety, tolerability, plasma PK and PD of PF-07328948 following 
administration of escalating, single, oral doses to healthy adult participants. 
This statistical analysis plan (SAP) provides the detailed methodology for summary and 
statistical analyses of the data collected in this study - Study C4921001. This document may 
modify the plans outlined in the protocol; however, any major modifications of the primary 
endpoint definition or its analysis will also be reflected in a protocol amendment. 
Text in italics is taken directly from the protocol. 
2.1. Modifications to the Analysis Plan Described in the Protocol 
N/A. 
time-dependent BCAA and BCKA lowering in plasma and CCI 
in mouse, rat and/or dog. In 
addition, CCI 


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2.2. Study Objectives, Endpoints, and Estimands 
 
Type 
Objectives 
Endpoints 
Estimand 
Primary: 
Primary: 
Safety 
• To evaluate the safety and tolerability of 
single ascending doses of PF-07328948 
administered orally to healthy adult 
participants. 
• 
Assessment of adverse events, clinical safety 
laboratory tests, vital signs, continuous 
cardiac monitoring, 12-lead 
electrocardiograms, and physical 
examinations. 
N/A 
Secondary: 
Secondary: 
PK 
• To evaluate the pharmacokinetics of PF- 
07328948 following single doses of PF- 
07328948 administered orally to healthy 
adult participants. 
• 
PK parameters derived from plasma PF- 
07328948 concentrations: Cmax, Tmax, 
AUClast, and if data permit, AUCinf, and t½. 
N/A 
Tertiary/Exploratory: 
Tertiary/Exploratory: 
PK 
• To evaluate additional pharmacokinetic 
parameters of PF-07328948 following 
single doses of PF-07328948 
administered orally to healthy adult 
participants. 
• 
Additional PK parameters derived from 
plasma PF-07328948 concentrations: 
Cmax(dn), AUClast(dn) and if data permit 
AUCinf(dn), CL/F and Vz/F. 
N/A 
C  
CI 
 
 
 
 
 
 
 
 
 
 
 
 
PK 
• To evaluate the effect of food (eg, a 
protein-rich meal such as MMTT), if 
administered, on the plasma PK of PF- 
07328948 following single dose of PF- 
07328948 administered orally to healthy 
adult participants. 
• 
PK parameters derived from plasma PF- 
07328948 concentrations after MMTT: Cmax, 
Tmax, AUClast, and if data permit, AUCinf, and 
t½. 
N/A 


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CCI 
2.3. Study Design 
This is a randomized, investigator- and participant-blind, sponsor-open, placebo-controlled, 
first-in-human, single ascending oral dose, 4-period, sequential, crossover study of 
PF-07328948 administered to healthy adult participants. 
The first 2 cohorts are planned, and the third cohort is optional. In each period, participants 
will be randomized to either PF-07328948 or placebo in a ratio of 3:1. Each participant is 
planned to undergo up to 4 treatment periods receiving up to 4 doses of PF-07328948 and up 
to 2 placebo. 
Precautionary sentinel dosing will be used in any period evaluating escalating doses of PF- 
07328948 and may be omitted for periods when repeating a dose level or administering a 
lower dose level than previously evaluated. For periods with sentinel dosing, 2 participants (1 
receiving PF-07328948 and 1 receiving placebo) will be dosed initially before the remaining 
participants of that period are dosed. Safety and tolerability data through at least 24 hours 
post-dose for the sentinel participants will be reviewed prior to dosing the remaining 
participants of that period. 
In each cohort, a washout interval of at least 7 days will be introduced between subsequent 
doses. 
Based on the review of emerging safety, tolerability, and PK data (and PD data if available) 
in Cohorts 1 and 2, the optional third cohort may enroll 8 participants (crossover, 
placebo-controlled design) to explore additional doses, to repeat a dose, to evaluate split 
dosing, or to investigate food effects on PK CCI 
 . 
The effect of a high-protein meal on safety, tolerability, PK exposure, 
may be 
assessed in at least 1 period within Cohort 2 and/or Cohort 3. 
If a participant drops out before completing all study periods within a cohort, or withdraws 
for a reason unrelated to safety, the participant may be replaced at the discretion of the 
investigator and sponsor. The replacement participant(s) may or may not be required to 
complete all periods of the cohort in which they are participating at the discretion of the 
investigator and sponsor. 
Number of Participants: Approximately 24 healthy adult participants (up to 3 cohorts of 
approximately 8 participants each) will be enrolled in this study. 


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Figure 1. Study Design Schemaa,b,c 
 
a. Doses shown for each cohort except the starting dose in Cohort 1 are planned doses and may be modified based on 
emerging data from previous cohorts. Similarly, assignment to study intervention may be modified. n represents number of 
participants 
b. Effect of food (eg, a protein-rich meal such as MMTT) may be evaluated in at least 1 period of Cohort 2 (eg, P3) and/or 
Cohort 3 
c. In the first period in each cohort (with red box) and the first period of assessment of food effect in any cohort (eg, P3 in 
Cohort 2 with red box), participants will be admitted on Day -2 and time-matched biomarker assessment will be collected on 
Day -1. 
d. Precautionary sentinel dosing will be used in any period evaluating escalating doses of PF-07328948. For such periods, 2 
participants (1 receiving PF-07328948 and 1 receiving placebo) will be dosed initially before the remaining participants of 
that period are dosed. Safety and tolerability data through at least 24 hours post-dose for the sentinel participants will be 
reviewed prior to dosing the remaining participants of that period. Sentinel dosing may be omitted when repeating a dose 
level or administering a lower dose level than previously evaluated. 
 
3. ENDPOINTS AND BASELINE VARIABLES: DEFINITIONS AND 
CONVENTIONS 
3.1. Primary Endpoint(s) 
As listed in Section 2.2, the primary endpoints are related to safety/tolerability and are 
described in Section 3.5. 
3.2. Secondary Endpoint(s) 
As listed in Section 2.2, the secondary endpoints are related to PK and are described in Section 
3.3.1. 
3.3. Other Endpoint(s) 
3.3.1. PK Endpoints 
Blood samples for PK analysis of PF-07328948 will be taken according to the Schedule of 
Activities given in the protocol. 
 
The plasma PK parameters for PF-07328948, following oral dose administration, will be 
derived from the plasma concentration-time profiles using standard noncompartmental 


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methods as detailed in Table 2, as data permit. Table 2 shows the analysis scale and method 
for each parameter. 
In all cases, actual PK sampling times will be used in the derivation of PK parameters. In the 
case that actual PK sampling times are not available, nominal PK sampling time will be used 
in the derivation of PK parameters. 
 
Table 2.  Plasma PF-07328948 PK Parameters 
 
Parameter 
Definition 
Method of Determination 
Analysis Scale 
PF-07328948 
AUClast 
Area under the plasma 
concentration-time 
curve from time 0 to 
the time of the Clast 
Linear/Log trapezoidal method 
ln 
D,A 
AUCinf* 
Area under the plasma 
concentration-time 
curve from time 0 
extrapolated to infinite 
time 
AUClast + (Clast*/kel), where 
Clast* is the predicted plasma 
concentration at the last 
quantifiable timepoint estimated 
from the log-linear regression 
analysis 
ln 
D,A 
Cmax 
Maximum plasma 
concentration 
Observed directly from data 
ln 
D,A 
Tmax 
Time for Cmax 
Observed directly from data as 
time of first occurrence 
R 
D 
t½ * 
Terminal elimination 
half-life 
Loge(2)/kel, where kel is the 
terminal phase rate constant 
calculated by a linear 
regression of the log-linear 
concentration-time curve. Only 
those data points judged to 
describe the terminal log-linear 
decline will be used in the 
regression. 
R 
D 
CL/F* 
Apparent clearance 
Dose/AUCinf 
ln 
D 
Vz/F* 
Apparent volume of 
distribution 
Dose/(AUCinf·kel) 
ln 
D 
AUClast(dn) 
Dose-normalized 
AUClast 
AUClast/Dose 
ln 
D 
AUCinf(dn)* 
Dose-normalized 
AUCinf 
AUCinf/Dose 
ln 
D 
Cmax(dn) 
Dose-normalized Cmax 
Cmax/Dose 
ln 
D 
Key: 
D=displayed with descriptive statistics, 
ln=natural-log transformed, R=raw (untransformed), 
A=analysed using a statistical model (for specific treatment groups for evaluating food effect) 
*=if data permits, dn = normalized to a 1mg PF-07321332 dose 
 
 
Tlast will also be provided as a support parameter for AUClast. Tlast values will only be listed 
and not summarized. 


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CCI 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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CCI 
 
 
 
3.4. Baseline Variables 
Baseline for PD endpoints, laboratory data, vital signs and ECG are defined in Sections 3.3.2, 
3.5.2, 3.5.3 and 3.5.4, respectively. 
3.5. Safety Endpoints 
3.5.1. Adverse Events 
An adverse event is considered a Treatment-Emergent Adverse Event (TEAE) if the event 
started during the effective duration of treatment. All events that start on or after the first dosing 
day and time/start time, if collected, but before the end of the study will be flagged as TEAEs. 
The algorithm will not consider any events that started prior to the first dose date. 
A 3-tier approach for summarizing adverse events (AEs) will not be used due to the low 
number of participants planned to be recruited. 
3.5.2. Laboratory Data 
Safety laboratory tests will be performed as described in the protocol. 
 
The investigator must review the laboratory report, document this review, and record any 
clinically significant changes occurring during the study in the AE section of the CRF. 
Clinically significant abnormal laboratory test findings are those that are not associated with 
the underlying disease, unless judged by the investigator to be more severe than expected for 
the participant’s condition. 
Baseline will be the last predose measurement in each study period. 
To determine if there are any clinically significant laboratory abnormalities, the hematological, 
clinical chemistry (serum) and urinalysis safety tests will be assessed against the criteria 
specified in the sponsor reporting standards. The assessment will take into account whether 
each participant’s baseline test result is within or outside the laboratory reference range for the 
particular laboratory parameter. 
3.5.3. Vital Signs 
Single assessment supine blood pressure and pulse rate measurements will be taken at 
screening, day 1 at hour 0, follow-up visit and at early termination (if applicable). Triplicate 
supine measurements will be taken at all other times as detailed in the Schedule of Activities 
given in the protocol. The average of the triplicate measurements will be calculated prior to 
analyzing the data. Respiratory rate will be measured as a single assessment at each timepoint 
specified in the protocol. 


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Baseline for these measures will be defined as the last predose measurement in each study 
period. 
The following endpoints will be determined: 
• Change from baseline (CFB) in systolic and diastolic BP, pulse rate and respiratory rate 
• The minimum and maximum post-dose systolic and diastolic BP, pulse rate and 
respiratory rate 
• The maximum increase and decrease from baseline over all measurements taken post- 
dose for systolic and diastolic BP, pulse rate and respiratory rate values 
The maximum decrease and increase from baseline over all measurements taken post-dose will 
be calculated for supine systolic and diastolic blood pressures and pulse rates. The maximum 
increase from baseline will be calculated by selecting the maximum change from baseline over 
the respective period, 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 change from baseline. In 
cases where a participant does not show a decrease, the minimum increase should be taken. 
 
3.5.4. Electrocardiograms 
A single 12-lead ECG will be obtained on all participants at screening, follow-up visit and at 
early termination (if applicable). 12-lead ECGs will be recorded in triplicate at all other times 
as detailed in the Schedule of Activities given in the protocol. The average of the triplicate 
readings collected at each assessment time will be calculated for each ECG parameter. 
The average of the triplicate ECG measurements over the 3 pre-dose measurement times (-1H, 
-0.5H, and predose 0H; total of 9 ECG measurements) collected before morning dose 
administration on Day 1 will serve as each participant’s baseline value in each study period. 
ECG endpoints include heart rate, QT interval, PR interval and QTcF and QRS complex. If 
not supplied QTcF will be derived using Fridericia’s heart rate correction formula: 
QTcF = QT / (RR)1/3 
where RR = 60/HR (if RR not provided). 
The following endpoints will be determined: 
• Change from baseline in QT, QTcF, PR, QRS interval and heart rate 
• The maximum post-dose QTcF, heart rate, PR and QRS interval 
• The maximum increase from baseline over all measurements taken post-dose for QTcF, 
heart rate, PR and QRS values 
The maximum increase from baseline will be calculated by selecting the maximum change 
from baseline over the respective period, except in the case where a participant does not show 
an increase. In such an instance, the minimum decrease should be taken. 


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3.5.5. Continuous Cardiac Monitoring 
Continuous cardiac monitoring will be performed using telemetry as outlined in the protocol. 
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. Events deemed of clinical concern will be 
recorded as AEs and will be summarized as part of the standard AE outputs. 
3.5.6. Physical Exam 
Complete physical exam will be carried out at screening or upon admission for a participants 
first period in the study; at all other timepoints a brief physical exam may be performed for the 
findings during a previous exam or new/open AEs at the investigators discretion. Height and 
weight will only be measured at the screening visit. 
Physical examination findings collected during the study will be considered source data and 
will not be required to be reported, unless otherwise noted. Any untoward physical 
examination findings that are identified during the active collection period will be captured as 
AEs or SAEs, if those findings meet the definition of an AE or SAE. 
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. 


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Table 3. 
Analysis Sets 
 
Participant 
Analysis Set 
Description 
Applicable Analysis 
(for additional 
information refer to 
section 6) 
Enrolled 
“Enrolled” means a participant’s agreement to 
participate in a clinical study following 
completion of the informed consent process and 
randomization to study intervention. A 
participant will be considered enrolled if the 
informed consent is not withdrawn prior to 
participating in any study activity after 
screening. Potential participants who are 
screened for the purpose of determining 
eligibility for the study, but do not participate in 
the study, are not considered enrolled, unless 
otherwise specified by the protocol. 
Safety 
analysis set 
All participants randomly assigned to study 
intervention and who take at least 1 dose of 
study intervention. Participants will be analyzed 
according to the study intervention they actually 
received. 
Section 6.6 Safety 
Summaries and 
Analyses 
PK 
Concentration 
Set 
All participants randomly assigned to study 
intervention and who receive at least 1 dose of 
study intervention and in whom at least 1 
plasma concentration value is reported. 
Section 6.3.1 PK 
Endpoints 
PK 
Parameter Set 
All participants randomly assigned to study 
intervention and who receive at least 1 dose of 
study intervention and have at least 1 of the PK 
parameters of interest calculated. 
Section 6.3.1 PK 
Endpoints 
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5. GENERAL METHODOLOGY AND CONVENTIONS 
5.1. Hypotheses and Decision Rules 
There are no formal statistical hypotheses or decision rules in this study. 
5.2. General Methods 
Unless otherwise stated, all summaries and plots will be presented by treatment. If a dose level 
is repeated across 2 or more cohorts, the data will be combined, unless the dose is in a different 
food state (e.g. after an MMTT), in which case the dose would be reported separately. 
Unless otherwise stated the summary tables and/or statistical analyses will only include a single 
pooled placebo group across all included cohorts. Placebo will be pooled from all dose 
escalation periods but not the fed period. 
5.2.1. Analyses for Continuous Endpoints 
Continuous variables will be presented using summary statistics: number of observations, 
arithmetic mean, standard deviation, cv%, median, minimum and maximum values. 
Log transformed continuous variables will be presented using summary statistics: number of 
observations, arithmetic mean, median, cv%, standard deviation, minimum, maximum, 
geometric mean and geometric cv%. 
5.2.2. Analyses for Categorical Endpoints 
Categorical variables will be presented using summary statistics: number of observations, 
counts and percentages. 
5.2.3. Mixed Model for Repeated Measurements (MMRM) 
An MMRM model will be used with treatment, time (as a factor), treatment-by-time 
interaction, baseline and baseline-by-time interaction as fixed effects. Time will be fitted as a 
repeated effect within each participant*period. Baseline will be included as two separate 
variables, the average baseline for the participant, and the deviation of each treatment period 
baseline from the average baseline for each participant. An unstructured covariance matrix will 
be fitted to the repeated times within participant (other covariance matrices will be considered 
if necessary, e.g. if the model does not converge). 
The Least Squares (LS) means (and standard errors, 90% confidence intervals and 2-sided p- 
values) will be obtained for each treatment at each timepoint. Differences (and standard errors, 
90% confidence intervals and 2-sided p-values) between LS means will also be obtained, 
comparing each dose versus placebo. If data have been logged, LS means and differences 
(including CI’s) will be back transformed to give percent changes from baseline ([relative 
change from baseline -1]*100), and percent change from placebo ([ratio of relative change 
from baseline -1]*100). 
Example SAS code is provided in Appendix 2. 


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Statistical Model Diagnostics 
The presence of outliers will be investigated for this model. An outlier will be defined as any 
response data value with a studentized (conditional) residual greater than 3, or less than -3. A 
listing will be presented of any participants meeting these criteria and will be included with 
standard SAS output. The assumptions of normality will be verified graphically using 
residual plots. For each fitted model, a set of conditional studentized residual plots will be 
produced, including residual plot, histogram of normality, quartile-quartile (QQ) plot and 
summary of fit statistics. The residual plots will not be included in the CSR. 
If there are outliers or major deviations from normality, then the effect of these on the 
conclusions may be investigated through alternative transformations and/or analyses 
excluding outliers. Justification for any alternative to the planned analysis will be given in 
the report of the study. 
5.2.4. Mixed Effects Analysis of Variance (ANOVA) 
A mixed effects ANOVA with treatment as a fixed effect and participant as a random effect 
will be used for the analysis of PK endpoints. 
Least square (LS) estimates of the group means and mean differences along with standard 
errors, 90% confidence intervals and p-values will be presented, which will be back- 
transformed for data that was natural log-transformed prior to analysis. 
A figure showing the (back-transformed) LS means (with 90% confidence intervals) vs group 
will be produced. 
Example SAS code is provided in Appendix 2. 
Statistical model diagnostics as described in Section 5.2.3 would also be conducted for these 
analyses. 
5.2.5. Mixed Effects ANCOVA 
A mixed effects model with treatment as a fixed effect, baseline as a covariate and participant 
as a random effect will be used. Estimates of the adjusted mean differences (Test-Reference) 
and corresponding 90% confidence intervals will be obtained from the model. The adjusted 
mean differences and 90% confidence intervals for the differences will be exponentiated to 
provide estimates of the ratio of adjusted geometric means (Test/Reference) and 
90% confidence intervals for the ratios. 
Example SAS code is provided in Appendix 2. 
Statistical model diagnostics as described in Section 5.2.3 would also be conducted for these 
analyses. 


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5.3. Methods to Manage Missing Data 
5.3.1. Missing Safety Data 
For the analysis of safety endpoints, the sponsor data standard rules for imputation will be 
applied. 
5.3.2. Missing Pharmacokinetic (PK) Data 
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. 
Note that summary statistics will not be presented at a particular timepoint if more than 50% 
of the data are missing. 
If a PK parameter cannot be derived from a participant’s concentration data, the parameter will 
be coded as NC (ie not calculated). (Note that NC values will not be generated beyond the day 
that a participant discontinues). In summary tables, statistics will be calculated by setting NC 
values to missing; and statistics will be presented for a particular dose with ≥3 evaluable 
measurements. For statistical analyses (i.e. mixed effects model), PK parameters coded as NC 
will also be set to missing; and analyses will not be performed for a particular parameter if 
more than 50% of the data are NC. 
If an individual participant has a known biased estimate of a PK parameter (due for example 
to an unexpected event such as vomiting before all the compound is adequately absorbed in 
the body), this will be footnoted in summary tables and will not be included in the calculation 
of summary statistics or statistical analyses. 
6. ANALYSES AND SUMMARIES 
6.1. Primary Endpoint(s) 
The primary endpoints are related to safety/tolerability and their analyses are described in 
Section 6.6. 
6.2. Secondary Endpoint(s) 
The secondary endpoints as listed in Section 2.2 are related to PK and their analyses are 
described in Section 6.3.1. 


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6.3. Other Endpoints 
6.3.1. PK Endpoints 
The PK parameters detailed in Section 3.3.1 will be listed and summarized for participants in 
the PK Parameter Analysis Set (as defined in Section 4). Missing values will be handled as 
detailed in Section 5.3. Each PK parameter will be summarized by dose (and fasting condition, 
if appropriate) as applicable. Each summary will include the set of summary statistics as 
specified in Table 4. 
Table 4. 
PK Parameters to be Summarized Descriptively 
 
Parameter 
Summary Statistics 
AUClast, AUCinf, Cmax, CL/F, 
Vz/F, 
AUClast(dn), 
AUCinf(dn), Cmax(dn) 
N, arithmetic mean, median, cv%, standard deviation, 
minimum, maximum, geometric mean and geometric 
cv%. 
Tmax 
N, median, minimum, maximum. 
t1/2 
N, arithmetic 
mean, median, standard deviation, 
minimum, maximum. 
The plasma PK parameters will be summarized descriptively by dose (and fasting condition, if 
appropriate) as applicable. Dose-normalized AUCinf, AUClast, and Cmax will be plotted against 
dose (and fasting condition, if appropriate) using a logarithmic scale, and will include 
individual participant values and the geometric means for each dose. These plots will be used 
to understand the relationship between the PK parameters and dose (and fasting condition, if 
appropriate). 
Geometric means will have a different symbol than the individual values. A footnote will be 
added to the plots to indicate that geometric means are presented. All dose normalized 
parameters will be listed along with other individual PK parameters. 
Supporting data from the estimation of t½ will be listed by treatment and dose where applicable: 
terminal phase rate constant (kel); goodness of fit statistic from the log-linear regression (r2); 
the percent of AUCinf based on extrapolation (AUCextrap%); and the first, last, and number of 
time points used in the estimation of kel. These data may be included in the CSR. 
Presentations for PF-07328948 concentrations will be presented using participants in the PK 
Concentration Set (as defined in Section 4) and will include: 
• a listing of all concentrations sorted by participant ID, dose 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. 


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CCI 
• 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), 
coloured by dose. 
• individual concentration-time plots by participant (on both linear and semi-log scales) 
against actual time post-dose (there will be separate spaghetti plots for each dose per scale), 
coloured by dose. 
• median concentration-time plots (on both linear and semi-log scales) against nominal time 
post-dose by dose (all doses on the same plot per scale, based on the summary of 
concentrations by dose and time post-dose), coloured by dose. 
• mean concentration-time plots (on both linear and semi-log scales) against nominal time 
post-dose by dose (all doses on the same plot per scale, based on the summary of 
concentrations by dose and time post-dose), coloured by 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-07328948 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. 
If the food effect is assessed the PK parameters will also be summarized descriptively as 
described above by fasting condition. 
To assess any effect of food in Cohort 2 and/or Cohort 3, a mixed effects ANOVA will be 
performed separately on the natural log transformed AUCinf, AUClast, and Cmax (dose- 
normalized prior to analysis, if appropriate) with fasting condition included as a fixed effect 
and participant as a random effect, as described in Section 5.2.4. If performed, only data from 
the respective periods that includes the two treatments of interest will be included. The 
Kenward-Roger adjustment for the degrees of freedom will be used. Estimates of the adjusted 
mean differences (Test-Reference) and corresponding 90% CIs will be obtained from the 
model. The adjusted mean differences and 90% CIs for these differences will be exponentiated 
to provide estimates of the ratio of adjusted geometric means (Test/Reference) and 90% CIs 
for these ratios. The treatment in the fasted state will be the reference and the test treatment 
will be in the fed state. 
 
 
 


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6.4. Subset Analyses 
No subset analyses will be performed. 
6.5. Baseline and Other Summaries and Analyses 
6.5.1. Baseline Summaries 
Demographic data (age, biological sex, race, ethnicity, weight, body mass index and height) 
will be summarised overall in accordance with the sponsor reporting standards. 
CCI 


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6.5.2. Study Conduct and Participant Disposition 
Participant evaluation groups will show participant disposition by treatment, overall and will 
show which participants were analyzed for PK and safety. Frequency counts and percentages 
will be supplied for participant discontinuation(s) by treatment. Data will be reported in 
accordance with the sponsor reporting standards. 
6.5.3. 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 
All safety analyses will be performed on the Safety Analysis Set. 
6.6.1. Adverse Events 
Adverse events will be listed and summarized by treatment and overall, in accordance with 
sponsor reporting standards using the safety analysis set defined in Section 4. 
6.6.2. Laboratory Data 
Laboratory data will be listed and summarized by treatment in accordance with the sponsor 
reporting standards using the safety analysis set defined in Section 4. Baseline is as defined in 
Section 3.5.2. 
Data collected at screening that are used for inclusion/exclusion criteria, will be considered 
source data, and will not be required to be reported, unless otherwise noted. 
6.6.3. Vital Signs 
Absolute values and changes from baseline in supine systolic and diastolic blood pressure, 
pulse rate and respiratory rate will be summarized by treatment and timepoint, according to 
sponsor reporting standards, using the safety analysis set defined in Section 4. Baseline is as 
defined in Section 3.5.3. 
Mean changes from baseline for supine systolic and diastolic blood pressure, pulse rateand 
respiratory rate will be plotted against time post-dose. On each plot there will be one line for 
each treatment. Dats from all cohorts will be plotted on the same figure using a single line for 
the placebo group(s). Corresponding individual plots of changes from baseline will also be 
produced for each treatment. 
Maximum increase and decrease from baseline over all measurements taken post-dose for 
supine systolic and diastolic blood pressures, pulse rate and respiratory rate will be summarized 
by treatment, according to sponsor reporting standards. 
Minimum and/or maximum absolute values and changes from baseline for supine vital signs 
will also be summarized descriptively by treatment using categories as defined in Appendix 1. 


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Numbers and percentages of participants meeting the categorical criteria will be provided. All 
planned and unplanned post-dose time points will be counted in these categorical summaries. 
Data collected at screening that are used for inclusion/exclusion criteria, will be considered 
source data, and will not be required to be reported, unless otherwise noted. 
6.6.4. Electrocardiograms 
Absolute values and changes from baseline in QT, heart rate, QTcF, PR and QRS will be 
summarized by treatment and timepoint using sponsor reporting standards, using the safety 
analysis set defined in Section 4. Baseline is as defined in Section 3.5.4. 
Mean changes from baseline in QT, heart rate and QTcF will be plotted against time post-dose. 
On each plot there will be one line for each treatment. Corresponding individual plots of 
changes from baseline will also be produced for each treatment. 
Changes from baseline in QTcF will also be plotted separately against drug concentrations of 
PF-07328948. 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, heart rate, PR and QRS values 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. Numbers and 
percentages of participants meeting the categorical criteria will be provided. All planned and 
unplanned postdose time points will be counted in these categorical summaries. 
Listings of participants with any single post-dose value >500msec will also be produced for 
QTcF. 
Data collected at screening that are used for inclusion/exclusion criteria, will be considered 
source data, and will not be required to be reported, unless otherwise noted. 
6.6.5. Continuous Cardiac Monitoring 
Continuous cardiac monitoring will be performed using telemetry as outlined in the protocol. 
Data will be reviewed and summarized on an ongoing basis during the study to evaluate the 
safety of participants. 
All abnormal rhythms will be recorded and reviewed by the investigator 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. Events deemed of clinical concern will be 
recorded as AEs and will be summarized as part of the standard AE outputs. 
6.6.6. Physical Examination 
Physical examinations will be performed as described in the protocol. 


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Medical history and physical examination as applicable, collected during the course of the 
study will be considered source data and will not be required to be reported, unless otherwise 
noted. However, any untoward findings identified on physical and/or neurological 
examinations conducted during the active collection period will be captured as AEs, if those 
findings meet the definition of an AE. 
Data collected at screening that are used for inclusion/exclusion criteria, will be considered 
source data, and will not be required to be reported, unless otherwise noted. 
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 data during the course of the study 
for the purpose of safety and tolerability 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. 
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 
 
 
 
 
 
Categories for PR and QRS 
 
PR (ms) 
max. ≥300 
PR (ms) increase from baseline 
Baseline >200 and 
max. ≥25% increase 
Baseline ≤200 and 
max. ≥50% increase 
QRS (ms) 
max. ≥140 
QRS (ms) increase from baseline 
≥50% increase 
 
Categories for Vital Signs 
 
Systolic BP (mm Hg) 
min. <90 
Systolic BP (mm Hg) change from baseline 
max. decrease ≥30 
max. increase ≥30 
Diastolic BP (mm Hg) 
min. <50 
Diastolic BP (mm Hg) change from baseline 
max. decrease ≥20 
max. increase ≥20 
Supine pulse rate (bpm) 
min. <40 
max. >120 
Degree of Prolongation 
Mild 
Moderate 
Severe 
Absolute value (msec) 
 450 and 480 
>480 and 500 
>500 
Increase from baseline 
(msec) 
 30 and 60 
>60 


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Appendix 2. Example SAS Code for Statistical Analyses 
CCI 
 
 
 
 
Mixed Effects ANOVA: (PK parameters) 
 
proc mixed data = dataset method = ml; 
class subjid treattxt; 
model &var = treattxt /residual; 
random subjid; 
lsmeans treattxt / diff cl alpha = 0.1; 
run; 


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Appendix 3. List of Abbreviations 
 
Abbreviation 
Term 
AE 
Adverse Event 
ANCOVA 
Analysis of Covariance 
ANOVA 
Analysis of Variance 
CCI 
BCAA 
branched-chain amino acid 
BCKA 
branched-chain ketoacid 
BCKDH 
branched-chain ketoacid dehydrogenase 
BDK 
branched chain ketoacid dehydrogenase kinase 
BLQ 
below the limit of quantitation 
BP 
blood pressure 
CI 
confidence interval 
Cmax 
maximum observed concentration 
CRF 
case report form 
CSR 
clinical study report 
ECG 
electrocardiogram 
FDA 
Food and Drug Administration (United States) 
HR 
Heart Rate 
LLOQ 
lower limit of quantitation 
LOD 
limit of detection 
LS 
least-squares 
LSM 
least-squares mean 
MMRM 
mixed-effects model with repeated measures 
MMTT 
Mixed Meal Tolerance Test 
N/A 
not applicable 
CCI 
PD 
pharmacodynamic(s) 
PK 
pharmacokinetic(s) 
QTc 
corrected QT 
QTcF 
corrected QT (Fridericia method) 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SD 
standard deviation 
SOP 
standard operating procedure 
ULN 
upper limit of normal