Conditions: Healthy
Allocation: RANDOMIZED | Intervention model: SEQUENTIAL
Enrollment: 61
Healthy volunteers: yes

Brief summary:
The purpose of the study is to evaluate the safety, tolerability, pharmacokinetics (PK) and pharmacodynamic (PD) of single and multiple ascending oral doses of PF-07059013 in healthy adult participants. Additionally, effects of different formulations and food on parameters, including PK may be explored.

Detailed description:

Arms:
arm 1: PF-07059013 assignment arm 2: Placebo assignment

Interventions: intervention 1: PF-07059013 intervention 2: Placebo
Intervention descriptions: intervention 1: Participants will recieve PF-07059013 intervention 2: Participants will recieve placebo

Protocol document:
Prot_000.pdf: 
PF-07059013
Protocol C4061001
Final Protocol Amendment 1, 24 July 2020
PFIZER CONFIDENTIAL
Page 1
A PHASE 1, RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED, 
SINGLE AND MULTIPLE DOSE ESCALATION STUDY TO EVALUATE SAFETY, 
TOLERABILITY, PHARMACOKINETICS AND PHARMACODYNAMICS OF 
PF-07059013 AND OPEN-LABEL ASSESSMENT OF FOOD AND FORMULATION 
ON PHARMACOKINETICS OF PF-07059013 IN HEALTHY ADULT
PARTICIPANTS
Study Intervention Number:
PF-07059013
Study Intervention Name:
N/A
US IND Number:
N/A
EudraCT Number:
2019-004918-34
Protocol Number:
C4061001
Phase:
1
Short Title: A Phase 1 Study of Single and Multiple Ascending Doses of PF-07059013 
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-07059013
Protocol C4061001
Final Protocol Amendment 1, 24 July 2020
PFIZER CONFIDENTIAL
Page 2
Protocol Amendment Summary of Changes Table
Document History
Document
Version Date
Summary and Rationale for Changes
Amendment 1
24 July 2020
Section 1.3. (Schedule of Activities), and 
4.2 (Scientific Rationale for Study Design)
have been revised to include sample for 
reticulocyte on Day 7 of Part 2 of the 
study.
Rationale: Alignment with pre-IND 
meeting feedback from FDA
Section 1.3. (Schedule of Activities), 
Section 3 (Objectives and Endpoints) and 
 
 
 
 
 
Section 5.3.1 (Meals and Dietary 
Restrictions) clarifies that water is 
permitted during the breakfast of fed 
treatment period in Part 3.
Section 5.1 (Inclusion Criteria) was 
updated to clarify cardiac monitoring in 
Part 1 only.
Section 6.1 (Study Intervention) was 
updated with tablet dose strength.
Section 1.3. (Schedule of Activities), 
Section 5.3.2 and Section 10.4.4 have been 
updated to incorporate Protocol 
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Protocol C4061001
Final Protocol Amendment 1, 24 July 2020
PFIZER CONFIDENTIAL
Page 3
AdministrativeClarification Letters (dated 
20 February 2020 and 04 June 2020).
Original protocol
12 February 2020
N/A
This amendment incorporates all revisions to date, including amendments made at the 
request of country health authorities and IRBs/ECs.


PF-07059013
Protocol C4061001
Final Protocol Amendment 1, 24 July 2020
PFIZER CONFIDENTIAL
Page 4
TABLE OF CONTENTS
LIST OF TABLES.....................................................................................................................9
1. PROTOCOL SUMMARY...................................................................................................10
1.1. Synopsis ..................................................................................................................10
1.2. Schema ....................................................................................................................14
1.3. Schedule of Activities .............................................................................................16
2. INTRODUCTION ...............................................................................................................24
2.1. Study Rationale .......................................................................................................24
2.2. Background .............................................................................................................24
2.2.1. Nonclinical Pharmacology..........................................................................25
2.2.2. Nonclinical Pharmacokinetics and Metabolism .........................................25
2.2.3. Nonclinical Safety ......................................................................................26
2.2.4. Biopharmaceutics .......................................................................................27
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.................................................................................................................32
4.1. Overall Design.........................................................................................................32
4.2. Scientific Rationale for Study Design.....................................................................34
4.3. Justification for Dose ..............................................................................................36
4.3.1. Prediction of Human Pharmacokinetics .....................................................36
4.3.2. Prediction of Efficacious Dose/Concentration ...........................................36
4.3.3. Dose Selection ............................................................................................36
4.3.3.1. Rationale for Dose Selection in Part 1 ......................................37
4.3.3.2. Rationale for Dose Selection in Part 2 ......................................39
4.3.3.3. Rationale for Dose Selection in Part 3 ......................................39
4.4. End of Study Definition ..........................................................................................40
5. STUDY POPULATION......................................................................................................40
5.1. Inclusion Criteria.....................................................................................................40
5.2. Exclusion Criteria....................................................................................................41


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Protocol C4061001
Final Protocol Amendment 1, 24 July 2020
PFIZER CONFIDENTIAL
Page 5
5.3. Lifestyle Considerations..........................................................................................43
5.3.1. Meals and Dietary Restrictions...................................................................43
5.3.2. Caffeine, Alcohol, and Tobacco .................................................................45
5.3.3. Activity .......................................................................................................45
5.3.4. Contraception..............................................................................................45
5.4. Screen Failures ........................................................................................................46
6. STUDY INTERVENTION..................................................................................................46
6.1. Study Intervention(s) Administered........................................................................46
6.1.1. Administration............................................................................................46
6.2. Preparation/Handling/Storage/Accountability ........................................................47
6.2.1. Preparation and Dispensing........................................................................48
6.3. Measures to Minimize Bias: Randomization and Blinding.....................................49
6.3.1. Allocation to Study Intervention ................................................................49
6.3.2. Breaking the Blind (Part 1 Period 1 to 3 and Part 2 only)..........................49
6.4. Study Intervention Compliance...............................................................................50
6.5. Concomitant Therapy..............................................................................................51
6.5.1. Rescue Medicine.........................................................................................51
6.6. Dose Modification...................................................................................................51
6.6.1. Dose Escalation and Stopping Rules..........................................................51
6.7. Intervention After the End of the Study..................................................................53
7. DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL...........................................................................53
7.1. Discontinuation of Study Intervention ....................................................................53
7.2. Participant Discontinuation/Withdrawal From the Study.......................................54
7.2.1. Withdrawal of Consent...............................................................................55
7.3. Lost to Follow up ....................................................................................................55
8. STUDY ASSESSMENTS AND PROCEDURES...............................................................56
8.1. Efficacy Assessments..............................................................................................57
8.2. Safety Assessments .................................................................................................57
8.2.1. Physical Examinations................................................................................57
8.2.2. Vital Signs ..................................................................................................58
8.2.2.1. Respiratory Rate........................................................................58


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Protocol C4061001
Final Protocol Amendment 1, 24 July 2020
PFIZER CONFIDENTIAL
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8.2.2.2. Temperature ..............................................................................59
8.2.3. Electrocardiograms.....................................................................................59
8.2.3.1. Continuous Cardiac Monitoring by Telemetry .........................59
8.2.4. Clinical Safety Laboratory Assessments ....................................................60
8.3. Adverse Events and Serious Adverse Events..........................................................60
8.3.1. Time Period and Frequency for Collecting AE and SAE Information.......61
8.3.1.1. Reporting SAEs to Pfizer Safety...............................................62
8.3.1.2. Recording Nonserious AEs and SAEs on the CRF...................62
8.3.2. Method of Detecting AEs and SAEs ..........................................................62
8.3.3. Follow-up of AEs and SAEs.......................................................................62
8.3.4. Regulatory Reporting Requirements for SAEs...........................................63
8.3.5. Exposure During Pregnancy or Breastfeeding, and Occupational 
Exposure ..........................................................................................................63
8.3.5.1. Exposure During Pregnancy......................................................63
8.3.5.2. Exposure During Breastfeeding ................................................65
8.3.5.3. Occupational Exposure .............................................................65
8.3.6. Cardiovascular and Death Events...............................................................65
8.3.7. Disease-Related Events and/or Disease-Related Outcomes Not 
Qualifying as AEs or SAEs..............................................................................65
8.3.8. Adverse Events of Special Interest.............................................................66
8.3.8.1. Lack of Efficacy........................................................................66
8.3.9. Medical Device Deficiencies......................................................................66
8.3.10. Medication Errors.....................................................................................66
8.4. Treatment of Overdose............................................................................................67
8.5. Pharmacokinetics ....................................................................................................68
8.5.1. Blood and Plasma for Analysis of PF-07059013 .......................................68
8.5.3. Urine for Analysis of PF-07059013 – Part 2, Only....................................69
8.6. Pharmacodynamics..................................................................................................70
8.7. Genetics...................................................................................................................71
8.7.1. Specified Genetics ......................................................................................71
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Protocol C4061001
Final Protocol Amendment 1, 24 July 2020
PFIZER CONFIDENTIAL
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8.9. Immunogenicity Assessments.................................................................................71
8.10. Health Economics .................................................................................................72
9. STATISTICAL CONSIDERATIONS ................................................................................73
9.1. Statistical Hypotheses .............................................................................................73
9.2. Sample Size Determination.....................................................................................73
9.3. Analysis Sets ...........................................................................................................73
9.4. Statistical Analyses .................................................................................................74
9.4.1. Safety Analyses ..........................................................................................74
9.4.1.1. Electrocardiogram Analyses......................................................75
9.4.2. Pharmacokinetic Analyses..........................................................................75
9.4.2.1. Derivation of Pharmacokinetic Parameters...............................75
9.4.2.2. Statistical Methods for PK Data................................................77
9.4.3. Pharmacodynamic Analyses.......................................................................78
9.5. Interim Analyses .....................................................................................................79
9.6. Data Monitoring Committee or Other Independent Oversight Committee.............79
10. SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS..........................................................................................................80
10.1. Appendix 1: Regulatory, Ethical, and Study Oversight Considerations...............80
10.1.1. Regulatory and Ethical Considerations ....................................................80
10.1.1.1. Reporting of Safety Issues and Serious Breaches of the 
Protocol or ICH GCP.........................................................................80
10.1.2. Financial Disclosure .................................................................................81
10.1.3. Informed Consent Process ........................................................................81
10.1.4. Data Protection .........................................................................................82
10.1.5. Dissemination of Clinical Study Data ......................................................82
10.1.6. Data Quality Assurance ............................................................................83
10.1.7. Source Documents....................................................................................85
10.1.8. Study and Site Start and Closure ..............................................................85
10.1.9. Publication Policy.....................................................................................86
10.1.10. Sponsor’s Qualified Medical Personnel .................................................86
10.2. Appendix 2: Clinical Laboratory Tests .................................................................88
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Final Protocol Amendment 1, 24 July 2020
PFIZER CONFIDENTIAL
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10.3. Appendix 3: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting ......................................................................90
10.3.1. Definition of AE .......................................................................................90
10.3.2. Definition of SAE.....................................................................................91
10.3.3. Recording/Reporting and Follow-up of AEs and/or SAEs.......................92
10.3.4. Reporting of SAEs....................................................................................95
10.4. Appendix 4: Contraceptive Guidance ...................................................................97
10.4.1. Male Participant Reproductive Inclusion Criteria....................................97
10.4.2. Female Participant Reproductive Inclusion Criteria.................................97
10.4.3. Woman of Childbearing Potential ............................................................97
10.4.4. Contraception Methods.............................................................................98
10.6. Appendix 6: Liver Safety: Suggested Actions and Follow-up Assessments ......101
10.7. Appendix 7: ECG Findings of Potential Clinical Concern .................................103
10.8. Appendix 8: Criteria for Vital Signs Abnormality..............................................105
10.9. Appendix 9: Abbreviations .................................................................................106
11. REFERENCES ................................................................................................................111
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Protocol C4061001
Final Protocol Amendment 1, 24 July 2020
PFIZER CONFIDENTIAL
Page 9
LIST OF TABLES
Table 1.
Predicted Human Exposure and Safety Margins Following 
Administration of Single Oral Doses of PF-07059013, in Part 1.............37
Table 2.
Predicted Human Exposure and Safety Margins Following 
Administration of Multiple Oral QD Doses of PF-07059013 for 14 
Days, in Part 2...........................................................................................39
Table 3.
Plasma and Blood PK Parameters Definitions for Part 1 (Single 
Ascending Dose) and Part 3 .....................................................................76
Table 4.
Plasma and Blood PK Parameters for Part 2 (Multiple Ascending 
Doses) .......................................................................................................77
Table 6.
Protocol-Required Safety Laboratory Assessments .................................88
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Protocol C4061001
Final Protocol Amendment 1, 24 July 2020
PFIZER CONFIDENTIAL
Page 10
1. PROTOCOL SUMMARY
1.1. Synopsis 
Short Title: A Phase 1 Study of Single and Multiple Ascending Doses of PF-07059013 in 
Healthy Adults
Rationale
PF-07059013 is a novel small molecule allosteric modulator of hemoglobin that is currently 
being developed for the treatment of Sickle Cell Disease. The purpose of the study is to 
evaluate the safety, tolerability, pharmacokinetics (PK) and pharmacodynamic (PD) of single 
and multiple ascending oral doses of PF-07059013 in healthy adult participants.  
Additionally, effects of different formulations and food on parameters, including PK may be 
explored.  This study is the first time that PF-07059013 will be administered to humans, and 
the results obtained from this study will inform future clinical development of PF-07059013.  
Based on modulation of the PD parameters (p20 and p50), results from Part 2 of this study 
may provide a demonstration of pharmacology for modulation of hemoglobin oxygen 
affinity.
Objectives and Endpoints
Objectives
Endpoints
Primary: 
Primary: 

Part 1 and 2

To evaluate safety and tolerability of single 
and multiple escalating oral doses of 
PF-07059013 suspension administered in 
healthy adult participants.

Assessment of AEs, clinical laboratory tests, vital 
signs (including blood pressure, pulse rate, 
respiratory rate and oral temperature) and cardiac 
conduction intervals and heart rate as assessed 
via 12-lead electrocardiogram (ECG).
Secondary: 
Secondary: 

Part 1 and 2 

To characterize the blood and plasma 
exposures of PF-07059013 following 
administration of single and multiple oral 
suspension doses in healthy adult participants.

PF-07059013 blood and plasma exposure 
parameters, as data permit: 

Part 1

Cmax, Tmax, and AUClast.

Part 2

Cmax, Tmax, AUCτ, on Days 1, 7 and 14.

Part 1 and 2

To evaluate the PD profile of PF-07059013 
following administration of single and 
multiple oral doses of suspension in healthy 
adult participants.

p20 and p50 change from baseline.


PF-07059013
Protocol C4061001
Final Protocol Amendment 1, 24 July 2020
PFIZER CONFIDENTIAL
Page 11
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Overall Design
This study consists of 3 parts, with ongoing review of safety, tolerability, PK and PD data 
planned. Part 1 comprises of 4 periods with 2 interleaving cohorts of healthy adult 
participants. Part 1 Period 1 to 3 is investigator- and participant-blinded, sponsor-open, 
randomized, single ascending dose, with 3-period placebo substitution crossover, and
Period 4 will be open-label.
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Protocol C4061001
Final Protocol Amendment 1, 24 July 2020
PFIZER CONFIDENTIAL
Page 12
Part 2 of this study will be investigator- and participant-blinded, sponsor-open, randomized, 
placebo-controlled, sequential, multiple ascending dose, with 3 planned cohorts of healthy 
adult participants.  Two additional cohorts of healthy adult participants may be included to 
permit assessment of any of the following: repeat of a previously administered dose level; 
studying additional dose levels as dictated by the evaluated safety, tolerability or PK of 
earlier dose levels; or any other assessment needed to meet the objectives of this study.
Part 3 of this study will be an open-label, randomized, 4-period crossover, single dose 
assessment of formulation and/or food effects in healthy adult participants.
Number of Participants
A total of approximately 50 (2 planned cohorts with approximately 9 in each cohort for 
Part 1 and 4 planned cohorts with approximately 8 in each cohort for Part 2 and 3) or up to 
approximately 70 (including optional Cohorts 6 and 7 and possible expansion to Part 3) 
healthy adult participants will be randomized.
Intervention Groups and Duration
For all parts of the study, participants will be screened within 28 days of their first dose of 
investigational product.  Participants will be admitted to the CRU on Day -1 and may be 
discharged at investigator discretion following completion of assessments per SoA.
Part 1 – Single Ascending Dose
Each participant may receive up to 3 single oral doses of PF-07059013 suspension and up to 
1 placebo dose.  For Period 1 to 3, at each period, approximately 6 participants will receive a 
single dose of PF-07059013 suspension formulated with polymer, and approximately 
3 participants will receive placebo.  In Period 4, a single dose of PF-07059013 suspension, 
formulated without polymer, will be administered at a dose level that has been previously 
administered in the same cohort. Between each dose administration to a given participant 
there will be a washout interval of at least 14 days.  The washout interval may be adjusted 
based on data emerging from previous cohorts/periods.  An on-site visit is scheduled for 
Day 8 (±1 day) of Period 3 and 4, and telephone follow-up contact will occur 28 to 35 days 
after the last dose of investigational product in the final period. The total planned duration of 
participation, from the Screening visit to the Follow-up phone call, is approximately 
15 weeks.


PF-07059013
Protocol C4061001
Final Protocol Amendment 1, 24 July 2020
PFIZER CONFIDENTIAL
Page 13
Part 2 – Multiple Ascending Dose
Each participant may receive multiple oral doses of PF-07059013 suspension (either with or 
without polymer, depending on results from Part 1) or placebo, over a duration of 14 days, 
depending on randomization. Participants will be required to stay at the CRU for the 
duration of the treatment phase.  An on-site follow-up visit and a telephone follow-up contact 
will take place at Day 21 (±1 day) and between Day 42-49, respectively. The total planned 
duration of participation, from the Screening visit to the Follow-up phone call, is 
approximately 10 weeks.
Part 3 – Formulation and Food Effects
Each participant may receive single oral dose of suspension with different formulations, or 
tablet, either under fasted condition or following a high-fat/high-caloric meal. Between each 
dose administration to a given participant there will be a washout interval of at least 14 days.  
The washout interval may be adjusted based on data emerging from previous cohorts/periods.  
A telephone follow-up contact will occur 28 to 35 days after the last dose of investigational 
product in the final period. The total planned duration of participation, from the Screening 
visit to the Follow-up phone call, is approximately 15 weeks.
Data Monitoring Committee or Other Independent Oversight Committee: No
Statistical Methods
Detailed methodology for summary and statistical analyses of the data collected in this study
is outlined here and further detailed in a statistical analysis plan (SAP), which will be
maintained by the sponsor.
No formal sample size calculation or statistical hypothesis testing will be performed in this 
study. Cohort size has been chosen to ensure appropriate sample size to provide adequate 
safety, toleration and PK information at each dose level and to provide a placebo comparison 
group, while minimizing exposure to humans of a new biologic entity. Safety data will be 
presented in tabular and/or graphical format and summarized descriptively, where 
appropriate. PK and PD data will be listed and descriptively summarized as required.


PF-07059013
Protocol C4061001
Final Protocol Amendment 1, 24 July 2020
PFIZER CONFIDENTIAL
Page 14
1.2. Schema
Sample study design schematics of Study Part 1, 2 and 3 are provided below. Doses are 
provided for illustrative purpose only.


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Protocol C4061001
Final Protocol Amendment 1, 24 July 2020
PFIZER CONFIDENTIAL
Page 15
Sample Dosing Scheme (Part 3 – Formulation and Food Effect)
Cohort
Period 1
Period 2
Period 3
Period 4
8
N=2
A
B
C
D
N=2
D
A
B
C
N=2
C
D
A
B
N=2
B
C
D
A
Treatment A: PF-07059013 oral suspension (Small particle size), fasted.
Treatment B: PF-07059013 oral suspension (Small particle size), fed.
Treatment C: PF-07059013 oral suspension (Moderate particle size), fasted.
Treatment D: PF-07059013 oral tablet, fasted.


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Protocol C4061001
Final Protocol Amendment 1, 24 July 2020
PFIZER CONFIDENTIAL
Page 16
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.
A.
Part 1 SoA – Single Ascending Dose
Visit Identifiera
Screening
Period 1 to Period 4b
F/U
Contactc
E/T
Days Relative to Day 1
Day -28 
to Day -2
Day 
-1
Day 1
Day 2
Day 3
Day 4
Day 5
Visitd
Day 81
28-35 
Days
Hours Post dose
0e
0.5
1
2
5
8
12
24
36
48
72
96
168
Informed consent
X
CRU confinement
X











X
Inclusion/exclusion criteria
X
Xo
Medical/medication history 
X
Demography
X
Physical exam (height and 
weight at Screening, only)f
X
X
X
12-Lead ECGg
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Supine blood pressureh and
pulse rate 
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Orthostatic blood pressure, 
respiratory rate and oral 
temperature
X
X
X
X
Continuous cardiac telemetry 
monitoring
Xi
X





X
Contraception check
X
X
X
X
X
X
Serious and nonserious adverse 
event monitoring
X














X
X
Study intervention
administrationj
X


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Protocol C4061001
Final Protocol Amendment 1, 24 July 2020
PFIZER CONFIDENTIAL
Page 17
A.
Part 1 SoA – Single Ascending Dose
Visit Identifiera
Screening
Period 1 to Period 4b
F/U
Contactc
E/T
Days Relative to Day 1
Day -28 
to Day -2
Day 
-1
Day 1
Day 2
Day 3
Day 4
Day 5
Visitd
Day 8±1
28-35 
Days
Hours Post dose
0e
0.5
1
2
5
8
12
24
36
48
72
96
168
Blood sampling:
HIV, HBsAg, HBsAb, HBcAb, 
HCVAb, PT/INR, aPTT and 
serum FSH (postmenopausal 
females only)
X
Safety laboratoryk
X
X
X
X
X
X
X
Lactatel
X
X
X
X
X
X
Ferritin and C reactive protein
X
X
X
X
Pharmacokinetic 
X
X
X
X
X
X
X
X
X
X
Xn
Xn
X
X
p20 and p50
X
X
X
 
Urine sampling:
Urine drug and cotinine testing
X
X
Urinalysis (and microscopy, if 
needed)
X
X
X
X
X
X
Abbreviations: →= ongoing/continuous event; aPTT = activated partial thromboplastin time; E/T = early termination; F/U = follow-up; HBcAb = hepatitis B core antibody; 
HBcAg = hepatitis B core antigen; HBsAg = hepatitis B surface antigen; HCVAb = hepatitis C antibody; HIV = human immunodeficiency virus; CRU = clinical research unit; 
ECG = electrocardiogram; FSH = follicle-stimulating hormone; H= hour; p20 = oxygen pressure at which 20% of the hemoglobin in a given blood sample is oxygenated; 
p50 = oxygen pressure at which 50% of the hemoglobin in a given blood sample is oxygenated; PT/INR = prothrombin time/internationalized normalized ratio.
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A.
Part 1 SoA – Single Ascending Dose
Visit Identifiera
Screening
Period 1 to Period 4b
F/U
Contactc
E/T
Days Relative to Day 1
Day -28 
to Day -2
Day 
-1
Day 1
Day 2
Day 3
Day 4
Day 5
Visitd
Day 8±1
28-35 
Days
Hours Post dose
0e
0.5
1
2
5
8
12
24
36
48
72
96
168
a.
Visit Identifier: Day relative to start of study treatment (Day 1).
b.
Period 1 to Period 4: Washout duration of at least 14 days between periods. May be adjusted based on emerging data. 
c.
F/U Contact: Follow-up phone call may occur via telephone and must occur 28 to 35 days after the last dose of investigational product in the final period.
d.
Visit Day 8: Only applicable for Period 3 and 4.
e.
Day 1 0 H: Predose sample collection/procedure, except for study treatment administration.
f.
Physical Examination: Complete physical examination will be conducted at Screening or upon admission (Day -1) in Period 1. Brief physical examination may be 
performed at other times, as appropriate, for findings during previous examination or new/open AEs, at investigator’s discretion.
g.
12-lead ECG: Single at Screening, and triplicate at all other timepoints.
h.
Supine blood pressure: Where orthostatic blood pressure assessment will be conducted, supine blood pressure does not need to be repeated separately.
i.
Continuous cardiac telemetry monitoring: Baseline telemetry to be recorded for at least 2 hours between admission and prior to dosing in Period 1 only while awake.  
Post dose telemetry will continue for 12 hours after dosing for each period.
j.
Study Treatment Administration: Participants should fast for at least 10 hours prior to dosing. Refer to Section 6.1.1 and Section 5.3.1.
k.
Safety laboratory: Participants should fast for at least 4 hours prior to sample collection, except Day 1 eight hours postdose sample. Only chemistry panel is required for 
Day 1 eight hours postdose.
l.
Lactate: Unless needed for screening, review of data is not required prior to dosing but data up to at least 8 hours post dose will be reviewed prior to dose escalation.
 
n.
Pharmacokinetic samples at 72 and 96 hours: Only applicable for Period 2 to 4.
o.
Inclusion/exclusion criteria Day -1: Period 1 only.
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B.
Part 2 SoA – Multiple Ascending Dose
Visit Identifiera
Scree
ning
Treatment Phase (all activities at 0H (predose) unless otherwise specified)
Follow-upb
E/T
Days Relative to Day 1
-28 
to -2
-1
1j
2
3
4
5
6
7j
8
9
10
11
12
13 
14j
15
16
17
18
Visit:
21±1
Contact:
42-49
Informed consent
X
CRU confinement
X
→
→
→
→
→
→
→
→
→
→
→
→
→
→
→
→
→
X
Inclusion/exclusion criteria
X
X
Medical/medication history 
X
Demography
X
Physical exam (height and weight at 
Screening, only)c
X
X
X
12-Lead ECGd
X
X
X
Xk
X
Xk
X
X
X
X
X
Supine blood pressure and pulse ratee
X
X
X
Xk
X
Xk
X
X
X
X
X
Orthostatic blood pressure, 
respiratory rate and oral temperature
X
X
X
X
Contraception check 
X
X
X
X
X
X
Serious and nonserious adverse event 
monitoring
X
→
→
→
→
→
→
→
→
→
→
→
→
→
→
→
→
→
→
→
→
X
X
Study intervention administrationf
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Blood Sampling:
HIV, HBsAg, HBsAb, HBcAb, 
HCVAb, PT/INR, aPTT and serum 
FSH (postmenopausal females only) 
X
Safety laboratoryg
X
X
X
X
X
X
X
X
X
X
X
Lactateh
X
X
X
X
X
X
X
X
X
X
X
EPOh
X
X
X
X
X
X
Reticulocytesh
X
X
X
X
X
X
X
Ferritin & C reactive protein
X
X
X
X
X
X
Pharmacokinetici
X
X
Xk
X
X
Xk
X
X
X
X
X
X
X
p20 and p50
X
X
X
X
X
X
X
Urine Sampling:
Urine drug and cotinine testing
X
X
Urinalysis (and microscopy, if 
needed)
X
X
X
X
X
X
X
X
X
X
CCI
C
C


PF-07059013
Protocol C4061001
Final Protocol Amendment 1, 24 July 2020
PFIZER CONFIDENTIAL
Page 20
B.
Part 2 SoA – Multiple Ascending Dose
Visit Identifiera
Scree
ning
Treatment Phase (all activities at 0H (predose) unless otherwise specified)
Follow-upb
E/T
Days Relative to Day 1
-28 
to -2
-1
1j
2
3
4
5
6
7j
8
9
10
11
12
13 
14j
15
16
17
18
Visit:
21±1
Contact:
42-49
a.
Visit Identifier: Day relative to start of study treatment (Day 1).
b.
Follow-up: Onsite follow-up visit to occur between Day 20 to Day 22. Follow-up contact may occur via telephone and must occur 28 to 35 days from administration of 
the final dose of investigational product (ie, Day 42 to Day 49). 
c.
Physical Examination: Complete physical examination will be conducted at Screening or upon admission (Day -1). Brief physical examination may be performed at 
other times, as appropriate, for findings during previous examination or new/open AEs, at investigator’s discretion.
d.
12-lead ECG: Single at Screening, and triplicate at all other timepoints.
e.
Supine blood pressure: Where orthostatic blood pressure assessment will be conducted, supine blood pressure does not need to be repeated separately.
f.
Study Treatment Administration: Refer to Section 6.1.1 and Section 5.3.1.
g.
Safety laboratory: Participants should fast for at least 4 hours prior to sample collection, except 8 hours postdose sample. Only chemistry panel is required for 8 hours 
postdose.
h.
Lactate, EPO, Reticulocytes: Unless needed for screening, review of data is not required prior to dosing but lactate and EPO data up to at least Day 7, and reticulocyte 
data up to at least Day 14 will be reviewed prior to dose escalation.  Refer to Section 6.6.1 for details.
i.
Pharmacokinetics:
For dosing days - Samples will be collected predose, where applicable. For Day 1, 7 and 14, refer to C List of Procedures for Part 2 Study Day 1, 7 and 14.
For post last dose - Day 15 samples will be collected 24H and 36H post last dose, Day 16 to 18 samples will be collected 48H, 72H and 96H post last dose respectively.
j.
Day 1, 7 and 14: Refer to C List of Procedures for Part 2 Study Day 1, 7 and 14 for details.
k.
Day 4 and 10: PK samples, 12-lead ECG, supine blood pressure and pulse rate will be taken at predose and 8 hours postdose.
 
CCI
C
C


PF-07059013
Protocol C4061001
Final Protocol Amendment 1, 24 July 2020
PFIZER CONFIDENTIAL
Page 21
C.
List of Procedures for Part 2 Study Day 1, 7 and 14
Hours Post dose
0a
0.5
1
2
4
6
8
12
24
Continued CRU confinement
→
→
→
→
→
→
→
→
→ 
12-Lead ECGb
X
X
X
X
X
X
X
X
Supine blood pressurec and pulse rate
X
X
X
X
X
X
X
X
Orthostatic blood pressure, respiratory rate and oral temperature
X
X
X
Serious and nonserious adverse event monitoring
→
→
→
→
→
→
→
→
→ 
Study intervention administrationd
X
Safety laboratorye
Xg
X
Lactatef
Xg
X
EPO (Day 7 and 14 only)f
X
Reticulocytes (Day 7 and 14 only)f
X
Ferritin & C reactive protein (Day 14 only)
X
Pharmacokinetic
X
X
X
X
X
X
X
X
p20 and p50
X
X
Urinalysis (and microscopy, if needed)
Xg
Urine blank (Day 1 only)
X
a.
0 H: Predose sample collection.
b.
12-lead ECG: Triplicate supine measurements.
c.
Supine blood pressure: Where orthostatic blood pressure assessment will be conducted, supine blood pressure does not need to be repeated separately.
d.
Study Treatment Administration: Refer to Section 5.3.1 and Section 6.1.1.
e.
Safety laboratory: Participants should fast for at least 4 hours prior to sample collection, except 8 hours postdose samples. Only chemistry panel is required for 8 hours 
postdose samples.
f.
Lactate, EPO, Reticulocytes: Unless needed for screening, review of data is not required prior to dosing but lactate and EPO data up to at least Day 7, and reticulocyte 
data up to at least Day 14 will be reviewed prior to dose escalation, and cumulative results will be reviewed as they become available. Refer to Section 6.6.1.
g.
Safety laboratory and lactate 0 H: For Day 7 and 14 only.
CCI
CCI
C
C


PF-07059013
Protocol C4061001
Final Protocol Amendment 1, 24 July 2020
PFIZER CONFIDENTIAL
Page 22
D.
Part 3 SoA
Visit Identifiera
Screening
Period 1 to Period 4b
F/U 
Contactc
E/T
Days Relative to Day 1
Day -28 to 
Day -2
Day -1
Day 1
Day 2
Day 3
Day 4
Day 5
28-35 
Days
Hours After Dose
0d
0.5
1
2
5
8
12
24
36
48
72
96
Informed consent
X
CRU confinement
X
→
→
→
→
→
→
→
→
→
→
→
X
Inclusion/exclusion criteria
X
Xk
Medical/medication history 
X
Demography
X
Physical exam (height and weight at 
Screening, only)e
X
X
X
12-Lead ECGf
X
X
X
X
X
X
X
X
X
X
Supine blood pressure and pulse 
rate
X
X
X
X
X
X
X
X
X
X
Respiratory rate and oral 
temperature
X
X
X
Contraception check 
X
X
X
X
X
Serious and nonserious adverse 
event monitoring
X
→
→
→
→
→
→
→
→
→
→
→
→
→
X
X
High-fat/High-caloric meal
Xg
Study intervention administration
Xg
Blood sampling:
HIV, HBsAg, HBsAb, HBcAb, 
HCVAb, PT/INR, aPTT and serum 
FSH (postmenopausal females only) 
X
Safety laboratoryh
X
X
X
X
X
Lactatei
X
X
X
X
X
Ferritin and C reactive protein
X
X
X
X
Pharmacokinetic 
X
X
X
X
X
X
X
X
X
X
X
X
X
Urine sampling:
Urine drug testing
X
X
Urinalysis (and microscopy, if 
needed)
X
X
X
X
X
CCI


PF-07059013
Protocol C4061001
Final Protocol Amendment 1, 24 July 2020
PFIZER CONFIDENTIAL
Page 23
D.
Part 3 SoA
Visit Identifiera
Screening
Period 1 to Period 4b
F/U 
Contactc
E/T
Days Relative to Day 1
Day -28 to 
Day -2
Day -1
Day 1
Day 2
Day 3
Day 4
Day 5
28-35 
Days
Hours After Dose
0d
0.5
1
2
5
8
12
24
36
48
72
96
a.
Visit Identifier: Day relative to start of study treatment (Day 1).
b.
Period 1 to Period 4: Washout duration of at least 14 days between periods. May be adjusted based on emerging data.
c.
F/U Contact: Follow-up contact may occur via telephone and must occur 28 to 35 days after the last dose of investigational product in the final period. 
d.
Day 1 0 H: Predose sample collection/procedure, except for study treatment administration.
e.
Physical Examination: Complete physical examination will be conducted at Screening or upon admission (Day -1) in Period 1. Brief physical examination may be 
performed at other times, as appropriate, for findings during previous examination or new/open AEs, at investigator’s discretion.
f.
12-lead ECG: Single at Screening, and triplicate at all other timepoints.
g.
Study Treatment Administration & Meal: As determined by randomization scheme, dosing to occur with either high-fat/high-caloric meal (ie, provided approximately 
30 mins prior to dosing at 0H and expected to be completed approximately 10 minutes prior to dosing) or following an overnight fast of at least 10-hours, without breakfast.
Refer to Section 5.3.1 and Section 6.1.1.
h.
Safety laboratory: Participants should fast for at least 4 hours prior to sample collection.
i.
Lactate: Unless needed for screening, review of data is not required prior to dosing; accumulative results will be reviewed as they become available.
 
k.
Inclusion/exclusion criteria Day -1: Period 1 only.
C
C


PF-07059013
Protocol C4061001
Final Protocol Amendment 1, 24 July 2020
PFIZER CONFIDENTIAL
Page 24
2. INTRODUCTION
PF-07059013 is a novel small molecule allosteric modulator of hemoglobin that is currently 
being developed for the treatment of Sickle Cell Disease.
2.1. Study Rationale
The purpose of Part 1 of the study is to evaluate the safety, tolerability, PK and PD of single 
ascending oral doses of PF-07059013 in healthy adult participants.  Part 2 of this study will 
evaluate safety, tolerability, PK and PD following repeated oral doses of PF-07059013 in 
healthy adult participants at multiple ascending dose levels and in Part 3, effects of different 
formulations and food on parameters, including PK, after single oral dose, may be explored.
This study is the first time that PF-07059013 will be administered to humans, and the results 
obtained from this study will inform future clinical development of PF-07059013.  Based on 
modulation of the PD parameters (p20 and p50), results from Part 2 of this study may 
provide a demonstration of pharmacology for modulation of hemoglobin oxygen affinity.
2.2. Background
Sickle cell disease (SCD) is a multisystem disorder associated with episodes of acute illness 
and progressive organ damage and is one of the most common genetic disorders worldwide.1  
SCD is caused by a single point mutation on the -chain of adult hemoglobin A (HbA),
6 glutamic acid (Glu) to valine (Val) hemoglobin S (HbS).  This mutation results in a gain 
of function; Hb S polymerizes in the deoxygenated state, leading to red blood cell (RBC) 
sickling, precipitating downstream consequences including vaso-occlusion (pain crisis), 
hemolytic anemia, stroke and related pathophysiology.1-3  Over time, these features cause 
significant organ damage and eventual organ failure, dramatically impacting both quality of 
life and expected lifespan.
HbS polymerization is highly concentration dependent and requires concentration levels 
found in RBCs (upwards of 5 mM).  The exponential dependence of polymerization on HbS 
concentration indicates that relatively small changes in deoxy HbS concentration will have 
significant impact on time to polymerization and ultimately the clinical course of the 
disease.4-6  Further, the cyclical nature of oxygen delivery by hemoglobin means that the 
polymerization reaction is initiated and terminated with every passage of RBCs through the 
circulatory system, with most of the HbS fibers dissociating upon reoxygenation.  This 
“resetting” predicts that a delay in polymerization long enough for the RBC’s to return to the 
lungs is sufficient to ameliorate RBC sickling.  Thus delaying polymerization by stabilizing 
the oxygenates state of HbS is likely to have a significant impact on sickling.  Stabilizing the 
oxygenated state of HbS by small molecule covalent modification is a clinically validated 
approach.7,8  Stabilization of the oxygenated state has been clinically demonstrated to inhibit 
HbS polymerization, reduce RBC sickling, reduce the frequency of VOC and resolve 
hemolytic anemia by reducing hemolysis.7,9  Further, SCD patients with co-inheritance of 
hereditary persistence of fetal hemoglobin (fetal hemoglobin does not participate in the 
polymerization process), have a mild course of SCD.10,11  Each of these conditions 
effectively reduces the concentration of deoxy-HbS available to polymerize, thereby 
inhibiting the degree of cell sickling and impacting the course of the disease.


PF-07059013
Protocol C4061001
Final Protocol Amendment 1, 24 July 2020
PFIZER CONFIDENTIAL
Page 25
2.2.1. Nonclinical Pharmacology
PF-07059013 is a selective allosteric modulator of hemoglobin that is being developed as a 
prophylactic therapy that reduces the severity of anemia and reduces the frequency of 
vaso-occlusive crisis (VOC) in patients with SCD.  The binding kinetics of PF-07059013 to 
purified human HbS were analyzed using Surface Plasmon Resonance (SPR) and the binding 
affinity found to be in the double digit nanomolar range.  Co-crystallization of purified 
human HbA with PF-07059013 and subsequent X-ray crystallographic analysis indicate that 
PF-07059013 stabilizes the oxy-state conformation of HbA with 2 molecules of 
PF-07059013 bound at the interface of 2 α-subunits of the HbA tetramer.  A series of in vitro 
functional assays demonstrated that PF-07059013 can maintain purified human HbS in an 
oxygenated state under deoxygenating conditions and inhibit HbS polymerization in a dose 
dependent manner based on the extent of hemoglobin binding.  In in vitro cell based assays 
PF-07059013 induced modulation of oxygen affinity in whole blood measured using a 
Hemox Analyzer to determine shifts in the partial pressure of oxygen.  P50 is the partial 
pressure at which the hemoglobin in the sample is 50% O2 saturated, and the p20 is the 
partial pressure at which the hemoglobin in the sample is 20% O2 saturated, and both 
measurements report on the oxygen affinity of the sample.  In these studies, the p20 and 
p50 of whole blood from human, dog, and mouse incubated with 1 mM PF-07059013 was 
shifted to a similar magnitude suggesting that the PF-07059013 is similarly active in relevant 
toxicology species.
The Townes SCD mouse model has a knock-in mutation for human α-globin and human β 
sickle globin,12,13 recapitulates the main features of the disease and was used to test 
PF-07059013 PD effects in vivo.  In a series of single dose studies in Townes SCD mice, 
PF-07059013 treatment reduced RBC sickling in a dose-dependent fashion.  In a 15-day 
multiple-dose study in Townes SCD mice, PF-07059013 (200 mg/kg, BID), significantly 
improved markers of hemolytic anemia including increasing both hemoglobin and hematocrit 
and reducing reticulocytes in peripheral blood.  Further, SCD mice treated with PF-07059013 
showed reduced levels of the inflammatory marker sVCAM-1 relative to control animals in 
the 2-week study.  
Details of the nonclinical pharmacology are included in the Investigator’s Brochure (IB).
2.2.2. Nonclinical Pharmacokinetics and Metabolism
The PK of PF-07059013 are driven by the ditopic nature of binding to Hb across species.  
PF-07059013 is moderately bound in plasma (fup ranging from 0.088 in mouse to 0.162 in 
human), but significantly more highly bound in blood.  The blood binding is concentration 
dependent, with fub ranging from 0.00661 to 0.000559 in human blood between 1 and 
3000 µM.  This indicates that PF-07059013 partitions extensively into RBCs due to 
concentration dependent binding to hemoglobin.  This concentration dependence leads to 
dose dependent PK based on blood concentrations.  Such dose dependent blood PK make 
interpretation of each PK study relevant only to the doses used in that study.


PF-07059013
Protocol C4061001
Final Protocol Amendment 1, 24 July 2020
PFIZER CONFIDENTIAL
Page 26
Single dose PK studies with PF-07059013 were conducted following intravenous (1 mg/kg) 
and oral (10 mg/kg) administration to dogs.  PF-07059013 was rapidly absorbed following 
oral administration with an oral bioavailability of greater than 100%, which likely reflects the 
dose dependency.  Blood clearance following intravenous administration was 2 mL/min/kg 
and volume of distribution at steady state was 0.3 L/kg.
In toxicology studies, higher oral doses of PF-07059013 (80 to 1000 mg/kg/day) were 
administered to mice and dogs once or twice daily for up to 29 days.  At these doses, the
blood concentrations generally increased with increase with dose.
The high dose PK in preclinical species indicate that oral absorption of PF-07059013 is likely 
extensive, despite limited aqueous solubility at pH 6.5 and the P-glycoprotein substrate 
potential of the molecule.
Based on the preliminary biotransformation studies, glucuronidation was the primary 
metabolic pathway of PF-07059013.  The major human clearance pathway for PF-07059013 
is expected to be UGT-mediated metabolism by UGT1A9 (predicted fm = 0.6) with minor 
contributions from other UGT (predicted fm = 0.36) and CYP (predicted fm = 0.04) enzymes.  
No human unique metabolites were observed from in vitro human hepatocytes compared to 
metabolic profiles in mouse and dog blood.  Renal excretion of PF-07059013 was limited in 
dog.
At the predicted clinically efficacious dose, following existing regulatory guidance, there is a 
low potential risk of a clinical interaction due to PF-07059013 time dependent 
inhibition (TDI) of CYP3A4, induction of CYP3A4 and CYP2B6, and inhibition of UGT1A9 
and UGT1A1.  Additionally, in vitro PF-07059013 is a weak inhibitor of P-glycoprotein, 
BCRP, OATP1B1 and OCT1.
Further details may be found in the IB.
2.2.3. Nonclinical Safety
PF-07059013 was evaluated in pivotal 1-month toxicity studies (with 1-month recovery) in 
mice (80, 250, 1000 mg/kg/day) and dogs (100 [50 BID], 300 [150 BID], 1000 [500] 
mg/kg/day).  Safety pharmacology studies included a 1-day dog cardiovascular
(CV; 80 [40 BID], 240 [120 BID], 540 [270 BID] mg/kg/day) and a single-dose mouse 
neuro-pulmonary (80, 250, 1000 mg/kg/day) assessment.  While the whole blood 
concentrations correlate with the pharmacological responses of PF-07059013, exposure 
margins are calculated based on unbound plasma concentrations because, at steady state, they 
are the concentrations that tissues (outside of the red blood cells) are exposed to. Safety 
margins are presented as multiples of unbound plasma Cmax (0.18 µg/mL) and AUC(0-24) 
(3.9 µg•h/mL) for the human projected Ceff. Further information for whole blood is provided 
in the IB.
Consistent with its pharmacology, the blood and hematopoietic organs are the primary target 
of PF-07059013, leading to increased erythropoiesis in the bone marrow, spleen, and/or liver 
and associated hematology changes (mainly RBC mass parameters and reticulocytes 
increases) in both species.  The increase in reticulocytes (up to 4.0 to 5.5-fold control or 
baseline in mouse and dog, respectively) was only noted at the high dose of 1000 mg/kg. 


PF-07059013
Protocol C4061001
Final Protocol Amendment 1, 24 July 2020
PFIZER CONFIDENTIAL
Page 27
Other effects such as heart rate (HR) increase (up to +53 bpm, baseline to Day 1 postdose)
and marginal blood pressure (BP) changes in dogs, decreases in body temperature and 
locomotor activity (up to -95% of control), lower respiratory rates (up to -50% of control)
and minute volume in mice, and iron deposition in the liver and/or kidney in mice and/or 
dogs (minimal to mild severity) are mostly considered secondary to the pharmacology of 
increased oxygen affinity to hemoglobin leading to transient tissue hypoxia.
None of the nonclinical findings were adverse in the context of the studies; therefore, the 
NOAEL was the highest dose tested in both mouse and dog pivotal toxicity studies, 
1000 mg/kg/day, which was associated with exposure (Cmax/AUC24) margins of 
24.6×/7.9× in mice and 8.6×/5.8× in dogs of the projected unbound plasma Cmax/AUC24 at 
the projected efficacious dose. The NOAEL in dog was associated with unbound plasma 
Cmax of 1.5 µg/mL and AUC(0-24) of 22.5 µg·h/mL.
PF-07059013 was weakly aneugenic at 1000 mg/kg with a NOEL of 250 mg/kg/day in mice 
(10.7× projected unbound plasma Cmax at the projected efficacious dose).  The follow-on 
chromosome aberration assessment at 1000 mg/kg was confirmed negative for clastogenicity.  
PF-07059013 absorbs ultraviolet/visible light and its risk for phototoxicity will be further 
assessed prior to large enrollment clinical trials.
Details of the nonclinical safety are provided in the IB.
2.2.4. Biopharmaceutics
PF-07059013 is a basic compound. cLogP and permeability, as measured in cell lines, 
indicate that the molecule should rapidly permeate the intestinal membrane. The solubility 
will be high in gastric fluid and moderate in intestinal pH. Based on preclinical exposure 
data and/or modelling, PF-07059013 is expected to be moderately to well absorbed at the 
predicted dosing range in the First in Human (FIH) study (100 – 3000 mg) using a 
suspension formulation. Based on physical chemical properties and in silico prediction, food 
is expected to have an ambiguous impact on PF-07059013 exposure.
A formulation with a small particle size and a formulation with a moderate particle size may 
be studied to determine the effect of particle size on bioperformance.  This data will be 
utilized to identify a preferred particle size range for optimal performance of the drug 
product. The impact of the presence of a polymer on the pharmacokinetics of the 
formulation may be evaluated and compared to the formulation without polymer.  This data 
will be utilized to select the preferred formulation composition for the drug product.  
Further details are included in the IB.
2.3. Benefit/Risk Assessment
More detailed information about the known and expected benefits and risks and reasonably 
expected adverse events (AEs) of PF-07059013 may be found in the IB, which is the single 
reference safety document (SRSD) for this study.


PF-07059013
Protocol C4061001
Final Protocol Amendment 1, 24 July 2020
PFIZER CONFIDENTIAL
Page 28
2.3.1. Risk Assessment
Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
Study Intervention(s) PF-07059013
Tissue hypoxia
Data from hemoglobin variants with excessively 
high oxygen affinity demonstrate homeostatic 
responses reflective of tissue hypoxia.
Treatment dose is modeled to target exposure 
levels that will not provide a level of hemoglobin 
coverage that would be anticipated to compromise 
oxygen delivery to tissues.
Monitor for evidence of impaired oxygen delivery 
based on endpoints of lactate and erythropoietin
level.
Monitor for excessive pharmacology that could 
result in impaired oxygen deliver to tissues based 
on endpoint of p50 with associated laboratory 
correlates of erythropoietin level, lactate, and 
absolute reticulocyte count, with stopping rule on 
dose escalation based on the above.
Tachycardia
In single dose cardiovascular and 1-month repeat 
dose GLP study in dogs, exposure above the 
NOEL was associated with dose responsive
increases in heart rate.
Monitor based on heart rate.
Can be pharmacologically treated.
Reversible.
Hypertension/Hypotension
Marginal changes in blood pressure were noted in 
both the single dose cardiovascular and 1-month 
repeat dose GLP studies in dogs at the highest dose 
level tested in those studies. These changes 
included increases in systolic and diastolic blood 
pressure, as well as a biphasic decrease in systolic 
blood pressure.
Monitor based on blood pressure.
Can be treated pharmacologically.
Reversible.


PF-07059013
Protocol C4061001
Final Protocol Amendment 1, 24 July 2020
PFIZER CONFIDENTIAL
Page 29
Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
Iron accumulation
In the 1-month GLP toxicology studies at the 
intermediate and high dose levels in mouse and 
dog there was evidence of pigment (iron 
deposition) in the kidney, as well as in the liver at 
the high dose in the dog.
Monitor based on serum ferritin.
Can be treated with iron chelator drugs or with 
phlebotomy.
Aneugenic genetic toxicity
Micronucleus induction was noted in the mouse 
blood and bone marrow at 1000 mg/kg with a 
NOEL at 250 mg/kg.
Maintain sufficient safety margin based on 
micronucleus NOEL.
Phototoxicity
UV absorption was noted in UV spectral analysis.
Light restriction on storage, preparation and 
administration.
Participants will be advised to avoid direct 
sunlight exposure or high intensity UV exposure 
and instructed to apply sunscreen.
Further risk assessment will be conducted prior to 
large enrollment clinical trials.


PF-07059013
Protocol C4061001
Final Protocol Amendment 1, 24 July 2020
PFIZER CONFIDENTIAL
Page 30
2.3.2. Benefit Assessment
Study C4061001 is the first time that PF-07059013 will be administered to humans.  For 
healthy participants participating in this study, no clinical benefit is expected.  The purpose 
of the study is to generate safety, tolerability, PK and PD data  to provide the basis for further 
clinical development of PF-07059013 as a potential new, pharmacological agent for the 
treatment of individuals with SCD. This is an area of unmet need. As of issuance of this 
protocol, no specific human risks have been identified; postulated risks based on nonclinical 
studies are summarized in Section 2.2.3.  The clinical impact of these potential risks will be 
minimized through the proposed cautious dose escalation process where in higher doses of 
PF-07059013 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 that have been incorporated into this study 
including erythropoietin, reticulocyte, lactate and ferritin levels, where appropriate.  In 
addition, this study includes standard, intensive, inpatient monitoring of the participants 
following administration of oral doses of the investigational product.
2.3.3. Overall Benefit/Risk Conclusion
PF-07059013 is not expected to provide any clinical benefit to healthy participants in this 
study. Taking into account the measures taken to minimize risk to participants of this study, 
the potential risks identified in association with PF-07059013 are justified by the anticipated 
benefit, in terms of contribution to the process of developing new therapy in an area of unmet 
medical need.
3. OBJECTIVES AND ENDPOINTS
Objectives
Endpoints
Primary: 
Primary: 

Part 1 and 2

To evaluate safety and tolerability of single 
and multiple escalating oral doses of 
PF-07059013 suspension administered in 
healthy adult participants.

Assessment of AEs, clinical laboratory tests, vital 
signs (including blood pressure, pulse rate, 
respiratory rate and oral temperature) and cardiac 
conduction intervals and heart rate as assessed 
via 12-lead electrocardiogram (ECG).
Secondary: 
Secondary: 

Part 1 and 2

To characterize the blood and plasma 
exposures of PF-07059013 following 
administration of single and multiple oral 
suspension doses in healthy adult participants.

PF-07059013 blood and plasma exposure 
parameters, as data permit: 

Part 1

Cmax, Tmax, and AUClast.

Part 2

Cmax, Tmax, AUCτ, on Days 1, 7 and 14.

Part 1 and 2 

To evaluate the PD profile of PF-07059013 
following administration of single and 
multiple oral doses of suspension in healthy 
adult participants.

p20 and p50 change from baseline.


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Objectives
Endpoints
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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4. STUDY DESIGN
4.1. Overall Design
This study consists of 3 parts, with ongoing review of safety, tolerability, PK and PD data 
planned.
Part 1 – Single Ascending Dose
The design for Period 1 to 3 for Part 1 of this study is investigator- and participant-blinded, 
sponsor-open, randomized, single ascending dose, with 3-period placebo substitution 
crossover, while Period 4 will be open-label. There will be 2 interleaving cohorts of healthy 
adult participants, with a total of approximately 18 participants planned (approximately 
9 participants in each cohort). Each participant may receive up to 3 single oral doses of 
PF-07059013 and up to 1 placebo dose. For Period 1 to 3, at each period, approximately 
6 participants will receive a single dose of PF-07059013 oral suspension formulated with 
polymer, and approximately 3 participants will receive placebo. In Period 4, a single dose of 
PF-07059013 oral suspension, formulated without polymer, will be administered at a dose 
level that has been previously administered in the same cohort.
Part 2 – Multiple Ascending Dose
Part 2 of this study will be investigator- and participant-blinded, sponsor-open, randomized, 
placebo-controlled, sequential, multiple ascending dose.  A total of approximately 24 healthy 
adult participants will be randomized for Cohort 3 to 5. In each cohort, approximately 
6 participants will receive PF-07059013 oral suspension (either with or without polymer, 
depending on results from Part 1) and approximately 2 participants will receive placebo, over 
a duration of 14 days, depending on randomization. Two additional cohorts (optional 
Cohort 6 and 7) with approximately 8 participants each, with the same randomization ratio 
may be included to permit assessment of any of the following: repeat of a previously 
administered dose level; studying additional dose levels as dictated by the evaluated safety, 
tolerability or PK of earlier dose levels; or any other assessment needed to meet the 
objectives of this study.
The first dose level in Part 2 will only initiate after review of safety and PK data from both 
cohorts in Part 1 Period 4. Refer to Section 4.3.3 for additional details regarding 
determination of initial dose in Part 2 relative to dose(s) evaluated in Part 1.
Part 3 – Formulation and Food Effects
Part 3 of this study is designed to allow exploration of potential effects of food, particle size 
and tablet versus suspension formulation, on the PK of a single oral dose of PF-07059013.  
This part will be an open-label, randomized, 4-period crossover design. Approximately 
8 healthy adult participants will be randomized in Cohort 8.
Depending on emerging data from Part 1 (dosing of suspension-small particle size under 
fasted condition), assessment of the effects of 1) high-fat/high-caloric meal versus a fasted 
state, 2) moderate particle size versus small particle size, and 3) tablet formulation versus 


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suspension-small particle size, on the pharmacokinetics of PF-07059013 may be undertaken 
in Part 3.  The reference treatment and dose for Part 3 will be based on Part 1 (refer to
Section 4.3.3.3). Part 3 will occur only after completion of Part 1, though it may occur in 
parallel to Part 2.  The number of participants in Part 3 may be altered to randomize up to 
12 healthy adult participants, depending on emerging PK data from Part 1 of this study.
For Part 1 and 3, between each dose administration to a given participant there will be a 
washout interval of at least 14 days.  Participants may stay at the clinical research unit (CRU) 
for the duration of the washout period at the discretion of the investigator, this may be for 
safety or for logistic reasons.  The washout interval may be adjusted based on data emerging 
from previous cohorts/periods. An on-site visit is scheduled for Day 8 (±1 day) of Part 1 
Period 3 and 4 only, and a telephone follow-up contact will occur 28 to 35 days after the last 
dose of investigational product in the final period.  At the discretion of the investigator, 
telephone follow-up contact may be substituted with an on-site visit in case of additional 
follow-up of open AEs or clinically significant laboratory findings. 
The total planned duration of participation, from the Screening visit to the Follow-up phone 
call, is approximately 15 weeks.
For Part 2, participants will be required to stay at the CRU for the duration of the treatment 
phase. An on-site follow-up visit will take place at Day 21 (±1 day) and a telephone 
follow-up contact between Day 42 to 49.  At the discretion of the investigator, telephone 
follow-up contact may be substituted with an on-site visit in case of additional follow-up of 
open AEs or clinically significant laboratory findings. 
The total planned duration of participation, from the Screening visit to the Follow-up phone 
call, is approximately 10 weeks.
For all parts of the study, participants will be screened within 28 days of their first dose of 
investigational product.  Participants will be admitted to the CRU on Day -1 and may be 
discharged at investigator discretion following completion of assessments per SoA.  If a 
participant has any clinically significant, study-related abnormalities at the conclusion of a 
scheduled inpatient portion of the study, the Pfizer medical monitor (or designated 
representative) should be notified and the participant may be asked to remain in the CRU 
until such abnormalities are deemed not clinically significant, or it is safe for outpatient 
follow-up.  
Participants who discontinue for non-safety related reasons prior to completion of the study 
may be replaced, at the discretion of the principal investigator (PI) and sponsor.  The 
replacement participant(s) may or may not be required to complete all Periods of the cohort 
in which they are participating at the discretion of the PI and sponsor.
Sample design overview of the study is shown in Section 1.2. Treatment sequences, actual 
doses and dose increments may be adjusted and intermediate or alternative dose levels may 
be substituted during the study based on emerging safety, tolerability and PK data.


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4.2. Scientific Rationale for Study Design
The population planned for this study will be healthy male and female participants.  Female 
participants will be confirmed to be of non-childbearing potential, since at the present time 
embryo-fetal developmental toxicity studies with PF-07059013 have not been conducted.  In 
male participants, appropriate measures should be expected to be followed to minimize 
potential transfer of PF-07059013 via semen to partners (see Appendix 4: Contraceptive
Guidance).
Part 1
Given the current study is the first to dose PF-07059013 to humans, an escalating single oral 
dose design with careful assessment and ongoing review of safety and PK data of 
PF-07059013 is planned.  The crossover design will permit both a within and between 
participant assessment of safety, tolerability and PK.  Furthermore, 2 interleaving cohorts 
will permit assessment of safety and PK over a wider dose range within a given participant 
compared to a sequential cohort design. 
To guide formulation development, PF-07059013 suspension formulated with and without 
polymer will be assessed in Period 1 to 3 and Period 4, respectively. As the purpose for 
inclusion of the polymer is to explore potential enhancement of absorption, conduct of the 
dose escalation through Period 1 to 3, with the suspension formulated with the polymer 
allows assessment of safety at potentially higher PF-07059013 exposures, prior to the 
open-label assessment of the suspension formulation without polymer in Period 4, at dose 
level(s) previously evaluated in Period 1 to 3 of the same cohort.  
To permit an unbiased assessment of safety, the administration of active versus placebo in 
Period 1 to 3 will be double blinded to site staff (except those involved in preparation of 
doses) as well as the study participants.  To permit real-time review of the safety, PK data (as 
well as PD data, when available), a limited number of sponsor study team members will be 
unblinded (see Section 9.5).
In addition, dosing in the initial part of the study (Part 1) will be conducted in the fasting 
state (at least 10 hours) to facilitate management of any AEs which may occur shortly after 
dosing. For a given participant, dosing will be separated by ≥14 days. This planned dosing 
interval is deemed sufficient to permit washout of previous treatment based on the projected 
PF-07059013 effective half-life (see Section 4.3.1). Given that shorter effective half-life are 
anticipated at lower doses in Period 1 to 2 and to minimize burden on participants, additional 
visit on Day 8 is only planned for Period 3 and 4.
Part 2
Part 2 of this study is designed to assess the safety, tolerability, and PK, as well as potential 
PD of escalating doses of PF-07059013 administered for 14 days as a once-daily (QD) 
regimen.  In addition, based on in vitro data (Section 2.2.2), potential of PF-07059013 to 
cause P450 CYP3A4 induction will also be explored. The proposed duration of dosing 
(14 days) is of shorter duration than the 30 days of non-clinical toxicology data currently 
available.  This duration is also deemed to be sufficient to assess steady-state safety, PK, and 
PD given the projected effective half-life of PF-07059013 (see Section 4.3.1).  The planned 


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doses in the escalation sequence (refer to Section 6.6.1) may be modified or repeated, as 
guided by emerging safety and PK data (as well as PD data, when available) but will follow 
the dose escalation rules defined in Section 6.6.1.
To permit an unbiased assessment of safety, the administration of active versus placebo in 
each period will be double blinded to site staff (except those involved in preparation of 
doses) as well as the study participants.  To permit real-time review of the safety, PK data (as 
well as PD data), a limited number of sponsor study team members will be unblinded (see
Section 9.5).Part 3 
Based on the biopharmaceutical profile of PF-07059013 (see Section 2.2.4) and preliminary 
in silico predictions, there is uncertainty in the potential impact of food on the rate and extent 
of absorption, hence preliminary evaluation of the effect of food on the PK of PF-07059013 
is planned, to help guide the dose and dosing condition (fed versus fasting state) for future 
clinical studies with PF-07059013.
To better understand and guide formulation development for future clinical studies, 
preliminary assessment of a tablet formulation and examination of different particle size is 
also planned.
Since the dose in this Part (refer to Section 4.3.3.3) will be selected based on observed safety 
and tolerability of single doses in Part 1 and the dose selected will be lower than the highest 
dose tested in Part 1, standard safety monitoring will be used in this part of the study, without 
placebo control, and without on-site visit following discharge.
For all parts of the study
Considering the nonclinical safety studies with PF-07059013 in mice and dogs (see
Section 2.2.3), the standard safety assessments used by the sponsor in trials administering 
investigational product for the first time to humans are deemed suitable (see Appendix 2:
Clinical Laboratory Tests). In addition to the standard safety assessments, levels of lactate 
(Part 1 to 3), EPO and reticulocyte count (Part 2 only) will also be monitored to evaluate the 
potential risk of reduction in tissue oxygen delivery per unit volume of blood, for this class of 
mechanism. Due to the long half-life of RBC and lag for EPO stimulation, any potential 
effects on reticulocyte count and EPO will likely only manifest after a sustained period, 
hence assessments are planned for Part 2, from Day 7 onwards for EPO and reticulocyte 
count. Ferritin levels and respiratory rate will be also assessed based on non-adverse 
findings in the nonclinical studies with PF-07059013 (see Section 2.2.3), with ferritin 
assessment planned on/after Day 5 due to physiologic rationale that this is likely the earliest 
point at which modulation of ferritin could be detected.
To ensure that participants with undiagnosed hematological conditions and elevated baseline 
lactate are not enrolled, hemoglobin, reticulocyte count (Part 2 only), lactate, PT/INR and 
aPTT levels will also be assessed at screening.
To further permit assessment of modulation of oxygen affinity and possibly limit excessive 
pharmacological effect, measures of hemoglobin oxygen affinity (p20 and p50) will be 


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assessed at multiple timepoints in Part 1 and 2, including at the projected blood Tmax. 
Stopping criterion for dose escalation in Part 1 and 2, based on excessive modulation of p50, 
in association with physiologic correlates such as EPO, reticulocyte, and lactate level, where 
applicable, is detailed in Section 6.6.1. Given the potential effect of smoking on p50 levels, 
participants who smoke or use nicotine containing products are excluded from Part 1 and 2 of
the study.
 
4.3. Justification for Dose
Doses and dosing scheme presented are projected based on nonclinical data and may be 
modified based on emerging safety, tolerability, and PK data.
4.3.1. Prediction of Human Pharmacokinetics
PF-07059013 binds ditopically and cooperatively to Hb (2 drug molecules/Hb tetramer) as
evidenced by a concentration dependent decrease in blood fraction unbound in vitro and in 
vivo. A 2-step binding Hb model was developed and applied to PF-07059013 blood binding 
data in multiple species which accounted for this concentration dependency.
Human PK was predicted using a minimal physiologically-based pharmacokinetic (PBPK) 
model that utilizes in vitro data and SimCYP predictions, and incorporates the binding to Hb. 
As a result of concentration dependent Hb binding properties of PF-07059013, non-linear 
concentration dependent PK profile is projected. Dose-dependent decrease in apparent blood 
clearance (CL) and Vss is projected. Effective half-life predicted from the model ranges from 
7 hours at 100 mg to 41 hours at 3000 mg for healthy participants.
4.3.2. Prediction of Efficacious Dose/Concentration
Efficacious concentration is defined as average concentration at the dose resulting in 
approximately 25% Hb coverage in sickle cell patients at steady state – a coverage level 
expected to significantly reduce RBC sickling and improve Hb levels in SCD patients.14,15  
Using the minimal PBPK model and ditopic Hb binding affinities for PF-07059013, the 
steady state average concentration meeting this objective is predicted to be 0.16 μg/mL 
unbound plasma and 260 μg/mL blood total drug achieved at 1500 mg QD oral dose. The 
associated unbound plasma Cmax and unbound plasma AUC24 are projected to be 0.18 μg/mL 
and 3.9 μg•hr/mL respectively.
4.3.3. Dose Selection
Projections of human PK exposure for PF-07059013, along with the toxicity study data, and 
a minimal anticipated biological effect level (MABEL) approach, based on projected Hb 
coverage, are used to establish the nominal dose range to be studied in Part 1 (single 
escalating doses) and Part 2 (repeated escalating doses), with the aim to bracket the expected 
clinically efficacious dose range in humans and provide safety coverage for a wide range of 
predicted levels of Hb coverage. Approximately 40% Hb coverage has been previously 
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studied in healthy adult participants, for compounds with the same pharmacological 
mechanism, with no safety concerns detected.16,17
4.3.3.1. Rationale for Dose Selection in Part 1
Based on PK and Hb coverage predictions from the minimal PBPK model, 100 mg is 
proposed as the starting dose in Part 1. A single oral dose of 100 mg is predicted to provide 
maximum Hb coverage of less than 0.5%, and >66-fold safety margin relative the PK 
stopping limits (refer to Table 1). To account for uncertainty in the prediction of unbound 
intrinsic clearance using human hepatocytes, sensitivity analysis was performed assuming 
30% lower unbound intrinsic clearance. Projected maximum Hb coverage based on this 
assumption is less than 0.7%. Considering the precedence of the pharmacological 
mechanism, along with the projected safety margins and Hb coverage, the starting dose of 
100 mg is anticipated to be safe and have minimal pharmacological effect.
The planned dose escalation procedure will be dictated by the rules summarized in
Section 6.6.1 and is aimed to occur in increments of ≤½-log (ie, 3.3-fold) based on predicted 
unbound exposure, with smaller increments envisioned at higher doses, and will not exceed
unbound exposures defined in the PK stopping limits (See Section 6.6.1), or the highest 
practical dose of 4000 mg, whichever is the most conservative.
At the current proposed maximum single dose of 3000 mg, projected Hb coverage is 23%, 
and >5-fold safety margin relative to the PK stopping limits is predicted. Projected exposure 
of PF-07059013 at each planned dose level, as well as corresponding safety margins relative 
to exposures at the NOAEL in dog are summarized in Table 1. The PK stopping limits were 
chosen based on unbound PF-07059013 exposure achieved at the NOAEL dose 
(1000 mg/kg/day) in the 30-day toxicity study in dog, which provides more conservative 
margins than mouse NOAEL dose– refer to Section 2.2.3.
Table 1.
Predicted Human Exposure and Safety Margins Following Administration 
of Single Oral Doses of PF-07059013, in Part 1
Dosea
(mg)
Predicted Human Exposure of blood and plasma PF-07059013b
Predicted Safety 
Margin based on 
unbound
PF-07059013c
Max Hb 
coverage 
(%)
Blood
Cmax
(µg/mL)
Plasma 
Cmax
(µg/mL)
Unbound
Cmaxd
(µg/mL)
Blood
AUC24
(µg•hr/
mL)
Plasma
AUC24
(µg•hr/
mL)
Unbound
AUC24d
(µg•hr/mL)
Cmax
AUC24
100
6.8
0.14
0.0227
81
2
0.324
66.1
69.4
0.47
250
21
0.26
0.0421
310
4.4
0.713
35.6
31.6
1.4
500
48
0.39
0.0632
820
7.5
1.22
23.7
18.5
3.2
1000
110
0.59
0.0956
2000
12
1.94
15.7
11.6
6.9
2000
230
0.91
0.147
4600
19
3.08
10.2
7.31
15
3000
370
1.2
0.194
7300
26
4.21
7.72
5.34
23


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Table 1.
Predicted Human Exposure and Safety Margins Following Administration 
of Single Oral Doses of PF-07059013, in Part 1
Dosea
(mg)
Predicted Human Exposure of blood and plasma PF-07059013b
Predicted Safety 
Margin based on 
unbound
PF-07059013c
Max Hb 
coverage 
(%)
Blood
Cmax
(µg/mL)
Plasma 
Cmax
(µg/mL)
Unbound
Cmaxd
(µg/mL)
Blood
AUC24
(µg•hr/
mL)
Plasma
AUC24
(µg•hr/
mL)
Unbound
AUC24d
(µg•hr/mL)
Cmax
AUC24
a.
Depending on the available safety and PK data, dose escalation may be adjusted to doses other than those outlined 
above with intermediate doses evaluated instead of or in addition to the planned dose levels with increments being 
≤½-log (ie, 3.3-fold) while following dose escalation and stopping rules outlined in Section 6.6.1.
b.
Human exposure was predicted based on a minimal PBPK model using in vitro data and SimCYP predictions.
c.
Derived using exposure of PF-07059013 at NOAEL (1000 mg/kg/day) from 1 month dog toxicity study of unbound 
Cmax = 1.5 µg/mL and AUC24 = 22.5 µg•hr/mL.
d.
Unbound values calculated taking into account plasma protein binding in humans(fup=0.162).


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4.3.3.2. Rationale for Dose Selection in Part 2
Initiation of dosing in Part 2 will occur following review of safety and PK data from both 
cohorts in Part 1 Period 4 (see Section 4.1). At the starting dose level for Part 2, projected
unbound exposures (Cmax and AUC) at steady-state will be covered (approximately 2-fold 
lower) by exposures observed to have an acceptable safety profile in Part 1 of this study.
Projected Hb coverage will not exceed that from Part 1, and will not be higher than 15%.
The proposed starting dose in Part 2 is 600 mg QD. At this planned initial dose level, 
projected maximum Hb coverage is 7.4%, and predicted steady-state unbound exposures are 
Cmax of 0.0972 µg/mL and AUC24 of 1.94 µg•h/mL (>11-fold exposure multiples relative to 
the PK stopping limits). Planned dose escalation procedure will be dictated by the rules 
summarized in Section 6.6.1 and is aimed to occur in increments of ≤½-log (ie, 3.3-fold) 
based on predicted unbound exposures, with smaller increments envisioned once the 
projected clinically efficacious dose is exceeded, and will not exceed the predefined PK 
stopping limits (Section 6.6.1), or the highest practical dose of 4000 mg, whichever is the 
most conservative. The proposed nominal doses, corresponding projected PK exposures 
based on QD dosing, and safety margins relative to PK stopping limits set based on NOAEL 
from dog are summarized in Table 2.
Table 2.
Predicted Human Exposure and Safety Margins Following Administration 
of Multiple Oral QD Doses of PF-07059013 for 14 Days, in Part 2
Dosea
(mg)
Predicted Steady-State Human Exposure of Blood and Plasma 
PF-07059013b
Predicted Safety 
Margin at 
Steady State 
based on 
unbound
PF-07059013c
Max Hb 
coverage 
(%)
Blood
Cmax
(µg/mL)
Plasma 
Cmax
(µg/mL)
Unbound
Cmaxd
(µg/mL)
Blood
AUC24
(µg•hr/m
L)
Plasma
AUC24
(µg•hr/m
L)
Unbound
AUC24d
(µg•hr/mL)
Cmax
AUC24
600
110
0.6
0.0972
2100
12
1.94
15.4
11.6
7.4
1200
350
1.1
0.150
7100
25
3.10
10.0
7.26
22
2000
700
1.9
0.308
15000
41
6.64
4.87
3.39
45
a.
Depending on the available safety and PK data, dose escalation may be adjusted to doses other than those outlined 
above with intermediate doses evaluated instead of or in addition to the planned dose levels with increments being 
≤½-log (ie, 3.3-fold) while following dose escalation and stopping rules outlined in Section 6.6.1.
b.
Human exposure was predicted based on a minimal PBPK model using in vitro data and SimCYP predictions.
c.
Derived using exposure of PF-07059013 at NOAEL (1000 mg/kg/day) from 1 month dog toxicity study of unbound 
Cmax = 1.5 µg/mL and AUC24 = 22.5 µg•hr/mL.
d.
Unbound values calculated taking into account plasma protein binding in humans(fup=0.162).
4.3.3.3. Rationale for Dose Selection in Part 3
Depending on emerging data from Part 1 (and if available, data from Part 2), if Part 3 is 
conducted, a single dose level of PF-07059013 will be studied, and the dose selected will be 
lower than the highest dose found to be safe and well tolerated in Part 1.  Furthermore, the 
dose selected will be in the range of likely pharmacologically active doses.  


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4.4. End of Study Definition
A participant is considered to have completed the study if he/she has completed all phases of 
the study, including the last scheduled procedure shown in the Schedule of Activities and any 
requested unplanned visits.
The end of the study is defined as the date of the last scheduled procedure shown in the 
Schedule of Activities for the last participant in the trial.
5. STUDY POPULATION
This study can fulfill its objectives only if appropriate participants are enrolled.  The 
following eligibility criteria are designed to select participants for whom participation in the 
study is considered appropriate.  All relevant medical and nonmedical conditions should be 
taken into consideration when deciding whether a particular participant is suitable for this 
protocol.
Prospective approval of protocol deviations to recruitment and enrollment criteria, also 
known as protocol waivers or exemptions, is not permitted.
5.1. Inclusion Criteria
Participants are eligible to be included in the study only if all of the following criteria apply:
Age and Sex:
1. Male and female (of non-child bearing potential) participants must be 18 to 55 years 
of age, inclusive, at the time of signing the ICD.

Refer to Appendix 4: Contraceptive Guidance for reproductive criteria for male 
(Section 10.4.1) and female (Section 10.4.2) participants.
Type of Participant and Disease Characteristics:
2. Male and female participants who are overtly healthy as determined by medical 
evaluation including medical history, physical examination, including blood pressure, 
pulse rate, respiratory rate and temperature measurement, standard 12-lead ECG,
laboratory tests, and cardiac monitoring (in Part 1 only).
3. Participants who are willing and able to comply with all scheduled visits, treatment 
plan, laboratory tests, lifestyle considerations, and other study procedures.
Weight:
4. BMI of 17.5 to 30.5 kg/m2; and a total body weight >50 kg (110 lb).


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Informed Consent:
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).
2. Any condition possibly affecting drug absorption (eg, gastrectomy, cholecystectomy).
3. History of human immunodeficiency virus (HIV) infection, hepatitis B, or hepatitis 
C; positive testing at screening for HIV, hepatitis B surface antigen (HBsAg), 
hepatitis B core antibody (HBcAb), or hepatitis C antibody (HCVAb). As an 
exception a positive HBsAb test due to hepatitis B vaccination is permissible.
4. Other medical or psychiatric condition including recent (within the past year) or 
active suicidal ideation/behavior or laboratory abnormality that may increase the risk 
of study participation or, in the investigator’s judgment, make the participant 
inappropriate for the study.
Prior/Concomitant Therapy:
5. Use of prescription or nonprescription drugs and dietary and herbal supplements 
within 7 days or 5 half-lives (whichever is longer) prior to the first dose of study 
intervention.  (Refer to Section 6.5 for additional details).
Prior/Concurrent Clinical Study Experience:
6. Previous administration with an investigational drug within 30 days (or as determined 
by the local requirement) or 5 half-lives preceding the first dose of study intervention
used in this study (whichever is longer). 
Diagnostic Assessments:
7. A positive urine drug test at screening or admission.
8. A positive urine cotinine test at screening or admission in Part 1 and 2.


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9. 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.
10. Baseline 12-lead ECG that demonstrates clinically relevant abnormalities that may
affect participant safety or interpretation of study results (eg, baseline QTc interval 
>450 msec, complete left bundle branch block (LBBB), signs of an acute or 
indeterminate-age myocardial infarction, ST-T interval changes suggestive of 
myocardial ischemia, second- or third-degree atrioventricular (AV) block, or serious 
bradyarrhythmias or tachyarrhythmias).  If the baseline uncorrected QT interval is 
>450 msec, this interval should be rate-corrected using the Fridericia method and the 
resulting QTcF should be used for decision making and reporting.  If QTc exceeds 
450 msec, or QRS exceeds 120 msec, the ECG should be repeated 2 more times and 
the average of the 3 QTc or QRS values should be used to determine the participant’s 
eligibility.  Computer-interpreted ECGs should be overread by a physician 
experienced in reading ECGs before excluding participants.
11. Participants with ANY of the following abnormalities in clinical laboratory tests at 
screening, as assessed by the study specific laboratory and confirmed by a single 
repeat test, if deemed necessary: 

AST or ALT level ≥1.5 × ULN;

Total bilirubin level ≥1.5 × ULN; participants with a history of Gilbert's 
syndrome may have direct bilirubin measured and would be eligible for this study 
provided the direct bilirubin level is ≤ULN;

PT/INR >1.2 × ULN;

aPTT ≥1.5 × ULN;

Hemoglobin <11.0 g/dL;

Lactate >1 x ULN.
12. For Part 2 only, participants with absolute reticulocyte count >150,000/uL at 
screening, as assessed by the study specific laboratory and confirmed by a single 
repeat test, if deemed necessary.
Other Exclusions:
13. History of alcohol abuse or binge drinking and/or any other illicit drug use or 
dependence within 6 months of Screening.  Binge drinking is defined as a pattern of 
5 (male) and 4 (female) or more alcoholic drinks in about 2 hours.  As a general rule, 
alcohol intake should not exceed 14 units per week (1 unit = 8 ounces (240 mL) beer, 
1 ounce (30 mL) of 40% spirit or 3 ounces (90 mL) of wine).


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14. Use of tobacco/nicotine containing products for Part 1 or 2, and use of more than 
5 cigarettes/day for Part 3.
15. Blood donation (excluding plasma donations) of approximately 1 pint (500 mL) or 
more within 60 days prior to dosing.  
16. Unwilling or unable to comply with the criteria in the Lifestyle Considerations
section of this protocol.
17. Investigator site staff or Pfizer employees directly involved in the conduct of the 
study, site staff otherwise supervised by the investigator, and their respective family 
members.
5.3. Lifestyle Considerations
The following guidelines are provided:
5.3.1. Meals and Dietary Restrictions

Participants must abstain from all food and drink (except water) at least 4 hours prior 
to any safety laboratory evaluations, except for 8 hour post dose samples.

For Part 1 and Part 3, water is permitted until 1 hour prior to dosing and during 
breakfast when dosing under fed (high-fat/high-caloric) condition. Water may be 
consumed without restriction beginning 1 hour after dosing. 

For Part 2, there are no water restriction prior to or after dosing.

Noncaffeinated drinks (except grapefruit or grapefruit related citrus fruit juices see 
below) maybe consumed with meals and the evening snack.
Part 1 and when dosing under fasted condition in Part 3:
On Day 1 of each period, with dosing under fasted condition (overnight fast of at least
10 hours): 

Breakfast will not be provided.

Lunch will be provided approximately 4 hours after dosing.

Dinner will be provided approximately 9 to 10 hours after dosing.

An evening snack may be permitted.


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Part 2:
On all dosing days,

A standard breakfast will be provided approximately 30 minutes prior to 
administration of the investigational product and is expected to be completed 
approximately 10 minutes prior to dosing. Participants will be encouraged to 
consume the entire meal. If participants are unable to complete the meals, the 
portion consumed in 25% increments will be documented and potential impact on 
results assessed by the Sponsor study team on a case-by-case basis.   

Lunch will be provided approximately 4 hours after dosing.

Dinner will be provided approximately 9 to 10 hours after dosing.

An evening snack may be permitted.
When dosing under fed (high-fat/high-caloric) condition in Part 3:

Following an overnight fast of at least 10 hours, participants will receive high-fat
(approximately 50% of the total caloric content of the meal)/high-caloric
(approximately 800 to 1000 calories) breakfast approximately 30 minutes prior to 
administration of the investigational product on Day 1.

The breakfast will be consumed over approximately a 20-minute period and the 
investigational product administered within approximately 10 minutes of 
completion of the meal. Participants will be encouraged to consume the entire 
meal. If participants are unable to complete the meals, the portion consumed in 
25% increments will be documented and potential impact on results assessed by 
the sponsor study team on a case-by-case basis.   

Lunch will be provided approximately 4 hours after dosing.

Dinner will be provided approximately 9 to 10 hours after dosing.

An evening snack may be permitted.

Participants will refrain from consuming red wine, grapefruit, or grapefruit-related 
citrus fruits (eg, Seville oranges, pomelos, fruit juices) from 7 days prior to the first 
dose of investigational product 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 (except when 
investigational product is administered with high-fat/high-calorie breakfast).  The 
daily caloric intake per participant should not exceed approximately 3200 kcal.


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5.3.2. Caffeine, Alcohol, and Tobacco

Participants will abstain from caffeine -containing products for 24 hours prior to the 
start of dosing until collection of the final PK sample of each study period in Part 1 
and 3 and final PK sample of Part 2.  

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 in Part 1 and 3 and final PK sample of 
Part 2.  Participants may undergo an alcohol breath test or blood alcohol test at the 
discretion of the investigator.

For Part 3, participants will abstain from the use of tobacco- or nicotine -containing 
products for 24 hours prior to dosing and during confinement in the CRU. 
5.3.3. Activity

Participants will abstain from strenuous exercise (eg, heavy lifting, weight training, 
calisthenics, aerobics) for at least 48 hours prior to each blood collection for clinical 
laboratory tests.  Walking at a normal pace will be permitted;

In order to standardize the conditions on PK sampling days, participants will be 
required to refrain from lying down (except when required for BP, pulse rate, 
respiratory rate, oral temperature and ECG measurements), eating, and drinking 
beverages other than water during the first 4 hours after dosing;

For Part 1 only, participants will be confined to the procedure room/participant room, 
as appropriate, 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 continuous cardiac 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 
ultraviolet light exposure, from the first day of dosing with investigational product 
and until 14 days after the last dose of investigational product. In addition, 
participants will be instructed to apply sun cream/lotion with a high sun protection 
factor, as appropriate.
5.3.4. Contraception
The investigator or his or her designee, in consultation with the participant, will confirm that 
the participant has selected an appropriate method of contraception for the individual 
participant and his partner(s) from the permitted list of contraception methods (see 
Appendix 4: Contraceptive Guidance, Section 10.4.4) and will confirm that the participant
has been instructed in its consistent and correct use.  At time points indicated in the Schedule 


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of Activities, the investigator or designee will inform the participant of the need to use highly 
effective contraception consistently and correctly and document the conversation and the 
participant’s affirmation in the participant’s chart (participants need to affirm their consistent 
and correct use of at least 1 of the selected methods of contraception).  In addition, the 
investigator or designee will instruct the participant to call immediately if the selected 
contraception method is discontinued or if pregnancy is known or suspected in the participant
or partner.
5.4. Screen Failures
Screen failures are defined as participants who consent to participate in the clinical study but 
are not subsequently randomly assigned to study intervention/enrolled in the study. Screen 
failure data are collected and remain as source and are not reported to the clinical database.
Individuals who do not meet the criteria for participation in this study (screen failure) may 
not be rescreened. 
6. STUDY INTERVENTION
Study intervention is defined as any investigational intervention(s), marketed product(s), 
placebo, medical device(s), or study procedure(s) intended to be administered to a study 
participant according to the study protocol.
For the purposes of this protocol, study intervention refers to PF-07059013 and placebo.
6.1. Study Intervention(s) Administered
For this study, the investigational product(s) is PF-07059013 and placebo.
PF-07059013 and placebo will be provided by Pfizer as bulk powders for extemporaneous 
preparation of oral suspensions at the CRU.
PF-07059013 and placebo will be presented to the participants in individual dosing 
containers.
PF-07059013 will be supplied by Pfizer as 200-mg tablets.
Tablets will be supplied to the CRU in bulk along with individual dosing containers for unit 
dosing.
6.1.1. Administration
Administration of the investigational product will occur with and without meals, as outlined 
below.  Further details on meals and dietary requirements are provided in Section 5.3.1.
For tablet formulation, participants will swallow the study intervention whole, and will not 
manipulate or chew the study intervention prior to swallowing. Investigator site personnel 
will administer study intervention during each period with ambient temperature water or 
polymer solution (if required, this will be provided and investigator site personnel will be 


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notified prior to start of dosing in Part 3) to a total volume of approximately 240 mL. If 
needed, an additional volume of water up to 150 mL may be provided for tablet dosing. This 
will be documented by the site.
For suspensions, administer study intervention according to the EDR.
In order to standardize the conditions on PK sampling days, all participants will be required 
to refrain from lying down (except when required for BP, pulse rate, respiratory rate, oral 
temperature and ECG measurements), eating, and drinking beverages other than water during 
the first 4 hours after dosing.
For Part 1: 
Following an overnight fast of at least 10 hours, participants will receive investigational 
product at approximately 0800 hours (plus or minus 2 hours) without breakfast.  
For Part 2:
On each dosing day, participants will receive a standard breakfast approximately 30 minutes 
prior to dosing which is to be completed within approximately 20 minutes as outlined in
Section 5.3.1. The participants will then receive investigational product at approximately 
0800 hours (plus or minus 2 hours). 
For Part 3: 
As determined by randomization scheme, dosing will occur either with or without breakfast.
For fed assignment, following an overnight fast of at least 10 hours, participants will receive 
high fat/high caloric breakfast approximately 30 minutes prior to dosing which is to be 
completed within approximately 20 minutes as outlined in Section 5.3.1. The participants 
will then receive investigational product at approximately 0800 hours (plus or minus 
2 hours). 
For fasted assignment, following an overnight fast of at least 10 hours, participants will 
receive investigational product at approximately 0800 hours (plus or minus 2 hours) without 
breakfast.
6.2. Preparation/Handling/Storage/Accountability
1. The investigator or designee must confirm appropriate temperature conditions have 
been maintained during transit for all study interventions received and any 
discrepancies are reported and resolved before use of the study intervention. 


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


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PF-07059013 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.
See the EDR for instructions on how to prepare the study intervention for administration.  
Study intervention should be prepared and dispensed by an appropriately qualified and 
experienced member of the study staff (eg, physician, nurse, physician’s assistant, nurse 
practitioner, pharmacy assistant/technician, or pharmacist) as allowed by local, state, and 
institutional guidance.  A second staff member will verify the dispensing.
PF-07059013 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. 
Tablets will be prepared at the CRU in the individual dosing containers by 2 operators, 1 of 
whom is an appropriately qualified and experienced member of the study staff (eg, physician, 
nurse, physician’s assistant, nurse practitioner, pharmacy assistant/technician, or pharmacist).  
The tablets will be provided in unit dose containers and labeled in accordance with Pfizer 
regulations and the clinical site’s labeling requirements. Polymer solution, if needed for the 
tablets administration, will be prepared by qualified site personnel according to the EDR.
6.3. Measures to Minimize Bias: Randomization and Blinding
6.3.1. Allocation to Study Intervention
The investigator will assign participant numbers to the participants as they are screened for 
the study.  Pfizer will provide a randomization schedule to the investigator and, in 
accordance with the randomization numbers, the participant will receive the study treatment 
regimen assigned to the corresponding randomization number.
Participants will be randomly assigned to receive study intervention from a central 
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 (for example, pharmacist) will be responsible for the preparation and 
dispensing of all study intervention according to the randomization schedule and assigned 
treatment for the individual participant.
Blinding procedures do not apply to Part 1 Period 4 and Part 3 of this study because it will be 
conducted as open-label. Where the design is open-label, the investigator’s knowledge of the 
treatment should not influence the decision to enroll a particular participant or affect the 
order in which participants are enrolled.
6.3.2. Breaking the Blind (Part 1 Period 1 to 3 and Part 2 only)
The method for breaking the blind in this study will be manual.  A sealed envelope that 
contains the study intervention assignment(s) for each participant will be provided to the 
investigator.  The sealed envelope will be retained by the investigator (or representative) in a 


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secured area. In case of an emergency, the investigator has the sole responsibility for 
determining if unblinding of a participant’s treatment assignment is warranted. Participant 
safety must always be the first consideration in making such a determination.  If the 
investigator decides that unblinding is warranted, the investigator should make every effort to 
contact the sponsor prior to unblinding a participant’s treatment assignment unless this could 
delay further management of the participant. If a participant’s treatment assignment is 
unblinded, the sponsor must be notified within 24 hours after breaking the blind. When the 
blinding code is broken, the reason must be fully documented and entered on the case report 
form (CRF).
Once the study is complete, all envelopes (sealed and opened) must be inventoried and 
retained until authorization for destruction has been provided.
Blinding codes should be broken only in exceptional circumstances when knowledge of the 
actual treatment code is absolutely essential for further management of the participant.  
Investigators are encouraged to discuss with a member of the study team if they believe that 
unblinding is necessary.  When the blinding code is broken, the reason must be fully 
documented and entered on the CRF.
Blood specimens will be obtained from all participants for PK analysis to maintain the study 
blind at the investigator site.  Only the investigator site staff and blinded study monitor, if 
assigned, will be blinded to study treatment.  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.
6.4. 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 
electronic CRF. The study treatment assignment and study participant identification will be 
confirmed at the time of dosing by a member of the study site staff other than the person 
administering the study intervention.  Study site personnel will examine each participant’s 
mouth to ensure that the study intervention was ingested.


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6.5. Concomitant Therapy
Use of prescription or nonprescription drugs and dietary and herbal supplements are 
prohibited within 7 days or 5 half-lives (whichever is longer) prior to the first dose of study 
intervention.  Limited use of nonprescription medications that are not believed to affect 
participant safety or the overall results of the study may be permitted on a case-by-case basis 
following approval by the sponsor.  Acetaminophen/paracetamol may be used at doses of 
≤1 g/day.
All concomitant treatments taken during the study must be recorded with indication, daily 
dose, and start and stop dates of administration.  All participants will be questioned about 
concomitant treatment at each clinic visit.
Treatments taken within 28 days before the first dose of study intervention will be 
documented as a prior treatment.  Treatments taken after the first dose of study intervention
will be documented as concomitant treatments.
6.5.1. Rescue Medicine 
There is no rescue therapy to reverse the AEs observed with PF-07059013; standard medical 
supportive care must be provided to manage the AEs. 
6.6. Dose Modification
The decision to proceed to the next dose level of PF-07059013 (either an increase, decrease 
or repeat of previous dose level) will be made by the study team and the investigator based 
on safety, tolerability, and preliminary PK data obtained in at least 6 participants (at least 
5 out of 6 actively treated participants and at least 1 placebo-treated participant) dosed at the 
prior dose level.
The dosing schedule may also be adjusted to add cohorts to evaluate additional 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
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 (as described in Appendix 8: Criteria for Vital Signs 
Abnormality), in the same organ class, indicating dose-limiting intolerance.


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
If post-treatment p50 values in 2 or more of the participants receiving active drug at a 
given dose level (but not participants receiving placebo), drops below 20 mmHg, in 
association with one or more of the following, in any of the respective participants:

Treatment emergent increase in EPO above the upper limit of reference range
(Part 2 only).

Treatment emergent increase from baseline in absolute reticulocyte count, with 
magnitude of increase ≥250,000 /uL (Part 2 only).

Treatment emergent increase in lactate to above upper limit of normal.

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 
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 plasma Cmax = 1.5 µg/mL or unbound plasma AUC24 = 22.5 µg•hr/mL.  

If, based on the observed data, the group mean of unbound plasma Cmax or AUC of 
the next planned dose is projected to exceed the escalation limits, that dose will not be 
explored.  Modified doses may be explored if they are not expected to exceed PK 
stopping criteria.
Progression to the next dose will occur if the last dose was well tolerated and after 
satisfactory review of the available safety and PK data.


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For Part 1, each dose escalation will be based on review of lactate and p50 data up to at least 
8 hour post dose and all other safety data up to a minimum of 72-hours post dose plus PK 
assessments up to 24-hours post dose, in at least 5 out of 6 actively treated participants and at 
least 1 placebo-treated participant dosed in the previous dose level.
For Part 2, each dose escalation will be based on review of EPO and lactate data up to at least
Day 7, reticulocyte and p50 data up to at least Day 14, and all other safety data up to Day 15 
plus PK assessments up to Day 8, in at least 5 out of 6 actively treated participants and at 
least 1 placebo-treated participant dosed in the previous dose level.
6.7. Intervention After the End of the Study
No intervention will be provided to study participants at the end of the study.
7. DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL
7.1. Discontinuation of Study Intervention
In rare instances, it may be necessary for a participant to permanently discontinue study 
intervention (definitive discontinuation). Reasons for definitive discontinuation of study 
intervention include the following: withdrawal of consent by the participant, SAE or 
clinically significant finding that impacts safety of participant per PI judgement, death, 
protocol deviation impacting study data or integrity, study terminated by study sponsor.
Note that discontinuation of study intervention does not represent withdrawal from the study.  
If study intervention is definitively discontinued, the participant will remain in the study to 
be evaluated at the early termination/discontinuation visit. See the Schedule of Activities for 
data to be collected at the time of discontinuation of study intervention and follow-up for any 
further evaluations that need to be completed.
In the event of discontinuation of study intervention, it must be documented on the 
appropriate CRF/in the medical records whether the participant is discontinuing further 
receipt of study intervention or also from study procedures, posttreatment study follow-up, 
and/or future collection of additional information.
ECG Changes
A participant who meets either bulleted criterion based on the average of triplicate ECG 
readings will be withdrawn from the study intervention. 

QTcF >500 msec.

Change from baseline: QTcF >60 msec.


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If a clinically significant finding is identified (including, but not limited to, changes from 
baseline in QTcF after enrollment), the investigator or qualified designee will determine if 
the participant can continue in the study and if any change in participant management is 
needed. This review of the ECG printed at the time of collection must be documented. Any 
new clinically relevant finding should be reported as an AE.
Potential Cases of Acute Kidney Injury
Abnormal values in SCr concurrent with presence or absence of increase in BUN that meet 
the criteria below, in the absence of other causes of kidney injury, are considered potential 
cases of acute kidney injury and should be considered important medical events.
An increase of ≥0.3 mg/dL (or ≥26.5 µmol/L) in SCr level relative to the participant’s own 
baseline measurement should trigger another assessment of SCr as soon as practically 
feasible, preferably within 48 hours from awareness.
If the second assessment (after the first observations of ≥0.3 mg/dL [or ≥26.5 µmol/L] in SCr
relative to the participant’s own baseline measurement) is ≥0.4 mg/dL (or ≥35.4 µmol/L), the 
participant should be discontinued from the study and adequate, immediate, supportive 
measures taken to correct apparent acute kidney injury.
Participants should return to the investigator site and be evaluated as soon as possible, 
preferably within 48 hours from awareness of the second assessment confirming abnormal 
SCr result.  This evaluation should include laboratory tests, detailed history, and physical 
assessment.  In addition to repeating SCr, laboratory tests should include serum BUN, serum 
creatine kinase, and serum electrolytes (including at a minimum potassium, sodium, 
phosphate/phosphorus, and calcium), in addition to urinary dipstick, urine microscopic 
examination, and urinary indices.  All cases confirmed on repeat testing as meeting the 
laboratory criteria for acute kidney injury, with no other cause(s) of laboratory abnormalities 
identified, should be considered potential cases of drug-induced kidney injury irrespective of 
availability of all the results of the investigations performed to determine etiology of the 
abnormal SCr.  If ≥2 healthy participants in a given period/treatment arm are noted to have 
2 consecutive SCr results of ≥0.3 mg/dL (or ≥26.5 µmol/L), an assessment of whether the 
finding may be considered an adverse drug reaction should be undertaken.
7.2. Participant Discontinuation/Withdrawal From the Study
A participant may withdraw from the study at any time at his/her own request.  Reasons for 
discontinuation from the study include the following:

Refused further follow-up;

Lost to follow-up;

Death;

Study terminated by sponsor.


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At the time of discontinuing from the study, if possible, an early discontinuation visit should 
be conducted.  See the SoA for assessments to be collected at the time of study 
discontinuation and follow-up and for any further evaluations that need to be completed.
The early discontinuation visit applies only to participants who are enrolled/randomized and 
then are prematurely withdrawn from the study.  Participants should be questioned regarding 
their reason for withdrawal.
The participant will be permanently discontinued both from the study intervention and from 
the study at that time.
If a participant withdraws from the study, he/she may request destruction of any remaining 
samples taken and not tested, and the investigator must document any such requests in the 
site study records and notify the sponsor accordingly.
If the participant withdraws from the study and also withdraws consent (see Section 7.2.1) 
for disclosure of future information, no further evaluations should be performed and no 
additional data should be collected.  The sponsor may retain and continue to use any data 
collected before such withdrawal of consent.
Lack of completion of all or any of the withdrawal/early termination procedures will not be 
viewed as protocol deviations so long as the participant’s safety was preserved.
7.2.1. Withdrawal of Consent
Participants who request to discontinue receipt of study intervention will remain in the study 
and must continue to be followed for protocol-specified follow-up procedures.  The only 
exception to this is when a participant specifically withdraws consent for any further contact 
with him or her or persons previously authorized by the participant to provide this 
information.  Participants should notify the investigator in writing of the decision to 
withdraw consent from future follow-up, whenever possible.  The withdrawal of consent 
should be explained in detail in the medical records by the investigator, as to whether the 
withdrawal is only from further receipt of study intervention or also from study procedures 
and/or posttreatment study follow-up, and entered on the appropriate CRF page.  In the event 
that vital status (whether the participant is alive or dead) is being measured, publicly 
available information should be used to determine vital status only as appropriately directed 
in accordance with local law.
7.3. Lost to Follow up
A participant will be considered lost to follow-up if he or she repeatedly fails to return for 
scheduled visits and is unable to be contacted by the study site.


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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 and counsel the participant on the importance of maintaining the 
assigned visit schedule and ascertain whether or not the participant wishes to and/or 
should continue in the study;
•
Before a participant is deemed lost to follow-up, the investigator or designee must 
make every effort to regain contact with the participant (where possible, 3 telephone 
calls and, if necessary, a certified letter to the participant’s last known mailing 
address or local equivalent methods). These contact attempts should be documented 
in the participant’s medical record;
•
Should the participant continue to be unreachable, he/she will be considered to have 
withdrawn from the study. 
8. STUDY ASSESSMENTS AND PROCEDURES
The investigator (or an appropriate delegate at the investigator site) must obtain a signed and
dated ICD before performing any study-specific procedures.  
Study procedures and their timing are summarized in the SoA. Protocol waivers or 
exemptions are not allowed.
Safety issues should be discussed with the sponsor immediately upon occurrence or 
awareness to determine whether the participant should continue or discontinue study 
intervention.
Adherence to the study design requirements, including those specified in the SoA, is essential 
and required for study conduct.
All screening evaluations must be completed and reviewed to confirm that potential 
participants meet all eligibility criteria. The investigator will maintain a screening log to 
record details of all participants screened and to confirm eligibility or record reasons for 
screening failure, as applicable.
Participants will be screened within 28 days prior to administration of the study intervention 
to confirm that they meet the study population criteria for the study.  If the time between 
screening and dosing exceeds 28 days as a result of unexpected delays (eg, delayed drug 
shipment), then participants do not require rescreening if the laboratory results obtained prior 
to first dose administration meet eligibility criteria.
A participant who qualified for this protocol but did not enroll from an earlier cohort/group 
may be used in a subsequent cohort/group without rescreening, provided laboratory results 
obtained prior to the first dose administration meet eligibility criteria for this study.  In 
addition, other clinical assessments or specimen collections, 
 may 
be used without repeat collection, as appropriate.
CCI


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Every effort should be made to ensure that protocol-required tests and procedures are 
completed as described.  However, it is anticipated that from time to time there may be 
circumstances outside the control of the investigator that may make it unfeasible to perform 
the test.  In these cases, the investigator must take all steps necessary to ensure the safety and 
well-being of the participant.  When a protocol-required test cannot be performed, the 
investigator will document the reason for the missed test and any corrective and preventive 
actions that he or she has taken to ensure that required processes are adhered to as soon as 
possible.  The study team must be informed of these incidents in a timely manner.
For samples being collected and shipped, detailed collection, processing, storage, and 
shipment instructions and contact information will be provided to the investigator site prior 
to initiation of the study.
The total blood sampling volume for individual participants in this study is approximately 
529 mL.  The actual collection times of blood sampling may change.  Additional blood 
samples may be taken for safety assessments at times specified by Pfizer, provided the total 
volume taken during the study does not exceed 550 mL during any period of 60 consecutive 
days.
To prepare for study participation, participants will be instructed on the information in the 
Lifestyle Considerations and Concomitant Therapy sections of the protocol.
8.1. Efficacy Assessments
Not applicable.
8.2. Safety Assessments
Planned time points for all safety assessments are provided in the SoA.  Unscheduled clinical 
laboratory measurements may be obtained at any time during the study to assess any 
perceived safety issues.
8.2.1. Physical Examinations
A complete physical examination will include, at a minimum, head, ears, eyes, nose, mouth, 
skin, heart and lung examinations, lymph nodes, and gastrointestinal, musculoskeletal, and 
neurological systems. 
A brief physical examination will include, at a minimum, assessments of general appearance, 
the respiratory and cardiovascular systems, and participant-reported symptoms. May be 
performed at other times, as appropriate, for findings during previous examination or 
new/open AEs, at investigator’s discretion.
Physical examinations may be conducted by a physician, trained physician's assistant, or 
nurse practitioner as acceptable according to local regulation. 


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Height and weight will also be measured and recorded as per the SoA.  For measuring 
weight, a scale with appropriate range and resolution is used and must be placed on a stable, 
flat surface.  Participants must remove shoes, bulky layers of clothing, and jackets so that 
only light clothing remains.  They must also remove the contents of their pockets and remain 
still during measurement of weight. 
8.2.2. Vital Signs
Supine BP will be measured with the participant’s arm supported at the level of the heart, and 
recorded to the nearest mm Hg after approximately 5 minutes of rest.  The same arm 
(preferably the dominant arm) will be used throughout the study. Participants should be 
instructed not to speak during measurements.
The same properly sized and calibrated BP cuff will be used to measure BP each time.  The 
use of an automated device for measuring BP and pulse rate is acceptable; however, when 
done manually, pulse rate will be measured in the brachial/radial artery for at least 
30 seconds.  When the timing of these measurements coincides with a blood collection, BP 
and pulse rate should be obtained prior to the nominal time of the blood collection.
Additional collection times, or changes to collection times, of BP and pulse rate will be 
permitted, as necessary, to ensure appropriate collection of safety data.
The procedure for collecting postural or orthostatic data will be:

Assess BP after the participant is in the supine position for a minimum of 5 minutes;

Have the participant stand up for 2 minutes;

Assess BP after the participant is in the standing position for approximately 
2 minutes.
Orthostatic hypotension is defined as a decrease of 20 mm Hg for systolic BP or
10 mm Hg for diastolic BP 2 minutes after standing from a supine position.  Orthostatic 
hypotension may be symptomatic or asymptomatic.  Symptoms of orthostatic hypotension 
are those that develop upon assuming the erect posture from a supine position and may 
include: lightheadedness, dizziness, blurred vision, weakness, fatigue, cognitive impairment, 
nausea, palpitations, tremulousness, headache, and/or neck ache.
If a participant has symptoms suggestive of orthostasis, but not documented orthostatic 
hypotension, repeated measurements of supine/standing BP should be obtained.  Lesser 
degrees of BP reduction may still be considered clinically significant if the participant 
becomes symptomatic upon standing, especially in the presence of a significant increase in 
pulse rate (30 beats per minute [bpm]).
8.2.2.1. Respiratory Rate 
Respiratory rate will be measured after approximately 5 minutes of rest in a supine position 
by observing and counting the respirations of the participant for 30 seconds and multiplying


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by 2.  When BP is to be taken at the same time, respiration measurement will be done during 
the 5 minutes of rest and before BP measurement.
8.2.2.2. Temperature 
Temperature will be measured orally.  No eating, drinking is allowed for 15 minutes prior to 
the measurement.
8.2.3. Electrocardiograms
Standard 12-Lead ECGs should be collected at times specified in the SoA section of this 
protocol using an ECG machine that automatically calculates the heart rate and measures PR, 
QT, and QTc intervals and QRS complex.  All scheduled ECGs should be performed after 
the participant has rested quietly for at least 10 minutes in a supine position. 
Triplicate 12-lead ECGs will be obtained approximately 2 to 4 minutes apart; the average of 
the triplicate ECG measurements collected before dose administration on Day 1 of each 
period will serve as each participant’s baseline QTc value. 
To ensure safety of the participants, a qualified individual at the investigator site will make 
comparisons to baseline measurements. Additional ECG monitoring will occur if a) the 
mean value from the triplicate measurements for any postdose QTcF interval is increased by
60 msec from the baseline and is >450 msec; or b) an absolute QTcF value is 500 msec 
for any scheduled ECG. If either of these conditions occurs, then a single ECG measurement 
must be repeated at least hourly until QTcF values from 2 successive ECGs fall below the 
threshold value that triggered the repeat measurement.
If a) a postdose QTcF interval remains 60 msec from the baseline and is >450 msec; or 
b) an absolute QTcF value is 500 msec for any scheduled ECG for greater than 4 hours (or 
sooner, at the discretion of the investigator), or c) QTcF intervals get progressively longer, 
the participant should undergo continuous ECG monitoring.  A cardiologist should be 
consulted if QTcF intervals do not return to less than the criterion listed above after 8 hours 
of monitoring (or sooner, at the discretion of the investigator). 
In some cases, it may be appropriate to repeat abnormal ECGs to rule out improper lead 
placement as contributing to the ECG abnormality.  It is important that leads be placed in the 
same positions each time in order to achieve precise ECG recordings.  If a machine-read 
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 7: ECG Findings of Potential 
Clinical Concern.
8.2.3.1. Continuous Cardiac Monitoring by Telemetry
All abnormal rhythms will be recorded and reviewed by the study physician for the presence 
of rhythms of potential clinical concern.  The time, duration, and description of the clinically 


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significant event will be recorded in the CRF/DCT.  In addition, a printed record of the 
tracing(s) of the clinically significant rhythm(s) will be made and retained with other source 
documents.
Telemetry should be collected using a centralized system that also allows for the storage and 
advanced analysis of all recorded data in order to preserve important events for future 
evaluations.  Holter monitoring should not be used in parallel with continuous telemetry, 
unless it is the only means of data storage available at the investigator site, or verifiable 
arrhythmia quantification is required.  To establish a baseline, telemetry should be recorded 
for at least 2 hours before dosing in Period 1.  This may be done immediately prior to dosing 
or at some 2-hour continuous interval in the 24 hours prior to dosing, as long as the recording 
is performed when the participant is awake.  Telemetry may be stopped within a reasonably 
short period of time prior to dosing, in order to avoid interference with study operations 
conducted immediately before dosing.  However, it is expected that the telemetry leads will 
be in place and the system connected prior to dosing.
8.2.4. Clinical Safety Laboratory Assessments
See Appendix 2 for the list of clinical safety laboratory tests to be performed and the SoA for 
the timing and frequency.  All protocol-required laboratory assessments, as defined in 
Appendix 2, must be conducted in accordance with the laboratory manual and the SoA. 
Unscheduled clinical laboratory measurements may be obtained at any time during the study 
to assess any perceived safety issues.  
The investigator must review the laboratory report, document this review, and record any 
clinically relevant changes occurring during the study in the AE section of the CRF. 
Clinically significant abnormal laboratory findings are those which are not associated with 
the underlying disease, unless judged by the investigator to be more severe than expected for 
the participant's condition.
All laboratory tests with values considered clinically significantly abnormal during 
participation in the study or within 7 days after the last dose of study intervention should be 
repeated until the values return to normal or baseline or are no longer considered clinically 
significant by the investigator or medical monitor.
If such values do not return to normal/baseline within a period of time judged reasonable by 
the investigator, the etiology should be identified and the sponsor notified.
See Appendix 6 for suggested actions and follow-up assessments in the event of potential 
drug-induced liver injury.
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. 
8.3. Adverse Events and Serious Adverse Events
The definitions of an AE and an SAE can be found in Appendix 3.


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AEs will be reported by the participant (or, when appropriate, by a caregiver, surrogate, or 
the participant's legally authorized representative).
The investigator and any qualified designees are responsible for detecting, documenting, and 
recording events that meet the definition of an AE or SAE and remain responsible to pursue 
and obtain adequate information both to determine the outcome and to assess whether the 
event meets the criteria for classification as an SAE or caused the participant to discontinue 
the study intervention (see Section 7.1).
Each participant will be questioned about the occurrence of AEs in a nonleading manner.
In addition, the investigator may be requested by Pfizer Safety to obtain specific follow-up 
information in an expedited fashion.
8.3.1. Time Period and Frequency for Collecting AE and SAE Information
The time period for actively eliciting and collecting AEs and SAEs (“active collection 
period”) for each participant begins from the time the participant provides informed consent, 
which is obtained before the participant’s participation in the study (ie, before undergoing 
any study-related procedure and/or receiving study intervention), through and including a 
minimum of 28 calendar days, except as indicated below, after the last administration of the 
study intervention.
Follow-up by the investigator continues throughout and after the active collection period and 
until the AE or SAE or its sequelae resolve or stabilize at a level acceptable to the 
investigator and Pfizer concurs with that assessment.
For participants who are screen failures, the active collection period ends when screen failure 
status is determined.
If the participant withdraws from the study and also withdraws consent for the collection of 
future information, the active collection period ends when consent is withdrawn.
If a participant definitively discontinues or temporarily discontinues study intervention 
because of an AE or SAE, the AE or SAE must be recorded on the CRF and the SAE 
reported using the CT SAE Report Form.


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Investigators are not obligated to actively seek AE or SAE after the participant has concluded 
study participation. However, if the investigator learns of any SAE, including a death, at any 
time after a participant has completed the study, and he/she considers the event to be 
reasonably related to the study intervention, the investigator must promptly report the SAE to 
Pfizer using the CT SAE Report Form.
8.3.1.1. Reporting SAEs to Pfizer Safety
All SAEs occurring in a participant during the active collection period as described in
Section 8.3.1 are reported to Pfizer Safety on the CT SAE Report Form immediately upon 
awareness and under no circumstance should this exceed 24 hours, as indicated in 
Appendix 3. The investigator will submit any updated SAE data to the sponsor within 
24 hours of it being available.
8.3.1.2. Recording Nonserious AEs and SAEs on the CRF
All nonserious AEs and SAEs occurring in a participant during the active collection period as 
described in Section 8.3.1 are recorded on the CRF.  AEs and SAEs that begin after obtaining 
informed consent but before the start of study intervention will be recorded on the Medical 
History/Current Medical Conditions section of the CRF, not the AE section. AEs and SAEs 
that begin after the start of study intervention are recorded on the AE section of the CRF. 
The investigator is to record on the CRF all directly observed and all spontaneously reported 
AEs and SAEs reported by the participant.
8.3.2. Method of Detecting AEs and SAEs
The method of recording, evaluating, and assessing causality of AEs and SAEs and the 
procedures for completing and transmitting SAE reports are provided in Appendix 3.
Care will be taken not to introduce bias when detecting AEs and/or SAEs.  Open-ended and 
nonleading verbal questioning of the participant is the preferred method to inquire about 
AE occurrences.
8.3.3. Follow-up of AEs and SAEs
After the initial AE/SAE report, the investigator is required to proactively follow each 
participant at subsequent visits/contacts. For each event, the investigator must pursue and 
obtain adequate information until resolution, stabilization, the event is otherwise explained, 
or the participant is lost to follow-up (as defined in Section 7.3).
In general, follow-up information will include a description of the event in sufficient detail to 
allow for a complete medical assessment of the case and independent determination of 
possible causality.  Any information relevant to the event, such as concomitant medications 
and illnesses, must be provided.  In the case of a participant death, a summary of available 
autopsy findings must be submitted as soon as possible to Pfizer Safety.
Further information on follow-up procedures is given in Appendix 3.


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8.3.4. Regulatory Reporting Requirements for SAEs
Prompt notification by the investigator to the sponsor of an SAE is essential so that legal 
obligations and ethical responsibilities towards the safety of participants and the safety of a 
study intervention under clinical investigation are met.
The sponsor has a legal responsibility to notify both the local regulatory authority and other 
regulatory agencies about the safety of a study intervention under clinical investigation. The 
sponsor will comply with country-specific regulatory requirements relating to safety 
reporting to the regulatory authority, IRBs/ECs, and investigators.
Investigator safety reports must be prepared for SUSARs according to local regulatory 
requirements and sponsor policy and forwarded to investigators as necessary.
An investigator who receives SUSARs or other specific safety information (eg, summary or 
listing of SAEs) from the sponsor will review and then file it along with the SRSD(s) for the 
study and will notify the IRB/EC, if appropriate according to local requirements.
8.3.5. Exposure During Pregnancy or Breastfeeding, and Occupational Exposure
Exposure to the study intervention under study during pregnancy or breastfeeding and 
occupational exposure are reportable to Pfizer Safety within 24 hours of investigator 
awareness.
8.3.5.1. Exposure During Pregnancy
An EDP occurs if: 

A male participant who is receiving or has discontinued study intervention exposes a 
female partner prior to or around the time of conception.

A female is found to be pregnant while being exposed or having been exposed to 
study intervention due to environmental exposure. Below are examples of 
environmental exposure during pregnancy:  

A female family member or healthcare provider reports that she is pregnant after 
having been exposed to the study intervention by inhalation or skin contact.
Specific for the study intervention in this study, skin contact is not applicable and 
exposure by inhalation refers to inhalation of the bulk powder.

A male family member or healthcare provider who has been exposed to the study 
intervention by inhalation or skin contact then exposes his female partner prior to 
or around the time of conception. Specific for the study intervention in this study, 
skin contact is not applicable and exposure by inhalation refers to inhalation of 
the bulk powder.


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The investigator must report EDP to Pfizer Safety within 24 hours of the investigator’s 
awareness, irrespective of whether an SAE has occurred. The initial information submitted 
should include the anticipated date of delivery (see below for information related to 
termination of pregnancy). 

If EDP occurs in a participant or a participant’s partner, the investigator must report 
this information to Pfizer Safety on the CT SAE Report Form and an EDP 
Supplemental Form, regardless of whether an SAE has occurred. Details of the 
pregnancy will be collected after the start of study intervention and until 28 days after 
the last dose.

If EDP occurs in the setting of environmental exposure, the investigator must report 
information to Pfizer Safety using the CT SAE Report Form and EDP Supplemental 
Form. Since the exposure information does not pertain to the participant enrolled in 
the study, the information is not recorded on a CRF; however, a copy of the 
completed CT SAE Report Form is maintained in the investigator site file.
Follow-up is conducted to obtain general information on the pregnancy and its outcome for 
all EDP reports with an unknown outcome. The investigator will follow the pregnancy until 
completion (or until pregnancy termination) and notify Pfizer Safety of the outcome as a 
follow-up to the initial EDP Supplemental Form. In the case of a live birth, the structural 
integrity of the neonate can be assessed at the time of birth. In the event of a termination, the 
reason(s) for termination should be specified and, if clinically possible, the structural 
integrity of the terminated fetus should be assessed by gross visual inspection (unless 
preprocedure test findings are conclusive for a congenital anomaly and the findings are 
reported).
Abnormal pregnancy outcomes are considered SAEs. If the outcome of the pregnancy meets 
the criteria for an SAE (ie, ectopic pregnancy, spontaneous abortion, intrauterine fetal 
demise, neonatal death, or congenital anomaly in a live-born baby, a terminated fetus, an 
intrauterine fetal demise, or a neonatal death), the investigator should follow the procedures 
for reporting SAEs. Additional information about pregnancy outcomes that are reported to 
Pfizer Safety as SAEs follows: 

Spontaneous abortion including miscarriage and missed abortion;

Neonatal deaths that occur within 1 month of birth should be reported, without regard 
to causality, as SAEs. In addition, infant deaths after 1 month should be reported as 
SAEs when the investigator assesses the infant death as related or possibly related to 
exposure to the study intervention. 
Additional information regarding the EDP may be requested by the sponsor. Further 
follow-up of birth outcomes will be handled on a case-by-case basis (eg, follow-up on 
preterm infants to identify developmental delays). In the case of paternal exposure, the 
investigator will provide the participant with the Pregnant Partner Release of Information 
Form to deliver to his partner.  The investigator must document in the source documents that 
the participant was given the Pregnant Partner Release of Information Form to provide to his 
partner.


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


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8.3.8. Adverse Events of Special Interest
Not applicable.
8.3.8.1. Lack of Efficacy
This section is not applicable because efficacy is not expected in the study population.
8.3.9. Medical Device Deficiencies
Not applicable.
8.3.10. Medication Errors
Medication errors may result from the administration or consumption of the study 
intervention by the wrong participant, or at the wrong time, or at the wrong dosage strength.


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Exposures to the study intervention under study may occur in clinical trial settings, such as 
medication errors.
Safety Event
Recorded on the CRF
Reported on the CT SAE Report 
Form to Pfizer Safety Within 
24 Hours of Awareness
Medication errors All (regardless of whether 
associated with an AE)
Only if associated with an SAE
Medication errors include:

Medication errors involving participant exposure to the study intervention;

Potential medication errors or uses outside of what is foreseen in the protocol that do 
or do not involve the study participant.
Such medication errors occurring to a study participant are to be captured on the medication 
error page of the CRF, which is a specific version of the AE page.
In the event of a medication dosing error, the sponsor should be notified immediately.
Whether or not the medication error is accompanied by an AE, as determined by the 
investigator, the medication error is recorded on the medication error page of the CRF and, if 
applicable, any associated AE(s), serious and nonserious, are recorded on the AE page of the 
CRF.
Medication errors should be reported to Pfizer Safety within 24 hours on a CT SAE Report 
Form only when associated with an SAE.
8.4. Treatment of Overdose
For this study, any dose of PF-07059013 greater than 4200 mg within a 24-hour time period 
will be considered an overdose.  Sponsor does not recommend specific treatment for an 
overdose.
In the event of an overdose, the investigator should:
1. Contact the medical monitor within 24 hours.
2. Closely monitor the participant for any AEs/SAEs and laboratory abnormalities for at 
least 5 half-lives or 28 calendar days after the overdose of PF-07059013 (whichever 
is longer)
3. Document the quantity of the excess dose as well as the duration of the overdose in 
the CRF.


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4. Overdose is reportable to Safety only when associated with an SAE.
5. Obtain a blood sample for PK analysis within 9 days from the date of the last dose of 
study intervention if requested by the medical monitor (determined on a case-by-case 
basis).
Decisions regarding dose interruptions or modifications will be made by the investigator in 
consultation with the medical monitor based on the clinical evaluation of the participant.
8.5. Pharmacokinetics 
8.5.1. Blood and Plasma for Analysis of PF-07059013
Blood samples of approximately 2 mL will be collected for measurement of whole blood 
concentrations of PF-07059013 as specified in the SoA.  Instructions for the collection and 
handling of biological samples will be provided in the laboratory manual or by the sponsor. 
The actual date and time (24-hour clock time) of each sample will be recorded.
Blood samples of approximately 4 mL, to provide an approximate of 1.5 mL of plasma, will 
be collected for measurement of plasma concentrations of PF-07059013 as specified in the 
SoA.  Instructions for the collection and handling of biological samples will be provided in 
the laboratory manual or by the sponsor.  The actual date and time (24-hour clock time) of 
each sample will be recorded.
The actual times may change, but the number of samples will remain the same.  All efforts 
will be made to obtain the samples at the exact nominal time relative to dosing.  Collection of 
samples up to and including 10 hours after dose administration that are obtained within 
10% of the nominal time relative to dosing (eg, within 6 minutes of a 60-minute sample) will 
not be captured as a protocol deviation, as long as the exact time of the collection is noted on 
the source document and the data collection tool (eg, CRF/DCT).  Collection of samples
more than 10 hours after dose administration that are obtained ≤1 hour away from the 
nominal time relative to dosing will not be captured as a protocol deviation, as long as the 
exact time of the collection is noted on the source document and the data collection tool (eg,
CRF/DCT). This protocol deviation window does not apply to samples to be collected more 
than 10 hours after dose administration at outpatient/follow-up visits with visit windows.
Samples will be used to evaluate the PK of PF-07059013. Samples collected for analyses of 
PF-07059013 plasma and blood concentration may also be used to evaluate safety or efficacy 
aspects related to concerns arising during or after the study, 
 
evaluation of the bioanalytical method, 
 
 
 
 Details for collection and handling of the 
samples for this cohort will be provided in the laboratory manual or by the sponsor, and the 
CRU will be informed prior to dosing.
CCI
CCI


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Genetic analyses will not be performed on these plasma and whole blood samples unless 
consent for this was included in the informed consent.  Participant confidentiality will be 
maintained.
Samples collected for measurement of plasma and whole blood concentrations of PF-
07059013 will be analyzed using a validated analytical method in compliance with applicable 
SOPs.
The PK samples must be processed and shipped as indicated in the instructions provided to 
the investigator site to maintain sample integrity. Any deviations from the PK sample 
handling procedure (eg, sample collection and processing steps, interim storage or shipping 
conditions), including any actions taken, must be documented and reported to the sponsor.  
On a case-by-case basis, the sponsor may make a determination as to whether sample 
integrity has been compromised.
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.
 
8.5.3. Urine for Analysis of PF-07059013 – Part 2, Only
Urine will be collected at times defined in the Schedule of Activities Table C (Part 2).
•
Prior to dosing on Day 1, each participant must complete a forced void with an aliquot
from this urine (“urine blank”) labeled and stored frozen for measurement of drug 
concentrations, per detailed instructions offered in a laboratory manual prior to the start 
of the study.
•
Prior to dosing on Day 14, each participant must complete a forced void with an aliquot
used to conduct urinalysis and microscopy, if needed; with remaining urine discarded.
•
Following dosing on Day 14, each void post dose will be collected, saved in a container 
and stored in refrigerated conditions (ie, 2-8°C) for the duration of the collection interval 
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(ie, 24 H). At the end of the dosing interval (ie, Day 15, 0 H [hour]), participants must 
complete a forced void with this complete void included as part of the interval collection.
The total volume will be measured and recorded. 
 
 
 Details regarding the collection, processing, storage and shipping of the 
urine samples will be provided in the lab manual, prior to the start of the study.
Samples will be analyzed using a validated analytical method in compliance with Pfizer 
standard operating procedures.
 
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.  Any deviation from the specified sample handling 
procedure resulting in compromised sample integrity, will be considered a protocol 
deviation.
As part of understanding the PK of the investigational product, urine samples may be used 
for evaluation of the bioanalytical method,
 
 for drug transporters and/or drug metabolizing enzymes.  
 
8.6. Pharmacodynamics
Blood samples of approximately 3 mL, will be collected for measurement of p20 and p50 at 
times specified in the Schedule of Activities.
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 data collection tool (eg, CRF/DCT).  Collection of samples more than 
10 hours after dose administration that are obtained ≤1 hour away from the nominal time 
relative to dosing will not be captured as a protocol deviation, as long as the exact time of the 
collection is noted on the source document and data collection tool (eg, CRF/DCT). 
 
  
These data will not be included in the clinical study report (CSR).
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Samples will be analyzed using a validated analytical method in compliance with applicable 
SOPs.
The PD samples must be processed and shipped as indicated in the lab manual or instructions 
provided to the investigator site to maintain sample integrity.  Any deviations from the PD 
sample handling procedure (eg, sample collection and processing steps, interim storage, or 
shipping conditions), including any actions taken, must be documented and reported to the 
sponsor.  On a case-by-case basis, the sponsor may make a determination as to whether 
sample integrity has been compromised.
8.7. Genetics
8.7.1. Specified Genetics
Genetics (specified analyses) are not evaluated in this study.
 
 
 
 
 
 
 
8.9. Immunogenicity Assessments
Immunogenicity assessments are not included in this study.
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8.10. Health Economics
Health economics/medical resource utilization and health economics parameters are not 
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9. STATISTICAL CONSIDERATIONS
Detailed methodology for summary and statistical analyses of the data collected in this study 
is outlined here and further detailed in a SAP, which will be maintained by the sponsor.  The 
SAP may modify what is outlined in the protocol where appropriate; however, any major 
modifications of the primary endpoint definitions or their analyses will also be reflected in a 
protocol amendment.
9.1. Statistical Hypotheses
No formal statistical hypothesis testing will be performed in this study.
9.2. Sample Size Determination
No formal sample size calculation was performed. Cohort size has been chosen to ensure 
appropriate sample size to provide adequate safety, toleration and PK information at each 
dose level and to provide a placebo comparison group, while minimizing exposure to humans 
of a new biologic entity. Participants who discontinue during the trial may be replaced at the 
discretion of the sponsor and investigator.

Part 1 and 2: A sample size of up to approximately 42 participants (58 including 
optional cohorts) was chosen based on the need to minimize exposure of humans to 
PF-07059013 and the requirement to provide adequate safety, tolerability, and PK 
information at each dose level.

Part 3: A sample size of up to approximately 8 participants was selected for the 
exploration of PK differences of different formulations and food effect. The sample 
size for Part 3 may be altered (up to 12 participants) depending on PK variability data 
from Part 1 of this study.
9.3. Analysis Sets
For purposes of analysis, the following analysis sets are defined:
Participant Analysis 
Set
Description
Enrolled/Randomly 
assigned to study 
intervention
“Enrolled” means a participant's, or their legally authorized 
representative’s, agreement to participate in a clinical study 
following completion of the informed consent process.  
Potential participants who are screened for the purpose of 
determining eligibility for the study, but do not participate in 
the study, are not considered enrolled, unless otherwise 
specified by the protocol.
All enrolled participants randomly assigned to investigational 
product regardless of whether or not the investigational 
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Participant Analysis 
Set
Description
PK Population
The PK concentration population will be defined as all 
randomized participants who received at least 1 dose of 
PF-07059103 and in whom at least 1 plasma and blood 
concentration value is reported.
The PK parameter analysis population will be defined as all 
randomized participants who received at least 1 dose of 
PF-07059103 and who have at least 1 of the PK parameters 
of interest calculated.
PD Population
The PD analysis population is defined as all randomized
participants who received at least one dose and have at least 
one PD assessment in at least one cohort.
Safety
All participants randomly assigned to study intervention and 
who take at least 1 dose of study intervention.  Participants 
will be analyzed according to the product they actually 
received.
9.4. Statistical Analyses
The SAP will be developed and finalized before any analyses are performed and will 
describe the analyses and procedures for accounting for missing, unused, and spurious data. 
This section is a summary of the planned statistical analyses of the primary and secondary 
endpoints.
9.4.1. Safety Analyses
All safety analyses will be performed on the safety population.
AEs, ECGs, BP, pulse rate, continuous cardiac monitoring, and safety laboratory data will be 
reviewed and summarized on an ongoing basis during the study to evaluate the safety of 
participants.  Any clinical laboratory, ECG, BP, and pulse rate abnormalities of potential 
clinical concern will be described.  Safety data will be presented in tabular and/or graphical 
format and summarized descriptively, where appropriate.
Medical history and physical examination and neurological examination information, as 
applicable, collected during the course of the study will be considered source data and will 
not be required to be reported, unless otherwise noted.  However, any untoward findings 
identified on physical and/or neurological examinations conducted during the active 
collection period will be captured as AEs, if those findings meet the definition of an AE.  
Data collected at screening that are used for inclusion/exclusion criteria, such as laboratory 
data, ECGs, and vital signs, will be considered source data, and will not be required to be 
reported, unless otherwise noted.  Demographic data collected at screening will be reported.


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9.4.1.1. Electrocardiogram Analyses
Changes from baseline for the ECG parameters QT interval, heart rate, QTcF interval, PR 
interval, and QRS complex will be summarized by treatment and time.  Baseline will be 
average of triplicate measurement at pre-dose on Day 1.
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 (msec)
Moderate (msec)
Severe (msec)
Absolute value
>450-480
>480-500
>500
Increase from baseline
30-60
>60
In addition, the number of participants with uncorrected QT values >500 msec will be 
summarized.
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 msec, but the mean of the triplicates is not >500 msec, the data from the participant’s 
individual tracing will be described in a safety section of the CSR in order to place the 
>500-msec value in appropriate clinical context.  However, values from individual tracings 
within triplicate measurements that are >500 msec will not be included in the categorical 
analysis unless the average from the triplicate measurements is also >500 msec.  Changes 
from baseline will be defined as the change between the postdose QTcF value and the 
average of the predose triplicate values 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 may be 
examined.
9.4.2. Pharmacokinetic Analyses
9.4.2.1. Derivation of Pharmacokinetic Parameters
PK parameters to be derived (if data permit) from the concentration-time data using standard 
noncompartmental methods following single and multiple dose administrations are defined in 
Table 3 and Table 4, respectively.  
 
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Table 3.
Plasma and Blood PK Parameters Definitions for Part 1 (Single 
Ascending Dose) and Part 3
Parameter
Definition
Method of Determination
 
 
 
 
 
 
 
 
  
Cmax
Maximum plasma concentration.
Observed directly from data
Tmax
Time for Cmax.
Observed directly from data as time of first 
occurrence.
 
 
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Table 4.
Plasma and Blood PK Parameters for Part 2 (Multiple Ascending Doses)
Parameter
Day
Definition
Method of Determination
AUCτ
1, 7, 14
Area under the plasma 
concentration-time profile from time 
zero to time τ (tau), the dosing interval.
Linear/Log trapezoidal method.
Cmax
1, 7, 14
Maximum plasma concentration during 
the dosing interval.
Observed directly from data.
Tmax
1, 7, 14
Time for Cmax.
Observed directly from data as time of 
first occurrence.
 
 
 
 
.
Actual PK sampling times will be used in derivation of PK parameters.
 
 
 
 
9.4.2.2. Statistical Methods for PK Data
No formal inferential statistics will be applied to the PK data from Part 1 and 2.
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Part 1 and Part 2
The PK parameters listed in Table 3 and Table 4 will be summarized descriptively by dose, 
treatment group (where applicable) and day (for Part 2). The blood and plasma concentration 
of PF-07059013 will be listed and descriptively summarized by nominal PK sampling time 
and treatment group.  Individual participant, as well as mean and median profiles of the 
blood and plasma concentration-time data will be plotted by treatment group using actual (for 
individual) and nominal (for mean and median) times respectively.  Mean and median 
profiles will be presented on both linear and log scales.
Dose normalized (to 1 mg) AUC and Cmax of PF-07059013 will be plotted against dose
(using a logarithmic scale) for single- and multiple dose phases, and will include individual
participant values as well as the geometric means for each dose. These plots will be used to 
help understand the relationship between the PK parameters and dose. 
Urine amounts of PF-07059013 
will be listed and summarized descriptively, if data
permits.
Additional specifications about the tables, listings, and figures will be outlined in the SAP.
Food Effect and Formulation Evaluation
The pharmacokinetic parameters 
 Cmax, and Tmax for 
PF-07059013 will be summarized descriptively by treatment group. For 
 
Cmax, individual participant parameters will be plotted by treatment group. Blood and 
plasma concentrations will be summarized descriptively by treatment group, fed versus
fasted condition, and PK sampling time. Individual participant, as well as mean and median 
profiles of concentration-time data will be plotted by treatment group using actual and 
nominal times, respectively. Mean and median profiles will be presented on both linear and 
log scales.
The statistical comparison of PF-07059013 PK parameters following high-fat/high-caloric 
meal (Test) versus overnight fast (Reference), moderate particle size (Test) versus small 
particle size (Reference) suspension administered under fasted condition, and tablet 
formulation (Test) versus small particle size suspension formulation (Reference) 
administered under fasted condition will be detailed in the SAP.  The analyses will include 
reporting the ratio of adjusted geometric means (Test/Reference) and 90% confidence 
intervals for the ratios for Cmax, 
 as data permit.
9.4.3. Pharmacodynamic Analyses
Absolute and change from baseline measurements of the PD endpoints (p20 and p50) will be 
listed and summarized descriptively by study part, dose, treatment group (where applicable)
and sampling time. Further details will be provided in the SAP.
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9.5. Interim Analyses
No formal interim analysis will be conducted for this study. As this is an sponsor-open 
study, the sponsor will conduct unblinded reviews of the data during the course of the study 
for the purpose of safety assessment, facilitating dose-escalation decisions, facilitating 
PK/PD modeling, and/or supporting clinical development.
9.6. Data Monitoring Committee or Other Independent Oversight Committee
This study will not use a DMC.
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10. SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS
10.1. Appendix 1: Regulatory, Ethical, and Study Oversight Considerations
10.1.1. Regulatory and Ethical Considerations
This study will be conducted in accordance with the protocol and with the following:

Consensus ethical principles derived from international guidelines including the 
Declaration of Helsinki and CIOMS International Ethical Guidelines;

Applicable ICH GCP guidelines;

Applicable laws and regulations, including applicable privacy laws.
The protocol, protocol amendments, ICD, SRSD(s), and other relevant documents 
(eg, advertisements) must be reviewed and approved by the sponsor and submitted to an 
IRB/EC by the investigator and reviewed and approved by the IRB/EC before the study is 
initiated.
Any amendments to the protocol will require IRB/EC approval before implementation of 
changes made to the study design, except for changes necessary to eliminate an immediate 
hazard to study participants.
The investigator will be responsible for the following:

Providing written summaries of the status of the study to the IRB/EC annually or 
more frequently in accordance with the requirements, policies, and procedures 
established by the IRB/EC;

Notifying the IRB/EC of SAEs or other significant safety findings as required by 
IRB/EC procedures;

Providing oversight of the conduct of the study at the site and adherence to 
requirements of 21 CFR, ICH guidelines, the IRB/EC, European regulation 536/2014 
for clinical studies (if applicable), and all other applicable local regulations.
10.1.1.1. Reporting of Safety Issues and Serious Breaches of the Protocol or ICH GCP
In the event of any prohibition or restriction imposed (ie, clinical hold) by an applicable 
regulatory authority in any area of the world, or if the investigator is aware of any new 
information that might influence the evaluation of the benefits and risks of the study 
intervention, Pfizer should be informed immediately.  
In addition, the investigator will inform Pfizer immediately of any urgent safety measures 
taken by the investigator to protect the study participants against any immediate hazard, and 
of any serious breaches of this protocol or of ICH GCP that the investigator becomes aware 
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10.1.2. Financial Disclosure
Not applicable.
10.1.3. Informed Consent Process
The investigator or his/her representative will explain the nature of the study to the 
participant and answer all questions regarding the study.  The participant should be given 
sufficient time and opportunity to ask questions and to decide whether or not to participate in 
the trial.
Participants must be informed that their participation is voluntary. Participants will be 
required to sign a statement of informed consent that meets the requirements of 21 CFR 50, 
local regulations, ICH guidelines, HIPAA requirements, where applicable, and the IRB/EC 
or study center.
The investigator must ensure that each study participant is fully informed about the nature 
and objectives of the study, the sharing of data related to the study, and possible risks 
associated with participation, including the risks associated with the processing of the 
participant’s personal data. 
The participant must be informed that his/her personal study-related data will be used by the 
sponsor in accordance with local data protection law. The level of disclosure must also be 
explained to the participant.
The participant must be informed that his/her medical records may be examined by Clinical 
Quality Assurance auditors or other authorized personnel appointed by the sponsor, by 
appropriate IRB/EC members, and by inspectors from regulatory authorities.
The investigator further must ensure that each study participant is fully informed about his or 
her right to access and correct his or her personal data and to withdraw consent for the 
processing of his or her personal data.
The medical record must include a statement that written informed consent was obtained 
before the participant was enrolled in the study and the date the written consent was obtained.
The authorized person obtaining the informed consent must also sign the ICD.
Participants must be reconsented to the most current version of the ICD(s) during their 
participation in the study.
A copy of the ICD(s) must be provided to the participant.
Unless prohibited by local requirements or IRB/EC decision, the ICD will contain a separate 
section that addresses the use of samples for optional additional research.  The optional 
additional research does not require the collection of any further samples. The investigator 
or authorized designee will explain to each participant the objectives of the additional
research. Participants will be told that they are free to refuse to participate and may 
withdraw their consent at any time and for any reason during the storage period. A separate 


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signature will be required to document a participant's agreement to allow specimens to be 
used for additional research. Participants who decline to participate in this optional
additional research will not provide this separate signature.
10.1.4. Data Protection
All parties will comply with all applicable laws, including laws regarding the implementation 
of organizational and technical measures to ensure protection of participant data.
Participants’ personal data will be stored at the study site in encrypted electronic and/or paper 
form and will be password protected or secured in a locked room to ensure that only 
authorized study staff have access.  The study site will implement appropriate technical and 
organizational measures to ensure that the personal data can be recovered in the event of 
disaster.  In the event of a potential personal data breach, the study site will be responsible 
for determining whether a personal data breach has in fact occurred and, if so, providing 
breach notifications as required by law.
To protect the rights and freedoms of participants with regard to the processing of personal 
data, participants will be assigned a single, participant-specific numerical code. Any 
participant records or data sets that are transferred to the sponsor will contain the numerical 
code; participant names will not be transferred. All other identifiable data transferred to the 
sponsor will be identified by this single, participant-specific code. The study site will 
maintain a confidential list of participants who participated in the study, linking each 
participant’s numerical code to his or her actual identity and medical record identification. In 
case of data transfer, the sponsor will protect the confidentiality of participants’ personal data 
consistent with the clinical study agreement and applicable privacy laws.
10.1.5. Dissemination of Clinical Study Data
Pfizer fulfills its commitment to publicly disclose clinical study results through posting the 
results of studies on www.clinicaltrials.gov (ClinicalTrials.gov), the EudraCT, and/or 
www.pfizer.com, and other public registries in accordance with applicable local 
laws/regulations.  In addition, Pfizer reports study results outside of the requirements of local 
laws/regulations pursuant to its SOPs.
In all cases, study results are reported by Pfizer in an objective, accurate, balanced, and 
complete manner and are reported regardless of the outcome of the study or the country in 
which the study was conducted.
www.clinicaltrials.gov
Pfizer posts clinical trial results on www.clinicaltrials.gov for Pfizer-sponsored interventional 
studies (conducted in patients) that evaluate the safety and/or efficacy of a product, 
regardless of the geographical location in which the study is conducted.  These results are 
submitted for posting in accordance with the format and timelines set forth by US law.


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EudraCT
Pfizer posts clinical trial results on EudraCT for Pfizer-sponsored interventional studies in 
accordance with the format and timelines set forth by EU requirements.
www.pfizer.com
Pfizer posts public disclosure synopses (CSR synopses in which any data that could be used 
to identify individual participants have been removed) on www.pfizer.com for 
Pfizer-sponsored interventional studies at the same time the corresponding study results are
posted to www.clinicaltrials.gov.
Documents within marketing authorization packages/submissions
Pfizer complies with the European Union Policy 0070, the proactive publication of clinical 
data to the EMA website.  Clinical data, under Phase 1 of this policy, includes clinical 
overviews, clinical summaries, CSRs, and appendices containing the protocol and protocol 
amendments, sample CRFs, and statistical methods. Clinical data, under Phase 2 of this 
policy, includes the publishing of individual participant data. Policy 0070 applies to new 
marketing authorization applications submitted via the centralized procedure since 
01 January 2015 and applications for line extensions and for new indications submitted via 
the centralized procedure since 01 July 2015.
Data Sharing
Pfizer provides researchers secure access to patient-level data or full CSRs for the purposes 
of “bona-fide scientific research” that contributes to the scientific understanding of the 
disease, target, or compound class. Pfizer will make available data from these trials 
24 months after study completion.  Patient-level data will be anonymized in accordance with 
applicable privacy laws and regulations. CSRs will have personally identifiable information 
redacted.
Data requests are considered from qualified researchers with the appropriate competencies to 
perform the proposed analyses. Research teams must include a biostatistician. Data will not 
be provided to applicants with significant conflicts of interest, including individuals 
requesting access for commercial/competitive or legal purposes.
10.1.6. Data Quality Assurance
All participant data relating to the study will be recorded on printed or electronic CRF unless 
transmitted to the sponsor or designee electronically (eg, laboratory data). The investigator is 
responsible for verifying that data entries are accurate and correct by physically or 
electronically signing the CRF.
The investigator must maintain accurate documentation (source data) that supports the 
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The investigator must ensure that the CRFs are securely stored at the study site in encrypted 
electronic and/or paper form and are password protected or secured in a locked room to 
prevent access by unauthorized third parties.
The investigator must permit study-related monitoring, audits, IRB/EC review, and 
regulatory agency inspections and provide direct access to source data documents.  This 
verification may also occur after study completion.  It is important that the investigator(s) 
and their relevant personnel are available during the monitoring visits and possible audits or 
inspections and that sufficient time is devoted to the process.
Monitoring details describing strategy (eg, risk-based initiatives in operations and quality 
such as risk management and mitigation strategies and analytical risk-based monitoring), 
methods, responsibilities, and requirements, including handling of noncompliance issues and 
monitoring techniques (central, remote, or on-site monitoring), are provided in the 
monitoring plan.
The sponsor or designee is responsible for the data management of this study, including 
quality checking of the data.
Study monitors will perform ongoing source data verification to confirm that data entered 
into the CRF by authorized site personnel are accurate, complete, and verifiable from source 
documents; that the safety and rights of participants are being protected; and that the study is 
being conducted in accordance with the currently approved protocol and any other study 
agreements, ICH GCP, and all applicable regulatory requirements.
Records and documents, including signed ICDs, pertaining to the conduct of this study must 
be retained by the investigator for 15 years after study completion unless local regulations or 
institutional policies require a longer retention period. No records may be destroyed during 
the retention period without the written approval of the sponsor. No records may be 
transferred to another location or party without written notification to the sponsor. The 
investigator must ensure that the records continue to be stored securely for as long as they are 
maintained.
When participant data are to be deleted, the investigator will ensure that all copies of such 
data are promptly and irrevocably deleted from all systems.
The investigator(s) will notify the sponsor or its agents immediately of any regulatory 
inspection notification in relation to the study.  Furthermore, the investigator will cooperate 
with the sponsor or its agents to prepare the investigator site for the inspection and will allow 
the sponsor or its agent, whenever feasible, to be present during the inspection.  The 
investigator site and investigator will promptly resolve any discrepancies that are identified 
between the study data and the participant's medical records.  The investigator will promptly 
provide copies of the inspection findings to the sponsor or its agent.  Before response 
submission to the regulatory authorities, the investigator will provide the sponsor or its 
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10.1.7. Source Documents
Source documents provide evidence for the existence of the participant and substantiate the 
integrity of the data collected.  Source documents are filed at the investigator site.
Data reported on the CRF or entered in the eCRF that are from source documents must be 
consistent with the source documents or the discrepancies must be explained. The 
investigator may need to request previous medical records or transfer records, depending on 
the study. Also, current medical records must be available.
Definition of what constitutes source data can be found in source document locator.
Description of the use of computerized system is documented in source document locator.
10.1.8. Study and Site Start and Closure
The study start date is the date on which the clinical study will be open for recruitment of 
participants.
The first act of recruitment is the date of the first participant’s first visit and will be the study 
start date.
The sponsor designee reserves the right to close the study site or terminate the study at any 
time for any reason at the sole discretion of the sponsor. Study sites will be closed upon 
study completion. A study site is considered closed when all required documents and study 
supplies have been collected and a study-site closure visit has been performed.
The investigator may initiate study-site closure at any time upon notification to the sponsor if 
requested to do so by the responsible IRB/EC or if such termination is required to protect the 
health of study participants.
Reasons for the early closure of a study site by the sponsor may include but are not limited 
to:

Failure of the investigator to comply with the protocol, the requirements of the 
IRB/EC or local health authorities, the sponsor's procedures, or GCP guidelines;

Inadequate recruitment of participants by the investigator;

Discontinuation of further study intervention development.
If the study is prematurely terminated or suspended, the sponsor shall promptly inform the 
investigators, the ECs/IRBs, the regulatory authorities, and any CRO(s) used in the study of 
the reason for termination or suspension, as specified by the applicable regulatory 
requirements. The investigator shall promptly inform the participant and should assure 
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Study termination is also provided for in the clinical study agreement.  If there is any conflict 
between the contract and this protocol, the contract will control as to termination rights.
10.1.9. Publication Policy
The results of this study may be published or presented at scientific meetings by the 
investigator after publication of the overall study results or 1 year after the end of the study 
(or study termination), whichever comes first. 
The investigator agrees to refer to the primary publication in any subsequent publications 
such as secondary manuscripts, and submits all manuscripts or abstracts to the sponsor 
30 days before submission. This allows the sponsor to protect proprietary information and to 
provide comments and the investigator will, on request, remove any previously undisclosed 
confidential information before disclosure, except for any study- or Pfizer-intervention 
related information necessary for the appropriate scientific presentation or understanding of 
the study results.
For all publications relating to the study, the investigator will comply with recognized ethical 
standards concerning publications and authorship, including those established by the 
International Committee of Medical Journal Editors.
The sponsor will comply with the requirements for publication of the overall study results 
covering all investigator sites.  In accordance with standard editorial and ethical practice, the 
sponsor will support publication of multicenter studies only in their entirety and not as 
individual site data.  In this case, a coordinating investigator will be designated by mutual 
agreement.
Authorship of publications for the overall study results will be determined by mutual 
agreement and in line with International Committee of Medical Journal Editors authorship 
requirements. 
If publication is addressed in the clinical study agreement, the publication policy set out in 
this section will not apply.
10.1.10. Sponsor’s Qualified Medical Personnel
The contact information for the sponsor's appropriately qualified medical personnel for the 
study is documented in the study contact list located in the study team on demand system. 
To facilitate access to appropriately qualified medical personnel on study-related medical 
questions or problems, participants are provided with a contact card at the time of informed 
consent.  The contact card contains, at a minimum, protocol and study intervention
identifiers, participant numbers, contact information for the investigator site, and contact 
details for a contact center in the event that the investigator site staff cannot be reached to 
provide advice on a medical question or problem originating from another healthcare 
professional not involved in the participant’s participation in the study.  The contact number 
can also be used by investigator staff if they are seeking advice on medical questions or 
problems; however, it should be used only in the event that the established communication 


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pathways between the investigator site and the study team are not available.  It is therefore 
intended to augment, but not replace, the established communication pathways between the 
investigator site and the study team for advice on medical questions or problems that may 
arise during the study.  For sites other than a Pfizer CRU, the contact number is not intended 
for use by the participant directly, and if a participant calls that number, he or she will be 
directed back to the investigator site.


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10.2. Appendix 2: Clinical Laboratory Tests
The following safety laboratory tests will be performed at times defined in the SoA section of 
this protocol.  Additional laboratory results may be reported on these samples as a result of 
the method of analysis or the type of analyzer used by the clinical laboratory, or as derived 
from calculated values.  These additional tests would not require additional collection of 
blood.  Unscheduled clinical laboratory measurements may be obtained at any time during 
the study to assess any perceived safety issues.
Table 6.
Protocol-Required Safety Laboratory Assessments
Hematology
Chemistry
Urinalysis
Other
Hemoglobin
Hematocrit
RBC count
MCV
MCH
MCHC
Platelet count
WBC count
Total neutrophils 
(Abs)
Eosinophils (Abs)
Monocytes (Abs)
Basophils (Abs)
Lymphocytes (Abs)
BUN and creatinine
Glucose (fasting)
Calcium
Sodium
Potassium
Chloride
Total CO2 (bicarbonate)
AST, ALT
Total bilirubin
Alkaline phosphatase
Uric acid
Albumin
Total protein
pH
Glucose (qual)
Protein (qual)
Blood (qual)
Ketones
Nitrites
Leukocyte esterase
Urobilinogen
Urine bilirubin
Microscopyc
Lactate
Ferritin 
C reactive protein
Urine drug screeninga
Urine cotinine test (Part 1 
and 2 only)
EPO (Part 2 only)
Reticulocytes (Abs and %) 
(Part 2 only)
At screening only:

Serum FSHb

Hepatitis B surface 
antigen

Hepatitis B suface 
antibody

Hepatitis B core 
antibody

Hepatitis C antibody

Human 
immunodeficiency virus

PT/INR

aPTT
Abbreviations: Abs = absolute; aPTT = activated partial thromboplastin time; ALT = alanine 
aminotransferase; AST = aspartate aminotransferase; BUN = blood urea nitrogen; CO2 = carbon dioxide 
(bicarbonate); EPO = erythropoietin; FSH = follicle-stimulating hormone; MCH = mean corpuscular 
hemoglobin;  MCHC = mean corpuscular hemoglobin concentration; MCV = mean corpuscular 
volume; PT/INR = prothrombin time/international normalized ratio; qual = qualitative; RBC = red 
blood cell; WBC = white blood cell.
a.
At Screening and Admission (Day -1) for each inpatient stay, the minimum requirement for drug 
screening includes cocaine, THC, opiates/opioids, benzodiazepines, and amphetamines (others are 
site and study specific).
b.
For confirmation of postmenopausal status only.
c.
Only if urine dipstick is positive for blood, protein, nitrites, or leukocyte esterase.
d.
Unless needed for screening, review is not required prior to dosing; accumulative data will be 
reviewed as they become available.  Refer to Section 6.6.1 for data needed for review prior to dose 
escalation, where applicable.
Investigators must document their review of each laboratory safety report.


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Laboratory/analyte results that could unblind the study will not be reported to investigator 
sites or other blinded personnel until the study has been unblinded.
Any remaining serum 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. 
 
 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 either 
an increase in frequency and/or intensity of the condition.

New conditions detected or diagnosed after study intervention administration 
even though it may have been present before the start of the study.

Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction.

Signs, symptoms, or the clinical sequelae of a suspected overdose of either study 
intervention or a concomitant medication. Overdose per se will not be reported 
as an AE/SAE unless it is an intentional overdose taken with possible 
suicidal/self-harming intent. Such overdoses should be reported regardless of 
sequelae.


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


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Hospitalization for elective treatment of a preexisting condition that did not worsen from 
baseline is not considered an AE.
d. Results in persistent disability/incapacity

The term disability means a substantial disruption of a person’s ability to conduct 
normal life functions.

This definition is not intended to include experiences of relatively minor medical 
significance such as uncomplicated headache, nausea, vomiting, diarrhea, 
influenza, and accidental trauma (eg, sprained ankle) which may interfere with or 
prevent everyday life functions but do not constitute a substantial disruption.
e.
Is a congenital anomaly/birth defect
f.
Other situations:

Medical or scientific judgment should be exercised in deciding whether SAE 
reporting is appropriate in other situations such as important medical events that 
may not be immediately life-threatening or result in death or hospitalization but 
may jeopardize the participant or may require medical or surgical intervention to 
prevent one of the other outcomes listed in the above definition. These events 
should usually be considered serious.

Examples of such events include invasive or malignant cancers, intensive 
treatment in an emergency room or at home for allergic bronchospasm, blood 
dyscrasias or convulsions that do not result in hospitalization, or development of 
drug dependency or drug abuse.
10.3.3. Recording/Reporting and Follow-up of AEs and/or SAEs
AE and SAE Recording/Reporting
The table below summarizes the requirements for recording adverse events on the CRF 
and for reporting serious adverse events on the CT SAE Report Form to Pfizer Safety.  
These requirements are delineated for 3 types of events: (1) SAEs; (2) nonserious AEs; 
and (3) exposure to the study intervention under study during pregnancy or 
breastfeeding, and occupational exposure. 
It should be noted that the CT SAE Report Form for reporting of SAE information is not 
the same as the AE page of the CRF.  When the same data are collected, the forms must 
be completed in a consistent manner.  AEs should be recorded using concise medical 
terminology and the same AE term should be used on both the CRF and the CT SAE 
Report Form for reporting of SAE information.


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Safety Event
Recorded on the CRF
Reported on the CT SAE 
Report Form to Pfizer 
Safety Within 24 Hours 
of Awareness
SAE
All
All
Nonserious AE
All
None
Exposure to the study 
intervention under study 
during pregnancy or 
breastfeeding, and 
occupational exposure
All AEs/SAEs associated 
with exposure during 
pregnancy or breastfeeding
Occupational exposure is 
not recorded.
All (and EDP 
supplemental form for 
EDP)
Note:  Include all SAEs 
associated with exposure 
during pregnancy or 
breastfeeding. Include all 
AEs/SAEs associated with 
occupational exposure.

When an AE/SAE occurs, it is the responsibility of the investigator to review all 
documentation (eg, hospital progress notes, laboratory reports, and diagnostic 
reports) related to the event.

The investigator will then record all relevant AE/SAE information in the CRF.

It is not acceptable for the investigator to send photocopies of the participant’s 
medical records to Pfizer Safety in lieu of completion of the CT SAE Report 
Form/AE/SAE CRF page.

There may be instances when copies of medical records for certain cases are 
requested by Pfizer Safety. In this case, all participant identifiers, with the 
exception of the participant number, will be redacted on the copies of the medical 
records before submission to Pfizer Safety.

The investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information. Whenever possible, the diagnosis 
(not the individual signs/symptoms) will be documented as the AE/SAE.
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: 
GRADE
Clinical Description of Severity
1
MILD adverse event


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2
MODERATE adverse event
3
SEVERE adverse event
4
LIFE-THREATENING consequences; urgent intervention indicated
5
DEATH RELATED TO adverse event

Common Terminology Criteria for Adverse Events (CTCAE) Version v5 will be 
utilized for grading, and Grade 1 will be recorded as mild, Grade 2 as moderate, 
and Grade 3 and above as severe.

An event is defined as “serious” when it meets at least 1 of the predefined 
outcomes as described in the definition of an SAE, NOT when it is rated as 
severe.
Assessment of Causality

The investigator is obligated to assess the relationship between study intervention 
and each occurrence of each AE/SAE.

A “reasonable possibility” of a relationship conveys that there are facts, 
evidence, and/or arguments to suggest a causal relationship, rather than a 
relationship cannot be ruled out.

The investigator will use clinical judgment to determine the relationship.

Alternative causes, such as underlying disease(s), concomitant therapy, and other 
risk factors, as well as the temporal relationship of the event to study intervention 
administration, will be considered and investigated.

The investigator will also consult the IB and/or product information, for 
marketed products, in his/her assessment.

For each AE/SAE, the investigator must document in the medical notes that 
he/she has reviewed the AE/SAE and has provided an assessment of causality.

There may be situations in which an SAE has occurred and the investigator has 
minimal information to include in the initial report to the sponsor. However, it is 
very important that the investigator always make an assessment of causality 
for every event before the initial transmission of the SAE data to the 
sponsor.


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
The investigator may change his/her opinion of causality in light of follow-up 
information and send an SAE follow-up report with the updated causality 
assessment.

The causality assessment is one of the criteria used when determining regulatory 
reporting requirements.

If the investigator does not know whether or not the study intervention caused the 
event, then the event will be handled as “related to study intervention” for 
reporting purposes, as defined by the sponsor.  In addition, if the investigator 
determines that an SAE is associated with study procedures, the investigator 
must record this causal relationship in the source documents and CRF, and report 
such an assessment in the dedicated section of the CT SAE Report Form and in 
accordance with the SAE reporting requirements.
Follow-up of AEs and SAEs

The investigator is obligated to perform or arrange for the conduct of 
supplemental measurements and/or evaluations as medically indicated or as 
requested by the sponsor to elucidate the nature and/or causality of the AE or 
SAE as fully as possible. This may include additional laboratory tests or 
investigations, histopathological examinations, or consultation with other 
healthcare providers.

If a participant dies during participation in the study or during a recognized 
follow-up period, the investigator will provide Pfizer Safety with a copy of any 
postmortem findings including histopathology.

New or updated information will be recorded in the originally completed CRF.

The investigator will submit any updated SAE data to the sponsor within 
24 hours of receipt of the information.
10.3.4. Reporting of SAEs
SAE Reporting to Pfizer Safety via an Electronic Data Collection Tool

The primary mechanism for reporting an SAE to Pfizer Safety will be the 
electronic data collection tool.

If the electronic system is unavailable, then the site will use the paper SAE data 
collection tool (see next section) in order to report the event within 24 hours.


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
The site will enter the SAE data into the electronic system as soon as the data
become available.

After the study is completed at a given site, the electronic data collection tool 
will be taken off-line to prevent the entry of new data or changes to existing data.

If a site receives a report of a new SAE from a study participant or receives 
updated data on a previously reported SAE after the electronic data collection 
tool has been taken off-line, then the site can report this information on a paper 
SAE form (see next section) or to Pfizer Safety by telephone.
SAE Reporting to Pfizer Safety via CT SAE Report Form

Facsimile transmission of the CT SAE Report Form is the preferred method to 
transmit this information to Pfizer Safety.

In circumstances when the facsimile is not working, notification by telephone is 
acceptable with a copy of the CT SAE Report Form sent by overnight mail or 
courier service.

Initial notification via telephone does not replace the need for the investigator to 
complete and sign the CT SAE Report Form pages within the designated 
reporting time frames.


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10.4. Appendix 4: Contraceptive Guidance 
10.4.1. Male Participant Reproductive Inclusion Criteria
Male participants are eligible to participate if they agree to the following requirements during 
the intervention period and for at least 28 days after the last dose of study intervention, which
corresponds to the time needed to eliminate reproductive safety risk of the study 
intervention(s) :

Refrain from donating sperm.
PLUS either:

Be abstinent from heterosexual intercourse with a female of childbearing potential as 
their preferred and usual lifestyle (abstinent on a long-term and persistent basis) and 
agree to remain abstinent. 
OR

Must agree to use a male condom when engaging in any activity that allows for 
passage of ejaculate to another person.

In addition to male condom use, a highly effective method of contraception may be 
considered in WOCBP partners of male participants (refer to the list of highly 
effective methods below in Section 10.4.4).
10.4.2. Female Participant Reproductive Inclusion Criteria
A female participant is eligible to participate if she is not a WOCBP (see definitions below 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).
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;


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
Documented bilateral salpingectomy;

Documented bilateral oophorectomy.
For individuals with permanent infertility due to an alternate medical cause other than 
the above, (eg, mullerian agenesis, androgen insensitivity), investigator discretion 
should be applied to determining study entry.
Note: Documentation for any of the above categories can come from the site 
personnel’s review of the participant’s medical records, medical examination, or 
medical history interview.  The method of documentation should be recorded in the 
participant’s medical record for the study.
2. Postmenopausal female.

A postmenopausal state is defined as no menses for 12 months without an 
alternative medical cause. In addition, a

High FSH level in the postmenopausal range must be used to confirm a 
postmenopausal state in women under 60 years old and not using hormonal 
contraception or HRT. 

Female on HRT and whose menopausal status is in doubt will be required to 
use one of the nonestrogen hormonal highly effective contraception methods 
if they wish to continue their HRT during the study.  Otherwise, they must 
discontinue HRT to allow confirmation of postmenopausal status before study 
enrollment.
10.4.4. Contraception Methods
Contraceptive use by men or women should be consistent with local availability/regulations 
regarding the use of contraceptive methods for those participating in clinical trials.
Highly Effective Methods That Have Low User Dependency
1. Implantable progestogen--only hormone contraception associated with inhibition of 
ovulation.
2. Intrauterine device.
3. Intrauterine hormone--releasing system.
4. Bilateral tubal occlusion.
5. Vasectomized partner.

Vasectomized partner is a highly effective contraceptive method provided that the 
partner is the sole sexual partner of the WOCBP and the absence of sperm has 


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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 
1. Combined (estrogen- and progestogen-containing) hormonal contraception associated 
with inhibition of ovulation.

Oral;

Intravaginal;

Transdermal;

Injectable.
2. Progestogen-only hormone contraception associated with inhibition of ovulation.

Oral;

Injectable.
3. Sexual abstinence

Sexual abstinence is considered a highly effective method only if defined as 
refraining from heterosexual intercourse during the entire period of risk associated 
with the study intervention.  The reliability of sexual abstinence needs to be 
evaluated in relation to the duration of the study and the preferred and usual 
lifestyle of the participant.
One of the following effective barrier methods must be used in addition to the highly 
effective methods listed above that are user dependent:

Male or female condom with or without spermicide;

Cervical cap, diaphragm, or sponge with spermicide;

A combination of male condom with either cervical cap, diaphragm, or sponge with 
spermicide (double-barrier methods).


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


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


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


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Final Protocol Amendment 1, 24 July 2020
PFIZER CONFIDENTIAL
Page 104

Ventricular rhythms >30 seconds’ duration, including idioventricular rhythm 
(heart rate <40 bpm), accelerated idioventricular rhythm (HR >40 bpm to
<100 bpm), and monomorphic/polymorphic ventricular tachycardia (HR 
>100 bpm (such as torsades de pointes)).

Type II second-degree (Mobitz II) AV block.

Complete (third-degree) heart block.
ECG Findings That Qualify as Serious Adverse Events

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.


PF-07059013
Protocol C4061001
Final Protocol Amendment 1, 24 July 2020
PFIZER CONFIDENTIAL
Page 105
10.8. Appendix 8: Criteria for Vital Signs Abnormality
Pulse Rate
Supine: <40 or >120 bpm 
Standing: <40 or >140 bpm
Blood Pressure
Systolic ≥30 mm Hg change from baseline in same posture
Systolic <90 mm Hg
Diastolic ≥20 mm Hg change from baseline in same posture
Diastolic <50 mm Hg
Assessment should be based on at least 2 consecutive measurements. Repeat measurements should be taken
within 15 minutes if values fall outside the normal range.


PF-07059013
Protocol C4061001
Final Protocol Amendment 1, 24 July 2020
PFIZER CONFIDENTIAL
Page 106
10.9. Appendix 9: Abbreviations
The following is a list of abbreviations that may be used in the protocol.
Abbreviation
Term
→
ongoing/continuous event
Abs
absolute
ADE
adverse device effect
AE
adverse event
 
 
AESI
adverse events of special interest
ALT
alanine aminotransferase
aPTT
activated partial thromboplastin time
AST
aspartate aminotransferase
AUC
area under the curve
AUC24
area under the plasma concentration-time profile from time 
zero to 24 hours
AUCτ
area under the plasma concentration-time profile from time 
zero to time τ (tau), the dosing interval
 
 
AV
atrioventricular
BA
bioavailability
BBS
Biospecimen Banking System
BCRP
Breast Cancer Resistance Protein
BE
bioequivalence
β-hCG
beta-human chorionic gonadotropin
BID
twice daily
BMI
body mass index
BP
blood pressure
bpm
beats per minute
BUN
blood urea nitrogen
Ceff
efficacious concentration
CFR
Code of Federal Regulations
CIOMS
Council for International Organizations of Medical Sciences
CK
creatine kinase
CL
clearance
Clast
last quantifiable concentration
CCI
CCI
CCI
CCI
CCI


PF-07059013
Protocol C4061001
Final Protocol Amendment 1, 24 July 2020
PFIZER CONFIDENTIAL
Page 107
Abbreviation
Term
Cmax
maximum plasma concentration
CO2
carbon dioxide (bicarbonate)
CONSORT
Consolidated Standards of Reporting Trials
CRF
case report form
CRO
contract research organization
CRU
clinical research unit
CSF
cerebrospinal fluid
CSR
clinical study report
CT
clinical trial
CTCAE
Common Terminology Criteria for Adverse Events
CTMS
clinical trial management system
CT SAE
clinical trial serious adverse event
CV
cardiovascular
CYP
Cytochrome P450
DCT
data collection tool
DILI
drug-induced liver injury
DMC
data monitoring committee
DNA
deoxyribonucleic acid
DRE
disease-related event
DU
dispensable unit
EC
ethics committee
ECG
electrocardiogram
eCRF
electronic case report form
EDP
exposure during pregnancy
EDR
extemporaneous dispensing record
EMA
European Medicines Agency
EPO
erythropoietin
E/T
early termination
EU
European Union
EudraCT
European Clinical Trials Database
FIH
First in Human
FSH
follicle-stimulating hormone
F/U
follow-up
fup
fraction unbound in plasma
fm
fraction metabolized
GCP
Good Clinical Practice
GGT
gamma-glutamyl transferase
Glu
glutamic acid
Hb
hemoglobin
HbA
hemoglobin A
HBcAb
hepatitis B core antibody
HBcAg
hepatitis B core antigen
HbS
hemoglobin S


PF-07059013
Protocol C4061001
Final Protocol Amendment 1, 24 July 2020
PFIZER CONFIDENTIAL
Page 108
Abbreviation
Term
HBsAg 
hepatitis B surface antigen
HCVAb
hepatitis C antibody
HIPAA
Health Insurance Portability and Accountability Act
HIV
human immunodeficiency virus
HR
heart rate
HRT
hormone replacement therapy
IB
Investigator’s Brochure
ICD
informed consent document
ICH
International Council for Harmonisation
ID
identification
IEC
Independent Ethics Committee
IND
investigational new drug 
INR
international normalized ratio
IP manual
investigational product manual
IPAL
Investigational Product Accountability Log
IRB
institutional review board
IRC
internal review committee
IRT
interactive response technology
ISO
International Organization for Standardization
IV
intravenous
IWR
interactive Web-based response
K2EDTA
dipotassium ethylenediaminetetraacetic acid
LBBB
left bundle branch block
LFT
liver function test
MABEL
minimal anticipated biological effect level
MCH
mean corpuscular hemoglobin
MCHC
mean corpuscular hemoglobin concentration
MCV
mean corpuscular volume
msec
millisecond
N/A
not applicable
NDCMC
newly diagnosed chronic medical condition
NOAEL
no-observed-adverse-effect level
NOEL
no observed effect level
OATP
organic anion transporting polypeptide
OCT
organic cation transporter
p20
oxygen pressure at which 20% of the hemoglobin in a given 
blood sample is oxygenated
p50
oxygen pressure at which 50% of the hemoglobin in a given 
blood sample is oxygenated
PBMC1
peripheral blood mononuclear cells
PBPK
physiologically-based pharmacokinetic
PCRU
Pfizer clinical research unit
PD
pharmacodynamic(s)


PF-07059013
Protocol C4061001
Final Protocol Amendment 1, 24 July 2020
PFIZER CONFIDENTIAL
Page 109
Abbreviation
Term
PGx
pharmacogenomic(s)
PI
principal investigator
PIB
powder in bottle
PK
pharmacokinetic(s)
PT
prothrombin time
PT/INR
prothrombin time/internationalized normalized ratio
PVC
premature ventricular contraction/complex
QD
once daily
QRS
time from ECG Q wave to the end of the S wave 
corresponding to ventricle depolarization
QT
time between the start of the Q wave and the end of the T 
wave in the heart's electrical cycle
QTc
corrected QT
QTcF
corrected QT (Fridericia method)
qual
qualitative
RBC
red blood cell
RNA
ribonucleic acid
SADE
serious adverse device effect
SAE
serious adverse event
SAP
statistical analysis plan
SCD
sickle cell disease
SCr
serum creatinine
SoA
schedule of activities
SOP
standard operating procedure
SPR
Surface Plasmon Resonance
SRSD
single reference safety document
SToD
study team on demand
SUSAR
suspected unexpected serious adverse reaction
sVCAM
soluble Vascular Cell Adhesion Molecule
TBili
total bilirubin
TDI
time dependent inhibition
THC
tetrahydrocannabinol
Tmax
time for Cmax
UGT
uridine diphosphate glycosyltransferase
ULN
upper limit of normal
US
United States
USADE
unanticipated serious adverse device effect
Val
valine
VOC
vaso-occlusive crisis
Vss
volume of distribution
CCI
CC
I
C
C


PF-07059013
Protocol C4061001
Final Protocol Amendment 1, 24 July 2020
PFIZER CONFIDENTIAL
Page 110
Abbreviation
Term
WBC
white blood cell
WOCBP
woman of childbearing potential
CCI


PF-07059013
Protocol C4061001
Final Protocol Amendment 1, 24 July 2020
PFIZER CONFIDENTIAL
Page 111
11. REFERENCES
1.
Rees DC, Williams TN, Gladwin MT. Sickle-cell disease. The Lancet. 2010 Dec 11; 
376(9757): 2018-31.
2.
Kato GJ, Gladwin MT, Steinberg MH. Deconstructing sickle cell disease: Reappraisal 
of the role of hemolysis in the development of clinical subphenotypes. Blood Rev 2007; 
21(1): 37-47.
3.
Piel FB, Steinberg MH, Rees DC. Sickle cell disease. N Engl J Med 2017; 
376(16):1561-73.
4.
Hofrichter J, Ross PD, Eaton WA. Kinetics and mechanism of deoxyhemoglobin S 
gelation: a new approach to understanding sickle cell disease. Proceedings of the 
National Academy of Sciences. 1974 Dec 1;71(12):4864-8.
5.
Sunshine HR, Hofrichter J, Eaton WA. Requirement for therapeutic inhibition of sickle 
haemoglobin gelation. Nature 1978; 275:238-40.
6.
Ferrone FA, Hofrichter J, Eaton WA. Kinetics of sickle hemoglobin polymerization. II. 
A double nucleation mechanism. J Mol Biol 1985; 183(4):611-31.
7.
Arya R, Rolan PE, Wootton R, et al. Tucaresol increases oxygen affinity and reduces 
haemolysis in subjects with sickle cell anaemia. Br J Haematol 1996; 93(4):817-21.
8.
Howard J, Hemmaway CJ, Telfer P, et al. A phase 1/2 ascending dose study and open-
label extension study of voxelotor in patients with sickle cell disease. Blood 2019; 
133(17):1865-75.
9.
Deiderich DA, Trueworthy RC, Gill P, Cader AM, Larsen WE. Hematologic and 
clinical responses in patients with sickle cell anemia after chronic extracorporeal red 
cell carbamylation. The Journal of clinical investigation. 1976 Sep 1;58(3):642-53.
10.
Steinberg MH, Sebastiani P. Genetic modifiers of sickle cell disease. Am J Hematol 
2012; 87(8):795-803.
11.
Antwi-Boasiako C, Frimpong E, Ababio GK, et al. Sickle cell disease: reappraisal of the 
role of foetal haemoglobin levels in the frequency of vaso-occlusive crisis. Ghana Med 
J 2015; 49(2):102-6.
12.
Paszty C, Brion CM, Manci E, Witkowska HE, Stevens ME, Mohandas N, Rubin EM. 
Transgenic knockout mice with exclusively human sickle hemoglobin and sickle cell 
disease. Science. 1997 Oct 31;278(5339):876-8.
13.
Ryan TM, Ciavatta DJ, Townes TM. Knockout-transgenic mouse model of sickle cell 
disease. Science. 1997 Oct 31;278(5339):873-6.


PF-07059013
Protocol C4061001
Final Protocol Amendment 1, 24 July 2020
PFIZER CONFIDENTIAL
Page 112
14.
Estepp, J.H., et al., A clinically meaningful fetal hemoglobin threshold for children with 
sickle cell anemia during hydroxyurea therapy. Am J Hematol, 2017. 92(12): p. 1333-
1339.
15.
Vichinsky, E., et al., A Phase 3 Randomized Trial of Voxelotor in Sickle Cell Disease. 
N Engl J Med, 2019. 381(6): p. 509-519.
16.
Hutchaleelaha A, Patel M, Washington C, Siu V, Allen E, Oksenberg D, Gretler DD, 
Mant T, Lehrer-Graiwer J. Pharmacokinetics and pharmacodynamics of voxelotor 
(GBT440) in healthy adults and patients with sickle cell disease. Br J Clin Pharmacol.
2019 Jun; 85(6): 1290-1302.
17.
Rolan PE, Mercer AJ, Wootton R, Posner J. Pharmacokinetics and pharmacodynamics 
of tucaresol, an antisickling agent, in healthy volunteers. British journal of clinical 
pharmacology, 1995 Apr; 39(4): 375-380.

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Protocol C4061001 (PF-07059013) Statistical Analysis Plan 
 
 
 
Page 6 of 28 
 
          
 
 
 
PFIZER CONFIDENTIAL 
 
1. AMENDMENTS FROM PREVIOUS VERSION(S)  
This document is the original version from February 28, 2020. 
2. INTRODUCTION 
PF-07059013 is a novel small molecule allosteric modulator of hemoglobin that is currently 
being developed for the treatment of Sickle Cell Disease.   
The purpose of the study is to evaluate the safety, tolerability, pharmacokinetics (PK) and 
pharmacodynamic (PD) of single and multiple ascending oral doses of PF-07059013 in 
healthy adult participants.  Additionally, effects of different formulations and food on 
parameters, including PK, after single oral dose, may be explored.  This study is the first 
time that PF-07059013 will be administered to humans, and the results obtained from this 
study will inform future clinical development of PF-07059013. 
2.1. Study Design 
This study consists of 3 parts, with ongoing review of safety, tolerability, PK and PD data 
planned.  
Part 1 comprises of 4 periods with 2 interleaving cohorts of healthy adult participants. Part 
1 Period 1 to 3 is investigator- and participant-blinded, sponsor-open, randomized, single 
ascending dose, with 3-period placebo substitution crossover, and Period 4 will be open-
label. 
Part 2 of this study will be investigator- and participant-blinded, sponsor-open, randomized, 
placebo-controlled, sequential, multiple ascending dose, with 3 planned cohorts of healthy 
adult participants.  Two additional cohorts of healthy adult participants may be included to 
permit assessment of any of the following: repeat of a previously administered dose level; 
studying additional dose levels as dictated by the evaluated safety, tolerability or PK of 
earlier dose levels; or any other assessment needed to meet the objectives of this study. 
Part 3 of this study will be an open label, randomized, 4-period crossover, single dose 
assessment of formulation and/or food effects in healthy adult participants. 
Block randomization will be used to protect against possible temporal enrollment or dropout 
effects. In Part 1 with the 3-period crossover and no randomization for period 4, the block 
size of 3 (2:1 active to placebo ratio) will be used for each cohort (N=9). In Part 2 the block 
size of 4 (3:1 active to placebo ratio) will be used for each cohort (N=8). In Part 3 cohort 
(N=12) with the 4-period crossover, the block size of 4 will be used. 
 


Protocol C4061001 (PF-07059013) Statistical Analysis Plan 
 
 
 
Page 7 of 28 
 
          
 
 
 
PFIZER CONFIDENTIAL 
 
For all parts of the study, participants will be screened within 28 days of their first dose of 
investigational product.  Participants will be admitted to the CRU on Day -1 and may be 
discharged at investigator discretion following completion of assessments per Schedule of 
Activities. 
In Part 1 each participant may receive up to 3 single oral doses of PF-07059013 suspension 
and up to 1 placebo dose.  For Period 1 to 3, at each period, approximately 6 participants 
will receive a single dose of PF-07059013 suspension formulated with polymer, and 
approximately 3 participants will receive placebo formulated with polymer.  In Period 4, a 
single dose of PF-07059013 suspension, formulated without polymer, will be administered at 
a dose level that has been previously administered in the same cohort. Between each dose 
administration to a given participant there will be a washout interval of at least 14 days. 
In Part 2 each participant may receive multiple oral doses of PF-07059013 suspension 
(either with or without polymer, depending on results from Part 1) or placebo, over a 
duration of 14 days, depending on randomization. 
In Part 3 each participant may receive single oral dose of suspension with different 
formulations, or tablet, either under fasted condition or following a high fat/high caloric 
meal. Between each dose administration to a given participant there will be a washout 
interval of at least 14 days. 
Participants who discontinue for non-safety related reasons prior to completion of the study 
may be replaced, at the discretion of the principal investigator (PI) and sponsor.  The 
replacement participant(s) may or may not be required to complete all Periods of the cohort 
in which they are participating at the discretion of the PI and sponsor. 
A participant is considered to have completed the study if he/she has completed all phases of 
the study, including the last scheduled procedure shown in the Schedule of Activities and any 
requested unplanned visits. 
The end of the study is defined as the date of the last scheduled procedure shown in the 
Schedule of Activities for the last participant in the trial. 
A schematic of the overall study design is provided in Figure 1. 
 
 


Protocol C4061001 (PF-07059013) Statistical Analysis Plan 
 
 
 
Page 8 of 28 
 
          
 
 
 
PFIZER CONFIDENTIAL 
 
Figure 1. Sample Study Schematic 
 
 
 


Protocol C4061001 (PF-07059013) Statistical Analysis Plan 
 
 
 
Page 9 of 28 
 
          
 
 
 
PFIZER CONFIDENTIAL 
 
The table below presents the Part 3 randomization sequences. 
Cohort 
n 
Period 1 
Period 2 
Period 3 
Period 4 
N=12 
n=3 
A 
B 
C 
D 
n=3 
A 
B 
D 
C 
n=3 
B 
A 
C 
D 
n=3 
B 
A 
D 
C 
 
Treatment A: PF-07059013 oral suspension (Small particle size), fasted, with 
Polyvinylpyrrolidone (PVP). 
Treatment B: PF-07059013 oral tablet, fasted, without PVP. 
Treatment C: PF-07059013 oral suspension (Small particle size), fed, with PVP. 
Treatment D: PF-07059013 oral suspension (Moderate particle size), fasted, with PVP. 


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Protocol C4061001 (PF-07059013) Statistical Analysis Plan 
 
 
 
Page 13 of 28 
 
          
 
 
 
PFIZER CONFIDENTIAL 
 
A full list of protocol deviations will be compiled and reviewed to identify major and minor 
deviations prior to database closure. 
5.7.1 Deviations Assessed Prior to Randomization 
At screening, the investigator will assess participants against the inclusion and exclusion 
criteria as set out in Sections 5.1 and 5.2 of the protocol. 
5.7.2 Deviations Assessed Post-Randomization 
Any significant deviation from the protocol will be reviewed prior to database closure and a 
decision taken regarding evaluation for each analysis population. 
6. ENDPOINTS AND COVARIATES 
6.1. Efficacy Endpoint(s) 
None. 
6.2. Safety Endpoints 
In this section, the safety endpoints that will be measured during the study are detailed.  
Where applicable, details of the endpoints to be derived and definition of baseline are also 
provided. 
The following data are considered in standard safety summaries (see protocol for collection 
days and list of parameters): 
• adverse events, 
• clinical laboratory data, 
• vital signs data, 
• ECG and telemetry results. 
6.2.1. Adverse Events 
Any events occurring following start of treatment or increasing in severity will be counted as 
treatment emergent.  
Events that occur in a non-treatment period subsequent to dosing (for example, washout or 
follow-up) will be counted as treatment emergent and attributed to the previous treatment 
taken. 
6.2.2. Laboratory Safety Tests 
Safety laboratory tests will be performed as described in the protocol. 
To determine if there are any clinically significant laboratory abnormalities, the 
haematological, clinical chemistry (serum) and urinalysis safety tests will be assessed against 


Protocol C4061001 (PF-07059013) Statistical Analysis Plan 
 
 
 
Page 14 of 28 
 
          
 
 
 
PFIZER CONFIDENTIAL 
 
the criteria specified in the sponsor reporting standards. The assessment will take into 
account whether each participant’s baseline test result is within or outside the laboratory 
reference range for the particular laboratory parameter. 
 
Baseline will be defined as the measurement on Day -1 of each period of Part 1 and Part 3, 
and treatment phase of Part 2, or the last available corresponding pre-dose collection time 
point including unplanned measurements (whichever occurs later). 
6.2.3. Vital Signs 
Single supine blood pressure, pulse rate, oral temperature and respiratory rate measurements 
will be taken at times detailed in the Schedule of Activities given in the protocol.   
Baseline will be defined as pre-dose measurement on Day 1 of each period of Part 1 and Part 
3, and treatment phase of Part 2 or the last available corresponding pre-dose collection time 
point including unplanned measurements (whichever occurs later). 
The following vital signs endpoints will be determined: 
• Actual value of supine (and orthostatic if measured) systolic and diastolic blood pressure, 
pulse rate, oral temperature and respiratory rate at each time point. 
• Change from baseline in supine (and orthostatic if measured) systolic and diastolic blood 
pressure, pulse rate, oral temperature and respiratory rate at each time point. 
• The maximum decrease and increase from baseline over all measurements taken post-
dose for supine systolic and diastolic blood pressures, pulse rate, oral temperature and 
respiratory rate.  
The maximum increase from baseline will be calculated by first subtracting the baseline 
value from each post-dose measurement to give the change from baseline. The maximum of 
these values over the respective period will then be selected, except in the case where a 
subject does not show an increase.  In such an instance, the minimum decrease should be 
taken. 
Similarly, the maximum decrease from baseline will be determined by selecting the 
minimum value of the changes from baseline. In cases where a subject does not show a 
decrease, the minimum increase should be taken.  
6.2.4. ECG and Telemetry 
ECG 
A single 12-lead ECG will be obtained on all subjects at screening. 


Protocol C4061001 (PF-07059013) Statistical Analysis Plan 
 
 
 
Page 15 of 28 
 
          
 
 
 
PFIZER CONFIDENTIAL 
 
Triplicate 12-lead ECGs will be recorded on all subjects at all other time points as detailed in 
the Schedule of Activities given in the protocol. 
The QT, heart rate, QTcF, PR, RR and QRS will be recorded at each assessment time. 
If not supplied, QTcF will be derived using Fridericia’s heart rate correction formula: 
QTcF = QT / (RR)1/3  
where RR = 60/HR (if not provided) 
The average of the triplicate readings collected at each assessment time will be calculated for 
each ECG parameter.  Baseline will be defined as the average of the triplicate pre-dose 
recordings collected on Day 1 of each period of Part 1 and Part 3, and treatment phase of Part 
2. 
The maximum absolute value (post-dose) and the maximum increase from baseline for QT, 
heart rate, QTcF, PR and QRS, will be determined over all measurements taken post-dose for 
QTcF, PR and QRS. 
The maximum increase from baseline will be calculated by first subtracting the baseline 
value from each post-dose measurement to give the change from baseline.  The maximum of 
these values over the respective period will then be selected, except in the case where a 
subject does not show an increase.  In such an instance, the minimum decrease should be 
taken. 
Changes from baseline for the ECG parameters QT interval, heart rate, QTcF interval, PR 
interval, and QRS interval will also be calculated. 
Telemetry 
To establish a baseline, telemetry should be recorded for at least 2 hours before dosing in 
Period 1 of Part 1, and subsequently collected for 12 hours after the dosing. 
All abnormal rhythms will be recorded and reviewed by the study physician for the presence 
of rhythm of potential clinical concerns, which will document the time, duration and 
description of the clinically significant event. 
6.2.5. Other Safety Data 
Additional safety data will be collected as described in the protocol and will be listed if 
collected in the sponsor’s database. 
6.3. Pharmacokinetic Endpoints 
Blood samples for PK analysis of PF-07059013 will be taken according to the Schedule of 
Activities given in the protocol. The following PK parameters will be calculated for PF-


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Protocol C4061001 (PF-07059013) Statistical Analysis Plan 
 
 
 
Page 23 of 28 
 
          
 
 
 
PFIZER CONFIDENTIAL 
 
8.3. Safety Analysis 
A set of summary tables split by treatment will be produced to evaluate any potential risk 
associated with the safety and toleration of administering PF-07059013. 
No formal analyses are planned for safety data. The safety and other endpoints detailed in 
Section 6.2 will be listed and summarized in accordance with sponsor reporting standards, 
where the resulting data presentations will consist of subjects from the safety analysis set (as 
defined in Section 5.4). 
Descriptive statistics will be used to summarize the data for each Part of the study separately. 
Presentations for safety endpoints will include: 
− A listing of safety endpoints sorted by treatment, subject ID, and study day post first dose 
of the current treatment period. 
− A summary by treatment group including the number of subjects at risk, numbers and 
percentages of subjects meeting the categorical criteria.  
 
8.3.1. Treatment and Disposition of Subjects 
Subject evaluation groups will show end of study subject disposition and will show which 
subjects were analyzed for pharmacokinetics, as well as for safety (adverse events and 
laboratory data).  Frequency counts will be supplied for subject discontinuation(s) by 
treatment group and the study Part separately. 
 
Data will be reported in accordance with the sponsor reporting standards. 
8.3.2. Demographic Data 
A break down of demographic data will be provided for age, race, ethnicity, weight, body 
mass index and height.  Each will be summarized by treatment and study Part in accordance 
with the sponsor reporting standards. 
8.3.3. Discontinuation(s) 
Subject discontinuations, temporary discontinuations or dose reductions due to adverse 
events will be detailed and summarized by treatment and the study Part separately. 
Data will be reported in accordance with the sponsor reporting standards. 
8.3.4. Adverse Events 
Adverse events will be reported in accordance with the sponsor reporting standards. 


Protocol C4061001 (PF-07059013) Statistical Analysis Plan 
 
 
 
Page 24 of 28 
 
          
 
 
 
PFIZER CONFIDENTIAL 
 
8.3.5. Laboratory Data 
Laboratory data will be listed and summarized by treatment and study Part in accordance 
with the sponsor reporting standards.  Baseline is as defined in Section 6.2.2. 
8.3.6. Vital Signs Data 
Absolute values and changes from baseline in supine systolic and diastolic blood pressure, 
oral temperature, pulse rate and respiratory rate will be summarized by treatment and 
reported separately by Study Part in accordance with the sponsor reporting standards.  Tables 
will be paged by parameter.  Baseline is as defined in Section 6.2.3. 
Mean changes from baseline for supine systolic and diastolic blood pressure, oral 
temperature, pulse rate and respiratory rate for each treatment will be plotted against time 
post-dose, and by study day for Part 2 i.e. Day 1, 7 and 14, for each Study Part separately. On 
each plot there will be 1 line for each treatment.  Corresponding individual plots of changes 
from baseline will also be produced for each treatment. 
Maximum and minimum values and changes from baseline for vital signs will also be 
summarized descriptively by treatment, for each study Part separately, using categories as 
defined in Appendix 1. Numbers and percentages of subjects meeting the categorical criteria 
will be provided. All planned and unplanned post-dose timepoints will be counted in these 
categorical summaries. All values meeting the criteria of potential clinical concern will be 
listed. 
8.3.7. ECG and Telemetry Data 
ECG 
Absolute values and changes from baseline in QT, heart rate, QTcF, PR and QRS will be 
summarized by treatment, which will be reported for each study Part separately in 
accordance with the sponsor reporting standards.  Tables will be paged by parameter.  
Baseline is as defined in Section 6.2.4. 
Mean changes from baseline in QT, heart rate and QTcF will be plotted against time post-
dose, and by study day for Part 2 i.e. Day 1, 7 and 14, and separately reported for each study 
part. On each plot there will be 1 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.  
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. There will be a separate plot for each study Part. 


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Protocol C4061001 (PF-07059013) Statistical Analysis Plan 
 
 
 
Page 26 of 28 
 
          
 
 
 
PFIZER CONFIDENTIAL 
 
9. REFERENCES 
1.  
ICH E14 - The clinical evaluation of QT/QTc interval prolongation and 
proarrhythmic potential for non-antiarrhythmic drugs.  CHMP/ICH/2/04. 


Protocol C4061001 (PF-07059013) Statistical Analysis Plan 
 
 
 
Page 27 of 28 
 
          
 
 
 
PFIZER CONFIDENTIAL 
 
Appendix 1. Categorical Classes for ECG and Vital Signs of Potential Clinical Concern 
 
Categories for QTcF 
QTcF (ms) 
450< max. ≤ 480 
480< max. ≤500 
max. >500 
QTcF (ms) 
increase from 
baseline 
30≤ max. ≤60 
max. >60 
 
 
Categories for PR and QRS 
PR (ms) 
max. ≥300 
 
 
PR (ms) increase 
from baseline 
Baseline >200 
and max. 
≥25% increase 
Baseline ≤200 and 
max. ≥50% 
increase 
QRS (ms) 
max. ≥140 
QRS (ms) 
increase from 
baseline 
≥50% increase 
 
Categories for Vital Signs 
Systolic BP (mm Hg) 
min. <90 
 
Systolic BP (mm Hg) 
change from baseline 
max. decrease ≥30 
max. increase ≥30 
Diastolic BP (mm Hg) 
min. <50 
 
Diastolic BP (mm Hg) 
change from baseline 
max. decrease ≥20 
max. increase ≥20 
Supine pulse rate (bpm) 
min. <40 
max. >120 
 
Measurements that fulfill these criteria are to be listed in report. 
 


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