Conditions: Healthy
Allocation: NON_RANDOMIZED | Intervention model: SEQUENTIAL
Enrollment: 10
Healthy volunteers: yes

Brief summary:
This is a Phase 1, open label, fixed sequence study of the effect of multiple dose PF-06650833 on single dose OC PK in healthy female subjects.

Detailed description:

Arms:
arm 1: Subjects will receive a single dose of an oral contraceptive during the first period of the study arm 2: Subjects will receive PF-06650833 every day for 11 days and a single dose of an oral contraceptive on day 10.

Interventions: intervention 1: PF-06650833 intervention 2: Ethinyl estradiol (EE) and levonogestrel (LN)
Intervention descriptions: intervention 1: 400 mg by mouth (PO) Once daily (QD) for 11 days intervention 2: Single dose of Oral tablet containing 30 ug EE and 150 ug of LN

Protocol document:
Prot_000.pdf: 
PF-06650833
Protocol B7921026
Final Protocol, 29 July 2021
PFIZER CONFIDENTIAL
Page 1
A PHASE 1, OPEN LABEL, FIXED SEQUENCE STUDY TO ESTIMATE THE 
EFFECT OF MULTIPLE DOSE PF-06650833 ON THE PHARMACOKINETICS OF 
SINGLE DOSE ORAL CONTRACEPTIVE STEROIDS IN HEALTHY FEMALE 
PARTICIPANTS
Study Intervention Number:
PF-06650833
Study Intervention Name:
N/A
US IND Number:
EudraCT Number:
N/A
ClinicalTrials.gov ID:
N/A
Protocol Number:
B7921026
Phase:
1
Brief Title: A Phase 1 Drug-Drug Interaction Study of PF-06650833 With Oral 
Contraceptives in Healthy Female Participants
This document and accompanying materials contain confidential information belonging to Pfizer. Except as 
otherwise agreed to in writing, by accepting or reviewing these documents, you agree to hold this 
information in confidence and not copy or disclose it to others (except where required by applicable law) or 
use it for unauthorized purposes. In the event of any actual or suspected breach of this obligation, Pfizer 
must be promptly notified.
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Document History
Document
Version Date
Original protocol
29 July 2021


PF-06650833
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Final Protocol, 29 July 2021
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TABLE OF CONTENTS
LIST OF TABLES.....................................................................................................................7
1. PROTOCOL SUMMARY.....................................................................................................8
1.1. Synopsis ....................................................................................................................8
1.2. Schema ....................................................................................................................10
1.3. Schedule of Activities .............................................................................................11
2. INTRODUCTION ...............................................................................................................13
2.1. Study Rationale .......................................................................................................13
2.2. Background .............................................................................................................14
2.2.1. Nonclinical Pharmacology..........................................................................14
2.2.2. Nonclinical Pharmacokinetics and Metabolism .........................................14
2.2.3. Nonclinical Safety ......................................................................................15
2.2.4. Clinical Overview.......................................................................................15
2.3. Benefit/Risk Assessment.........................................................................................17
2.3.1. Risk Assessment.........................................................................................18
2.3.2. Benefit Assessment.....................................................................................19
2.3.3. Overall Benefit/Risk Conclusion................................................................19
3. OBJECTIVES AND ENDPOINTS.....................................................................................19
4. STUDY DESIGN.................................................................................................................19
4.1. Overall Design.........................................................................................................19
4.2. Scientific Rationale for Study Design.....................................................................20
4.2.1. Diversity of Study Population ....................................................................20
4.2.2. Choice of Contraception/Barrier Requirements .........................................20
4.3. Justification for Dose ..............................................................................................21
4.4. End of Study Definition ..........................................................................................21
5. STUDY POPULATION......................................................................................................21
5.1. Inclusion Criteria.....................................................................................................22
5.2. Exclusion Criteria....................................................................................................23
5.3. Lifestyle Considerations..........................................................................................26
5.3.1. Meals and Dietary Restrictions...................................................................26
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5.3.2. Caffeine, Alcohol, and Tobacco .................................................................27
5.3.3. Activity .......................................................................................................27
5.3.4. Contraception..............................................................................................27
5.4. Screen Failures ........................................................................................................28
6. STUDY INTERVENTION(S) AND CONCOMITANT THERAPY.................................28
6.1. Study Intervention(s) Administered........................................................................28
6.1.1. Administration............................................................................................28
6.1.2. Medical Devices .........................................................................................29
6.2. Preparation, Handling, Storage, and Accountability...............................................29
6.2.1. Preparation and Dispensing........................................................................30
6.3. Measures to Minimize Bias: Randomization and Blinding.....................................30
6.3.1. Allocation to Study Intervention ................................................................30
6.3.2. Breaking the Blind......................................................................................30
6.4. Study Intervention Compliance...............................................................................30
6.5. Dose Modification...................................................................................................30
6.6. Continued Access to Study Intervention After the End of the Study......................31
6.7. Treatment of Overdose............................................................................................31
6.8. Concomitant Therapy..............................................................................................31
6.8.1. Rescue Medicine.........................................................................................32
7. DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL...........................................................................32
7.1. Discontinuation of Study Intervention ....................................................................32
7.1.1. Liver Injury.................................................................................................32
7.1.2. ECG Changes..............................................................................................32
7.1.3. Potential Cases of Acute Kidney Injury .....................................................33
7.1.4. Pregnancy ...................................................................................................33
7.1.5. Laboratory Abnormalities...........................................................................33
7.2. Participant Discontinuation/Withdrawal From the Study.......................................34
7.2.1. Withdrawal of Consent...............................................................................35
7.3. Lost to Follow up ....................................................................................................35
8. STUDY ASSESSMENTS AND PROCEDURES...............................................................36
8.1. Efficacy Assessments..............................................................................................37


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8.2. Safety Assessments .................................................................................................37
8.2.1. Physical Examinations................................................................................37
8.2.2. Vital Signs ..................................................................................................37
8.2.3. Electrocardiograms.....................................................................................38
8.2.4. Clinical Safety Laboratory Assessments ....................................................39
8.2.5. COVID-19 Specific Assessments...............................................................39
8.2.6. Pregnancy Testing ......................................................................................39
8.3. Adverse Events, Serious Adverse Events, and Other Safety Reporting .................40
8.3.1. Time Period and Frequency for Collecting AE and SAE Information.......40
8.3.1.1. Reporting SAEs to Pfizer Safety...............................................41
8.3.1.2. Recording Nonserious AEs and SAEs on the CRF...................41
8.3.2. Method of Detecting AEs and SAEs ..........................................................41
8.3.3. Follow-Up of AEs and SAEs......................................................................41
8.3.4. Regulatory Reporting Requirements for SAEs...........................................42
8.3.5. Exposure During Pregnancy or Breastfeeding, and Occupational 
Exposure ..........................................................................................................42
8.3.5.1. Exposure During Pregnancy......................................................42
8.3.5.2. Exposure During Breastfeeding ................................................44
8.3.5.3. Occupational Exposure .............................................................44
8.3.6. Cardiovascular and Death Events...............................................................44
8.3.7. Disease-Related Events and/or Disease-Related Outcomes Not 
Qualifying as AEs or SAEs..............................................................................44
8.3.8. Adverse Events of Special Interest.............................................................44
8.3.8.1. Lack of Efficacy........................................................................45
8.3.9. Medical Device Deficiencies......................................................................45
8.3.10. Medication Errors.....................................................................................45
8.4. Pharmacokinetics ....................................................................................................46
8.7. Immunogenicity Assessments.................................................................................47
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8.8. Health Economics ...................................................................................................47
9. STATISTICAL CONSIDERATIONS ................................................................................47
9.1. Statistical Hypotheses .............................................................................................47
9.2. Analysis Sets ...........................................................................................................48
9.3. Statistical Analyses .................................................................................................48
9.3.1. Pharmacokinetic Analyses..........................................................................48
9.3.2. Safety Analyses ..........................................................................................49
9.3.2.1. Electrocardiogram Analyses......................................................50
9.4. Interim Analyses .....................................................................................................50
9.5. Sample Size Determination.....................................................................................51
10. SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS..........................................................................................................53
10.1. Appendix 1: Regulatory, Ethical, and Study Oversight Considerations...............53
10.1.1. Regulatory and Ethical Considerations ....................................................53
10.1.1.1. Reporting of Safety Issues and Serious Breaches of the 
Protocol or ICH GCP.........................................................................53
10.1.2. Financial Disclosure .................................................................................54
10.1.3. Informed Consent Process ........................................................................54
10.1.4. Data Protection .........................................................................................55
10.1.5. Committees Structure ...............................................................................55
10.1.5.1. Data Monitoring Committee ...................................................55
10.1.6. Dissemination of Clinical Study Data ......................................................55
10.1.7. Data Quality Assurance ............................................................................57
10.1.8. Source Documents....................................................................................58
10.1.9. Study and Site Start and Closure ..............................................................58
10.1.10. Publication Policy...................................................................................59
10.1.11. Sponsor’s Qualified Medical Personnel .................................................60
10.2. Appendix 2: Clinical Laboratory Tests .................................................................61
10.3. Appendix 3: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-Up, and Reporting .....................................................................63
10.3.1. Definition of AE .......................................................................................63
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10.3.2. Definition of an SAE ................................................................................64
10.3.3. Recording/Reporting and Follow-Up of AEs and/or SAEs During 
the Active Collection Period............................................................................65
10.3.4. Reporting of SAEs....................................................................................69
10.4. Appendix 4: Contraceptive and Barrier Guidance ................................................70
10.4.1. Male Participant Reproductive Inclusion Criteria....................................70
10.4.2. Female Participant Reproductive Inclusion Criteria.................................70
10.4.3. Woman of Childbearing Potential ............................................................70
10.4.4. Contraception Methods.............................................................................71
10.6. Appendix 6: Liver Safety: Suggested Actions and Follow-Up Assessments 
and Study Intervention Rechallenge Guidelines .......................................................74
10.7. Appendix 7: ECG Findings of Potential Clinical Concern ...................................76
10.8. Appendix 8: Abbreviations ...................................................................................78
11. REFERENCES ..................................................................................................................83
LIST OF TABLES
Table 1.
Study Design and Treatments...................................................................20
Table 2.
Plasma Pharmacokinetic Parameter Definitions.......................................49
Table 3.
Safety QTc Assessment ............................................................................50
Table 4.
Confidence Intervals Regarding the Effect of PF-06650833 on 
AUClast of OC............................................................................................51
Table 5.
Confidence Intervals Regarding the Effect of PF-06650833 on Cmax
of OC ........................................................................................................52
Table 6.
Protocol Required Safety Laboratory Assessments..................................62
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1. PROTOCOL SUMMARY 
1.1. Synopsis 
A Phase 1, open label, fixed sequence study to estimate the effect of multiple dose 
PF-06650833 on the pharmacokinetics of single dose oral contraceptive steroids in healthy 
female participants.
Brief Title: A Phase 1 Drug-Drug Interaction Study of PF-06650833 With Oral 
Contraceptives in Healthy Female Participants
Rationale
This study will evaluate the effect of PF-06650833 on pharmacokinetics of OC steroids, in 
order to select appropriate contraception requirements in Phase 2 studies. 
 
 
 
Objectives and Endpoints
Objectives
Endpoints
Primary: 
Primary: 
•
To estimate the effect of multiple oral doses of 
PF-06650833 on the PK of a single dose of a 
combination OC in healthy female participants.
•
Cmax and AUClast of EE and LN.
Secondary: 
Secondary: 
•
To evaluate the safety of PF-06650833 when 
co-administered with a single dose of a 
combination OC in healthy female participants.
•
Safety: laboratory tests, AEs reporting and vital 
signs.
Tertiary/Exploratory: 
Tertiary/Exploratory: 
•
To characterize the PK of a single dose of a 
combination OC with or without PF-06650833
in healthy female participants.
•
Tmax, and if data permit CL/F, t½ and AUCinf, of 
EE and LN.
Overall Design
Brief Summary
This is a Phase 1, fixed-sequence, multiple-dose, open-label study of the effect of multiple 
dose PF-06650833 on single dose OC PK in healthy female participants. The study will 
consist of 2 periods in a single fixed sequence. Participants will be screened within 28 days 
of the first dose of investigational product in Period 1. Participants will report to the CRU the 
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day prior to Day 1 dosing in Period 1. Participants will remain in the CRU for a total of 
16 days and 15 nights. There will be no washout period.
PF-06650833 is not expected to provide any clinical benefit to healthy participants. This 
study is designed primarily to generate safety, tolerability, and PK data for further clinical 
development.
Number of Participants
Approximately 10 participants will be enrolled to study intervention.
Note: “Enrolled” means a participant’s, or his or her legally authorized representative’s, 
agreement to participate in a clinical study following completion of the informed consent 
process and screening. A participant will be considered enrolled if the informed consent is 
not withdrawn prior to participating in any study activity after screening. Potential 
participants who are screened for the purpose of determining eligibility for the study, but do 
not participate in the study, are not considered enrolled, unless otherwise specified by the 
protocol.
Intervention Groups and Duration
The current study will use a PF-06650833 dose of 400 mg MR QD. This is the highest dose 
of PF-06650833 planned for use in future efficacy and safety trials.
On Period 1 Day 1, participants will be dosed with a single administration of OC in the form 
of 1 PORTIA® (EE and LN) or equivalent tablet, orally. OC (EE and LN) PK will then be 
assessed at pre-dose and over 48 hours, post OC dosing. Period 1 will be immediately 
followed by Period 2 with no washout, in which participants will be dosed orally with
PF-06650833 400 mg MR QD for 9 days followed by administration of a single dose of OC 
on the morning of Day 10. OC PK will be assessed at pre-dose and for 48 hours following 
OC dosing. The 48 hours post OC dose PK sample must be collected prior to receiving first 
dose of PF-06650833. On Day 10, the morning dose of PF-06650833 and the single OC dose 
will be administered simultaneously within 5 minutes. Dosing with PF-06650833 
400 mg PO QD will continue until Day 11.
Data Monitoring Committee or Other Independent Oversight Committee
No
Statistical Methods
To assess any effect of PF-06650833 on EE or LN exposures, natural log transformed 
AUClast and Cmax will be analyzed using a mixed effects model with treatment as a fixed 
effect and participant as a random effect. Estimates of the adjusted mean differences 
(Test-Reference) and corresponding 90% CIs will be obtained from the model and will be 


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exponentiated to provide estimates of the ratio of adjusted geometric means (Test/Reference) 
and 90% CIs for the ratios.
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1.3. Schedule of Activities
The SoA table provides an overview of the protocol visits and procedures. Refer to the STUDY ASSESSMENTS AND 
PROCEDURES section of the protocol for detailed information on each procedure and assessment required for compliance with the 
protocol. 
The investigator may schedule visits (unplanned visits) in addition to those listed in the SoA table, in order to conduct evaluations or 
assessments required to protect the well-being of the participant.
Screening
Period 1
Period 2m
Early 
Termination/
Discontinuation
Follow-upn
Visit Identifiera
Abbreviations used in this table 
may be found in Appendix 8
Day -28 to 
Day -2
Day -1
Day 1 Day 2 Day 3 Day 1 Day 2 to 
Day 8
Day 9 Day 10 Day 11
Day 12
28-35 days after 
last dose
Informed consent
X
CRU confinement
X
→
→
→
→
→
→
→
→
X
Inclusion/exclusion criteria
X
X
Medical, drug, tobacco and alcohol 
history
X
X
Contraception check
X
X
X
X
Pregnancy test (for WOCBP)
X
X
X
Demography
X
Physical examinationb
X
X
Safety laboratory
X
X
X
X
X
TB Screenc
X
Serum FSH (postmenopausal women 
only)
X
Serology: Viral screen, HBsAg, 
HCVAb, HIV, HBsAb and HBcAb
X
 
Urine drug screen 
X
X
12-Lead ECG (single)
X
X
X
X
Vital signs (supine BP, pulse rate)e
X
X
X
X
X
X
COVID-19 questionnairef
X
X
COVID-19 testingg
X
X
COVID-19 check temperatureh
X
X
→
→
→
→
→
→
→
→
X
X
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Screening
Period 1
Period 2m
Early 
Termination/
Discontinuation
Follow-upn
Visit Identifiera
Abbreviations used in this table 
may be found in Appendix 8
Day -28 to 
Day -2
Day -1
Day 1 Day 2 Day 3 Day 1 Day 2 to 
Day 8
Day 9 Day 10 Day 11
Day 12
28-35 days after 
last dose
OC dosingi
X
X
PF-06650833 QD dosingj
X
X
X
X
X
OC PK blood samplek,l
X
X
X
X
X
X
X
Serious and non-serious AE 
monitoring
X
→
→
→
→
→
→
→
→
→
→
X
X
Prior/concomitant treatment
assessment
X
→
→
→
→
→
→
→
→
→
X
X
X
CRU discharge 
X
a.
Visit Identifier: Day relative to start of study treatment (Day 1).
b.
Physical Examination: Complete physical exam could be done at screening or admission on Day -1. Brief physical exam to be done only in case of finding at previous exam 
or new/open AE if applicable, at the discretion of the investigator.
c.
TB Screen: QFT-G test.
 
e.
Vital signs (supine BP, pulse rate): Vital signs will be collected before dosing.
f.
COVID-19 questionnaire: Check exposure to positive participant, residence or travel in area of high incidence and COVID-19 related signs and symptoms. 
g.
COVID-19 testing: The testing for COVID-19 pathogen by PCR will be performed screening and D-1. A subsequent COVID-19 test can be performed if participants 
admitted for residence develop COVID-19 like symptom(s).
h.
COVID-19 check temperature: To be done twice daily during residence.
i.
OC dosing: Participants will be dosed with OC following an overnight fast of at least 10 hours. On the day of co-administration of OC and PF-06650833, the two will be 
administered simultaneously within 5 minutes.
j.
PF-06650833 QD dosing: The daily dose of PF-06650833 will be administered at approximately 08:00 ±2 hours.
k.
OC PK blood sample: PK blood samples are to be collected at predose, at 30 minutes and 1, 1.5, 2, 4, 6, 8, 12, 24, 36 and 48 hours post OC dose in Periods 1 and 2.
l.
OC PK blood sample: The 24 hour OC PK samples on Period 2 Day 11 must be collected pre PF-06650833 dose.
m.
Period 2: There is no washout phase between Period 1 and Period 2.
n.
Follow-up: Participants will have a telephone contact at least 28 calendar days, and up to 35 calendar days after the last administration of the investigational product(s). At 
the discretion of the investigator, telephone contact may be substituted with an on-site visit in case of additional follow-up of open AEs or clinically significant laboratory 
findings
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2. INTRODUCTION
PF-06650833 is a selective and reversible inhibitor of IRAK4 which is under clinical 
development as a potential treatment for RA, HS, COVID-19 and acne vulgaris.
2.1. Study Rationale 
This study will evaluate the effect of PF-06650833 on pharmacokinetics of OC steroids, in 
order to select appropriate contraception requirements in Phase 2 studies. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
The metabolism of OC steroids such as EE and LN, is mediated by the CYP3A and Phase 2 
enzymes such as UGT and SULT. Induction of the metabolic enzymes involved in 
metabolism of OC’s may result in reduction in the systemic exposure of these hormonal 
contraceptives leading to a potential failure of contraception. Therefore, the current study is 
designed to estimate the effect of multiple dose of PF-06650833 on the PK of 2 commonly 
concomitantly administered OCs, EE and LN.
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2.2. Background 
2.2.1. Nonclinical Pharmacology
PF-06650833 is a highly selective inhibitor of IRAK4 with nanomolar potency both in 
recombinant enzyme assays and in cellular assays. PF-06650833 inhibits IRAK4 with low 
nmol/L (IC50 <5 nmol/L) potency in cell based assays of TLR-mediated cytokine induction. 
In the rat CIA model, PF-06650833 dosed orally at 3 to 100 mg/kg BID or 30 and 
100 mg/kg QD significantly reduced hind paw swelling.
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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2.2.4. Clinical Overview
As of the date of this protocol, PF-06650833 has been evaluated in 7 completed Phase 1 
studies (B7921001, B7921002, B7921004, B7921006, B7921011, B7921009 and B7921028) 
and 1 completed Phase 2 study in RA patients (B7921005) and 3 ongoing Phase 2 studies in 
patients with RA (B7921023), HS (C2501007) and COVID-19 with ARDS (I-RAMIC).
Study B7921001 and B7921002 were SAD and MAD studies in healthy participants, 
respectively. B7921004 and B7921011 were relative bioavailability studies. B7921009 was a 
mass balance study while B7921006 was multiple dose PK and safety assessment in Japanese 
participants. 
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In all of the completed Phase 1 and Phase 2 studies, PF-06650833 was generally well 
tolerated and no maximally tolerated dose has been established. No deaths or other SAEs 
occurred in any of the studies. The most commonly observed AEs were headache and AEs 
within the SOC of ‘GI disorders’ (diarrhoea, abdominal discomfort, abdominal distension, 
abdominal pain, dry mouth, enterocolitis and flatulence). All TEAEs were mild to moderate 
in severity. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Summary of Clinical PK
In Studies B7921001 and B7921002, PF-06650833 exposure (AUC and Cmax) increased in a 
dose related manner up to the 100 mg dose, with less-than-proportional increases observed at 
higher doses. Accumulation ranged from 0.9-fold to 1.4-fold for AUCtau and 0.9 fold to 
1.3 fold for Cmax. Less than 1% of the dose was recovered unchanged in urine.
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2.3. Benefit/Risk Assessment
PF-06650833 is not expected to provide any clinical benefit to healthy participants. This 
study is designed primarily to generate safety, tolerability, and pharmacokinetic data for 
further clinical development.
In the clinical studies of PF-06650833 (see Section 2.2.4), the investigational product was
determined to be well tolerated and to have an acceptable safety profile. 
 
 
 
 
 
More detailed information about the known and expected benefits and risks and reasonably 
expected AEs of PF-06650833 may be found in the IB, which is the SRSD for this study.
The expected exposures of PF-06650833 in this study are lower than the highest exposures 
observed in the Phase 1 studies (see Justification for Dose in Section 4.3). 
 
herefore, the 
risk to the participants in this study is expected to be minimal. In addition, any risks are 
minimized by appropriate safety measures including safety laboratory measurements, ECGs, 
vital signs for study participants.
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2.3.1. Risk Assessment
Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
Study Intervention(s): PF-06650833
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Other 
The COVID-19 pandemic may pose risks to study 
participation. 
Participants may have increased risk of 
SARS-CoV-2 infection by undergoing a study 
procedure at a study facility.
Inclusion of COVID-19 specific assessments 
according to the Schedule of Activities and CRU 
confinement for the entire duration of study.
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2.3.2. Benefit Assessment
There is no benefit expected to the participants.
2.3.3. Overall Benefit/Risk Conclusion
PF-06650833 is not expected to provide any clinical benefit to healthy participants. Study in 
healthy participants is justified by taking into account the measures to minimize potential 
risk.
3. OBJECTIVES AND ENDPOINTS
Objectives
Endpoints
Primary: 
Primary: 

To estimate the effect of multiple oral doses of 
PF-06650833 on the PK of a single dose of a 
combination OC in healthy female participants.

Cmax and AUClast of EE and LN.
Secondary:
Secondary: 

To evaluate the safety of PF-06650833 when 
co-administered with a single dose of a 
combination OC in healthy female participants.

Safety: laboratory tests, AEs reporting and vital 
signs.
Tertiary/Exploratory: 
Tertiary/Exploratory: 

To characterize the PK of a single dose of a 
combination OC with or without PF-06650833
in healthy female participants.

Tmax, and if data permit CL/F, t½ and AUCinf, of 
EE and LN.
4. STUDY DESIGN
4.1. Overall Design
This is a Phase 1, fixed-sequence, multiple-dose, open-label study of the effect of multiple 
dose PF-06650833 on single dose OC PK in healthy female participants. A total of
approximately 10 healthy female participants will be enrolled in the study. The study will 
consist of 2 periods in a single fixed sequence. Participants will be screened within 28 days 
of the first dose of investigational product in Period 1. Participants will report to the CRU the 
day prior to Day 1 dosing in Period 1. Participants will remain in the CRU for a total of 
16 days and 15 nights. There will be no washout period. 
On Period 1 Day 1, participants will be dosed with a single administration of OC in the form 
of 1 PORTIA® (EE and LN) or equivalent tablet, orally. OC (EE and LN) PK will then be 
assessed at pre-dose and over 48 hours, post OC dosing. Period 1 will be immediately 
followed by Period 2 with no washout, in which participants will be dosed orally with 
PF-06650833 400 mg MR QD for 9 days followed by administration of a single dose of OC 
on the morning of Day 10. OC PK will be assessed at pre-dose and for 48 hours following 
OC dosing. On Day 10, the morning dose of PF-06650833 and the single OC dose will be 


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administered simultaneously within 5 minnutes. Dosing with PF-06650833 400 mg PO QD 
will continue until Day 11 (Table 1). Participants will be discharged on Day 12 only after 
review of safety laboratory by the PI.
Table 1.
Study Design and Treatments
Period 1
Washout
Period 2
Treatment A
None
Treatment B
Treatment A: Single dose of OC in the form of 1 PORTIA® (EE and LN) or equivalent oral tablet, containing 
EE 30 μg and LN 150 μg.
Treatment B: Single dose of combination OC in the form of 1 PORTIA® (EE and LN) or equivalent oral 
tablet, containing of EE 30 μg and LN 150 μg on the morning of Day 10 following 9 days of PF-06650833 
dosed at 400 mg PO QD. Dosing with PF-06650833 at 400 mg PO QD will continue through until Day 11.
4.2. Scientific Rationale for Study Design
Given the potential teratogenicity risk of PF-06650833 and potential of CYP3A induction 
risk, only WONCBP will be allowed in this study.
A fixed sequence design was selected for this study over a randomized 2-sequence crossover 
design based on operational considerations. It should be noted that the fixed sequence study 
design does not control for a period effect, however, the period effect is generally considered 
to be a low risk for PK DDI studies.
Based on the in vitro metabolic profiling, there is low potential of oral contraceptive steroids 
to impact PK of PF-06650833, only the effect of PF-06650833 will be evaluated in this 
study. In order to allow the full effect of potential enzyme induction of CYP3A4 to manifest, 
PF-06650833 will be dosed for 10 days prior to OC dosing. This is supported by Simcyp 
simulations showing maximal induction of CYP3A4 by PF-06650833 under the study design.
Due to the effect of food on PK of PF-06650833 MR and consistent with Phase 2 studies, 
PF-06650833 will be dosed in fasted state in this study. 
4.2.1. Diversity of Study Population
Not applicable.
4.2.2. Choice of Contraception/Barrier Requirements 
 
herefore, the use of a highly effective method 
of contraception is required (see Appendix 4).
 
CCI
CCI


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4.3. Justification for Dose
The current study will use a PF-06650833 dose of 400 mg MR QD. This is the highest dose 
of PF-06650833 planned for use in future efficacy and safety trials. 
PF-06650833 was well tolerated in doses up to 1000 mg QID for up to 14 days in healthy 
participants without dose-limiting adverse effects being demonstrated when administered as 
an orally- administered extemporaneously-prepared IR formulation (Study B7921002). 
 
 
 
 
The dose of combination OC is determined in part by the choice of commercially available 
products and recent precedents at Pfizer in the conduct of OC DDI studies. PORTIA®
(EE and LN) or equivalent containing 30 μg of EE and 150 μg of LN will be used in this 
study. OC will be administered as a single dose with and without PF-06650833. 
4.4. End of Study Definition
The end of the study is defined as the date of last scheduled procedure shown in the SoA for 
the last participant in the trial.
A participant is considered to have completed the study if he/she has completed all periods of 
the study, including the last visit as shown in the SoA.
5. STUDY POPULATION
This study can fulfill its objectives only if appropriate participants are enrolled. The 
following eligibility criteria are designed to select participants for whom participation in the 
study is considered appropriate. All relevant medical and nonmedical conditions should be 
taken into consideration when deciding whether a particular participant is suitable for this 
protocol.
Prospective approval of protocol deviations to recruitment and enrollment criteria, also 
known as protocol waivers or exemptions, is not permitted.
CCI
CCI
CCI


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5.1. Inclusion Criteria
Participants are eligible to be included in the study only if all of the following criteria apply:
Age and Sex:
1. Healthy female participants who, at the time of screening, are between the ages of 
18 and 60 years, inclusive. Healthy is defined as no clinically relevant abnormalities 
identified by a detailed medical history, full physical examination, including BP and 
pulse rate measurement, 12-lead ECG, or clinical laboratory tests.
2. Female participants of non-childbearing potential must meet at least 1 of the 
following criteria:
a.
Achieved postmenopausal status, defined as follows: cessation of regular menses 
for at least 12 consecutive months with no alternative pathological or 
physiological cause; and have a serum FSH level confirming the postmenopausal 
state;
b. Have undergone a documented hysterectomy and/or bilateral oophorectomy
and/or bilateral salpingectomy;
c.
Have medically confirmed ovarian failure.
All other female participants (including female participants with tubal ligations) are 
considered to be of childbearing potential. Refer to Appendix 4: Contraceptive and 
Barrier Guidance for reproductive criteria for female (Section 10.4.2) participants.
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).
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.


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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. Infection with hepatitis B or hepatitis C viruses according to protocol-specific testing 
algorithm.

For hepatitis B, all participants will undergo testing for HBsAg and HBcAb 
during Screening. Participants who are HBsAg positive will not be eligible for 
this study. Participants who are HBsAg negative but HBcAb positive will be 
reflex-tested for HBsAb. Please refer to Section 10.2 for testing algorithm, reflex 
testing, and full eligibility criteria.

For hepatitis C, all participants will undergo testing for HCVAb during Screening. 
Participants who are HCVAb positive will be reflex tested for HCV RNA. 
Participants who are HCVAb and HCV RNA positive are not eligible for the 
study. Participants who are HCVAb positive but HCV RNA negative will be 
considered eligible.
4. Have evidence of untreated or inadequately treated active or latent Mycobacterium 
TB infection as evidenced by the following:

A positive QFT-G test performed at screening . If the laboratory reports the test as 
indeterminate, the test should be repeated. If the result of the repeat test is 
indeterminate, a PPD test may be substituted for the QFT-G test only with 
approval from the Pfizer Medical Monitor on a case by case basis.

History of either untreated or inadequately treated latent or active TB infection.

If a participant has previously received an adequate course of therapy for 
either latent (9 months of isoniazid in a locale where rates of primary multi 
drug resistant TB infections are <5% or an acceptable alternative regimen) or 
active (acceptable multi-drug regimen) TB infection, nether a QFT-G test not 
a PPD test need to be obtained. Details of previous course of therapy 
(eg, medication(s) used, dose, duration of therapy) should be documented in 
the source documentation.


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
A participant who is currently being treated for active or latent TB infection 
must be excluded from the study.
5. Participants with any of the following acute or chronic infections or infection history:

Any infection requiring treatment within 2 weeks prior to the screening visit.

Any infection requiring hospitalization, parenteral antimicrobial therapy within 60 
days of the first dose of investigational product.

Any infection judged to be an opportunistic infection or clinically significant by 
the investigator, within the past 6 months of the first dose of the investigational 
product.

Known active or history of recurrent bacterial, viral, fungal, mycobacterial or 
other infections.

History of a recurrent (more than one episode of) localized, dermatomal herpes 
zoster, or history of disseminated (one single episode) herpes simplex or 
disseminated herpes zoster.
6. History of febrile illness within 5 days prior to the first dose of investigational 
product.
7. History of any lymphoproliferative disorder such as EBV related lymphoproliferative 
disorder, history of lymphoma, history of leukemia, or signs and symptoms 
suggestive of current lymphatic or lymphoid disease.
8. Participants have a known present or a history of malignancy other than a 
successfully treated or excised non metastatic basal cell or squamous cell cancer of 
the skin or cervical carcinoma in situ.
9. Benign ethnic (cyclic) neutropenia.
10. Having received any live (attenuated) vaccines, except COVID-19 vaccines within 
6 weeks prior to the first dose of investigational product.
11. Have received COVID-19 vaccine within 14 days before first dose of study 
intervention or have received only one of the 2 required doses of COVID-19 vaccine.
12. Cardiovascular risk factors including but not limited to myocardial injury, venous 
thromboembolism, and pulmonary embolism.
13. Pregnant female participants; breastfeeding female participants.


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14. Other medical or psychiatric conditions including recent (within the past year) or 
active suicidal ideation/behavior or laboratory abnormality or other conditions or 
situations related to COVID-19 pandemic (eg, Contact with positive case, residence, 
or travel to an area with high incidence) that may increase the risk of study 
participation or, in the investigator’s judgment, make the participant inappropriate for 
the study.
Prior/Concomitant Therapy:
15. Use of prescription or nonprescription drugs and dietary and herbal supplements 
within 7 days or 5 half-lives (whichever is longer) prior to the first dose of study 
intervention. (Refer to Section 6.8 Concomitant Therapy for additional details).
Prior/Concurrent Clinical Study Experience:
16. 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:
17. A positive urine drug test.
18. 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.
19. Baseline standard 12-lead ECG that demonstrates clinically relevant abnormalities that 
may affect participant safety or interpretation of study results (eg, baseline QTcF
interval >450 msec, complete LBBB, signs of an acute or indeterminate-age 
myocardial infarction, ST-T interval changes suggestive of myocardial ischemia, 
second- or third-degree AV block, or serious bradyarrhythmias or tachyarrhythmias). 
If the baseline uncorrected QT interval is >450 msec, this interval should be 
rate-corrected using the Fridericia method and the resulting QTcF should be used for 
decision making and reporting. If QTcF exceeds 450 msec, or QRS exceeds 
120 msec, the ECG should be repeated 2 more times and the average of the 3 QTcF or 
QRS values should be used to determine the participant’s eligibility. 
Computer-interpreted ECGs should be overread by a physician experienced in 
reading ECGs before excluding a participant.
20. 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;


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
Total bilirubin level ≥1.5 × ULN; participants with a history of Gilbert’s 
syndrome may have direct bilirubin measured and would be eligible for this study 
provided the direct bilirubin level is≤ULN.

eGFR ≤90 mL/min/1.73m2 based on CKD-EPI equation.

In the opinion of the investigator (or designee), have any clinically significant 
laboratory abnormality that could affect interpretation of study data or the 
participant’s participation in the study.
Other Exclusions:
21. 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).
22. Blood donation (excluding plasma donations) of approximately 1 pint (500 mL) or 
more within 60 days prior to dosing.
23. History of sensitivity to heparin or heparin-induced thrombocytopenia.
24. Unwilling or unable to comply with the criteria in the Lifestyle Considerations
section of this protocol.
25. 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 and 10 hours prior to the collection of the predose 
PK sample.

Water is permitted until 1 hour prior to study intervention administration. Water may 
be consumed without restriction beginning 1 hour after dosing. Noncaffeinated drinks 
(except grapefruit or grapefruit-related citrus fruit juices—see below) may be 
consumed with meals and the evening snack.

Lunch will be provided approximately 4 hours after dosing.


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
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 study intervention until collection of the final PK blood sample.  

While participants are confined, their total daily nutritional composition should be 
approximately 55% carbohydrate, 30% fat, and 15% protein. The daily caloric intake 
per participant should not exceed approximately 3200 kcal.
5.3.2. Caffeine, Alcohol, and Tobacco

Participants will abstain from caffeine-containing products for 24 hours prior to the 
start of dosing until collection of the final PK sample of each study period.  

Participants will abstain from alcohol for 24 hours prior (or as specified above for red 
wine) to admission to the CRU and continue abstaining from alcohol until collection 
of the final PK sample of each study period. Participants may undergo an alcohol 
breath test or blood alcohol test at the discretion of the investigator.

Participants will abstain from the use of tobacco- or nicotine-containing products for 
7 days prior to dosing, during confinement in the CRU and between Periods 1 and 2.
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, and 
ECG measurements), eating, and drinking beverages other than water during the first 
4 hours after dosing.
5.3.4. Contraception
The investigator or his or her designee, in consultation with the participant, will confirm that 
the participant has selected an appropriate method of contraception for the individual 
participant and his or her partner(s) from the permitted list of contraception methods (see 
Appendix 4 Section 10.4.4) and will confirm that the participant has been instructed in its 
consistent and correct use. At time points indicated in the SoA, the investigator or designee 
will inform the participant of the need to use highly effective contraception consistently and 
correctly and document the conversation and the participant’s affirmation in the participant’s 
chart (participants need to affirm their consistent and correct use of at least 1 of the selected 
methods of contraception) considering that their risk for pregnancy may have changed since 


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the last visit. In addition, the investigator or designee will instruct the participant to call 
immediately if the selected contraception method is discontinued or if pregnancy is known or 
suspected in the participant or partner.
5.4. Screen Failures
Screen failures are defined as participants who consent to participate in the clinical study but 
are not subsequently enrolled to study sequences. Screen failure data are collected and 
remain as source and are not reported on the CRF.
Individuals who do not meet the criteria for participation in this study (screen failure) may be 
rescreened. Only one rescreening will be permitted per participant.
6. STUDY INTERVENTION(S) AND CONCOMITANT THERAPY
Study intervention is defined as any investigational intervention(s), marketed product(s), 
placebo, or medical device(s) intended to be administered to a study participant according to 
the study protocol.
For the purposes of this protocol, the term investigational product may be used 
synonymously with study intervention.
6.1. Study Intervention(s) Administered
For the purposes of this protocol, study intervention refers to PF-06650833.
PORTIA® (or equivalent) is an NIMP.
PF-06650833 200-mg MR tablets will be provided by Pfizer to the CRU in bulk along with 
individual dosing containers and desiccants for unit dosing.
Study intervention will be presented to the participants in individual dosing containers.
PORTIA® (or equivalent) will be supplied by the CRU. All PORTIA® or equivalent oral 
tablet used in this study should be from the same manufacturing batch.
6.1.1. Administration
Following an overnight fast of at least 10 hours, participants will receive one PORTIA® or 
equivalent tablet on Period 1 Day 1 at approximately 08:00 hours (plus or minus 2 hours). On 
the days of co-administration of OC and PF-06650833 (Period 2 Day 10), one PORTIA® or
equivalent tablet should be administered simultaneously within 5 minutes of two 200-mg 
PF-06650833 MR tablets dosing. Investigator site personnel will administer investigational 
product during each period with ambient temperature water to a total volume of 
approximately 240 mL. Additional water is allowed if needed to complete administration of 
the entire dose. Participants will swallow the investigational product whole, and will not 
manipulate or chew the investigational product prior to swallowing.


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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, and ECG 
measurements), eating, and drinking beverages other than water 4 hours after dosing.
6.1.2. Medical Devices
Not applicable.
6.2. Preparation, Handling, Storage, and Accountability
1. The investigator or designee must confirm appropriate temperature conditions have 
been maintained during transit for all study interventions received and any 
discrepancies are reported and resolved before use of the study intervention. 
2. Only participants enrolled in the study may receive study intervention and only 
authorized site staff may supply or administer study intervention. All study 
interventions must be stored in a secure, environmentally controlled, and monitored 
(manual or automated recording) area in accordance with the labeled storage 
conditions with access limited to the investigator and authorized site staff. At a 
minimum, daily minimum and maximum temperatures for all site storage locations 
must be documented and available upon request. Data for nonworking days must 
indicate the minimum and maximum temperatures since previously documented for 
all site storage locations upon return to business.
3. Any excursions from the study intervention label storage conditions should be 
reported to Pfizer upon discovery along with any actions taken. The site should 
actively pursue options for returning the study intervention to the storage conditions 
described in the labeling, as soon as possible. Once an excursion is identified, the 
study intervention must be quarantined and not used until Pfizer provides permission 
to use the study intervention. Specific details regarding the definition of an excursion 
and information the site should report for each excursion will be provided to the site 
in the IP manual.
4. Any storage conditions stated in the SRSD will be superseded by the storage 
conditions stated on the label.
5. Study interventions should be stored in their original containers.
6. The investigator, institution, or the head of the medical institution (where applicable) 
is responsible for study intervention accountability, reconciliation, and record 
maintenance (eg, 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.


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7. Further guidance and information for the final disposition of unused study 
interventions are provided in the IP manual. All destruction must be adequately 
documented. If destruction is authorized to take place at the investigator site, the 
investigator must ensure that the materials are destroyed in compliance with 
applicable environmental regulations, institutional policy, and any special instructions 
provided by Pfizer.
Upon identification of a product complaint, notify the sponsor within 1 business day of 
discovery as described in the IP manual.
6.2.1. Preparation and Dispensing
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.
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. 
6.3. Measures to Minimize Bias: Randomization and Blinding
6.3.1. Allocation to Study Intervention
The investigator’s knowledge of the treatment should not influence the decision to enroll a 
particular participant or affect the order in which participants are enrolled.
The investigator will assign participant numbers to the participants as they are screened for 
the study.
6.3.2. Breaking the Blind
Not applicable.
6.4. Study Intervention Compliance
Investigational product will be administered under the supervision of investigator site 
personnel. The oral cavity of each participant will be examined following dosing to ensure 
the investigational product was taken.
6.5. Dose Modification
Not applicable.


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6.6. Continued Access to Study Intervention After the End of the Study
No intervention will be provided to study participants at the end of their study participation.
6.7. Treatment of Overdose
For this study, any dose of PF-06650833 greater than 6 g within a 24-hour time period will 
be considered an overdose.
There is no specific treatment for an overdose with PF-06650833.
In the event of an overdose, the investigator should:
1. Contact the medical monitor within 24 hours.
2. Closely monitor the participant for any AEs/SAEs and laboratory abnormalities for at 
least 5 half-lives or 28 calendar days after the overdose of study investigational 
products (whichever is longer).
3. Document the quantity of the excess dose as well as the duration of the overdose in 
the CRF.
4. Overdose is reportable to Pfizer Safety only when associated with an SAE.
5. Obtain a blood sample for PK analysis within 7 days from the date of the last dose of 
study intervention(s) 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.
6.8. Concomitant Therapy
Use of prescription or nonprescription drugs and dietary and herbal supplements are 
prohibited within 7 days or 5 half-lives (whichever is longer) prior to the first dose of study 
intervention. Limited use of nonprescription medications that are not believed to affect 
participant safety or the overall results of the study may be permitted on a case-by-case basis 
following approval by the sponsor. Acetaminophen/paracetamol may be used at doses of 
≤1 g/day.
Females using hormone replacement therapy may be eligible to participate in this study if 
they are willing to discontinue therapy at least 28 days prior to the first dose of study 
treatment and remain off hormonal therapy for the duration of the study.
All concomitant treatments taken during the study must be recorded with indication, daily 
dose, and start and stop dates of administration. All participants will be questioned about 
concomitant treatment at each clinic visit.


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Treatments taken within 28 days before the first dose of study intervention will be 
documented as a prior treatment. Treatments taken after the first dose of study intervention 
will be documented as concomitant treatments.
6.8.1. Rescue Medicine 
There is no rescue therapy to reverse the AEs observed with PF-06650833 or OC; standard 
medical supportive care must be provided to manage the AEs. 
7. DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL
7.1. Discontinuation of Study Intervention
It may be necessary for a participant to permanently discontinue study intervention. Reasons 
for permanent discontinuation of study intervention include the following: liver injury, ECG 
changes, acute kidney injury, pregnancy, or laboratory abnormalities. Please refer to 
subsections 7.1.1 through 7.1.5 for details of each. 
If study interventions are permanently discontinued, the participant will not remain in the 
study for further evaluation. See the SoA for data to be collected at the time of 
discontinuation of study interventions.
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 interventions or also from study procedures, posttreatment study follow-up, 
and/or future collection of additional information.
7.1.1. Liver Injury
All of the following laboratory abnormalities require discontinuation if they are confirmed:
AST or ALT that meet ANY of the following:

>3 × ULN with at least one total bilirubin value >2 × ULN.

>3 × ULN accompanied by signs or symptoms consistent with hepatic injury (eg, new 
onset elevated PT/INR).

Two sequential AST or ALT elevations >5 × ULN, regardless of total bilirubin or 
accompanying signs or symptoms.
7.1.2. ECG Changes
A participant who meets either bulleted criteria based on the average of triplicate ECG 
readings will be withdrawn from the study interventions. 

QTcF >500 msec.


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
Change from baseline: QTcF >60 msec and QTcF >450 msec.
If a clinically significant finding is identified (including, but not limited to, changes from 
baseline in QTcF after enrollment), the investigator or qualified designee will determine if 
the participant can continue in the study and if any change in participant management is 
needed. This review of the ECG printed at the time of collection must be documented. Any 
new clinically relevant finding should be reported as an AE.
7.1.3. 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 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.
7.1.4. Pregnancy
In the case of a positive serum pregnancy test, the participant will have investigational 
product stopped and result re-confirmed via a second urine test or serum sample collected on 
the same day (or as soon as possible) and submitted to the laboratory for pregnancy testing.
7.1.5. Laboratory Abnormalities
All of the following laboratory abnormalities require discontinuation if they are confirmed:

ANC <750/mm3 (<0.75 × 109/L).


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
Hemoglobin <9.0 g/dL (<5.59 mmol/L or <90 g/L) or a decrease of >30% from 
baseline (either criterion or both).

Platelet count <75,000/mm3 (<75.0 × 109/L).

ALC <500/mm3 (<0.5 × 109/L).
NOTE: Participants with ALC <500/mm3 (0.5 × 109/L) will be reflex tested for 
FACS-TBNK until the absolute lymphocyte count resolves or stabilizes at a level 
acceptable to the investigator and sponsor.

CK >10 × ULN.
NOTE: Urine myoglobin and SCr will be performed as reflex testing for any participant 
with CK >10 × ULN
7.2. Participant Discontinuation/Withdrawal From the Study
A participant may withdraw from the study at any time at his/her own request. Reasons for 
discontinuation from the study include the following:

Refused further study procedures;

Lost to follow-up;

Death;

Study terminated by sponsor;

At the discretion of the investigator for safety, behavioral, compliance, or 
administrative reasons.
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 and then are 
prematurely withdrawn from the study. Participants should be questioned regarding their 
reason for withdrawal. 
The participant will be permanently discontinued from the study interventions and 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.


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If the participant withdraws from the study and also withdraws consent (see Section 7.2.1) 
for disclosure of future information, no further evaluations should be performed and no 
additional data should be collected. The sponsor may retain and continue to use any data 
collected before such withdrawal of consent.
7.2.1. Withdrawal of Consent 
Participants who request to discontinue receipt of study intervention will remain in the study 
and must continue to be followed for protocol-specified follow-up procedures. The only 
exception to this is when a participant specifically withdraws consent for any further contact 
with him or her or persons previously authorized by the participant to provide this 
information. Participants should notify the investigator in writing of the decision to withdraw 
consent from future follow-up, whenever possible. The withdrawal of consent should be 
explained in detail in the medical records by the investigator, as to whether the withdrawal is 
only from further receipt of study intervention or also from study procedures and/or 
posttreatment study follow-up, and entered on the appropriate CRF page. In the event that 
vital status (whether the participant is alive or dead) is being measured, publicly available 
information should be used to determine vital status only as appropriately directed in 
accordance with local law.
7.3. Lost to Follow up 
A participant will be considered lost to follow-up if he or she repeatedly fails to return for 
scheduled visits and is unable to be contacted by the study site.
The following actions must be taken if a participant fails to attend a required study visit:

The site must attempt to contact the participant and reschedule the missed visit as 
soon as possible. Counsel the participant on the importance of maintaining the 
assigned visit schedule and ascertain whether the participant wishes to and/or should 
continue in the study.

Before a participant is deemed lost to follow-up, the investigator or designee must 
make every effort to regain contact with the participant (where possible, 3 telephone 
calls and, if necessary, a certified letter to the participant’s last known mailing 
address or local equivalent methods). These contact attempts should be documented 
in the participant’s medical record.

Should the participant continue to be unreachable, he/she will be considered to have 
withdrawn from the study. 


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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, eg, banked biospecimens, may 
be used without repeat collection, as appropriate.
Every effort should be made to ensure that protocol-required tests and procedures are 
completed as described. However, it is anticipated that from time to time there may be 
circumstances outside the control of the investigator that may make it unfeasible to perform 
the test. In these cases, the investigator must take all steps necessary to ensure the safety and 
well-being of the participant. When a protocol-required test cannot be performed, the 
investigator will document the reason for the missed test and any corrective and preventive 
actions that he or she has taken to ensure that required processes are adhered to as soon as 
possible. The study team must be informed of these incidents in a timely manner.
If an IV catheter is utilized for blood sample collections, ECGs and vital sign assessments 
(pulse rate and BP) should be collected prior to the insertion of the catheter.
For samples being collected and shipped, detailed collection, processing, storage, and 
shipment instructions and contact information will be provided to the investigator site prior 
to initiation of the study.


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The total blood sampling volume for individual participants in this study is approximately 
350 mL. The actual collection times of blood sampling may change. Additional blood 
samples may be taken for safety assessments at times specified by Pfizer, provided the total 
volume taken during the study does not exceed 550 mL during any period of 56 consecutive 
days.
To prepare for study participation, participants will be instructed on the information in the 
Lifestyle Considerations and 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.
Physical examinations may be conducted by a physician, trained physician's assistant, or 
nurse practitioner as acceptable according to local regulation. 
Physical examination findings collected during the study will be considered source data and 
will not be required to be reported, unless otherwise noted. Any untoward physical 
examination findings that are identified during the active collection period and meet the 
definition of an AE or SAE (Appendix 3) must be reported according to the processes in 
Sections 8.3.1 to 8.3.3.
8.2.2. Vital Signs
Supine BP will be measured with the participant’s arm supported at the level of the heart, and 
recorded to the nearest mm Hg after approximately 5 minutes of rest. The same arm 
(preferably the dominant arm) will be used throughout the study. Participants should be 
instructed not to speak during measurements.


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The same properly sized and calibrated BP cuff will be used to measure BP each time. The 
use of an automated device for measuring BP and pulse rate is acceptable; however, when 
done manually, pulse rate will be measured in the brachial/radial artery for at least 
30 seconds. When the timing of these measurements coincides with a blood collection, BP 
and pulse rate should be obtained prior to the nominal time of the blood collection. 
Additional collection times, or changes to collection times, of BP and pulse rate will be 
permitted, as necessary, to ensure appropriate collection of safety data.
8.2.3. Electrocardiograms
Standard 12-lead ECGs utilizing limb leads (with a 10 second rhythm strip) should be 
collected at times specified in the SoA section of this protocol using an ECG machine that 
automatically calculates the heart rate and measures PR, QT, and QTc intervals and QRS 
complex. Alternative lead placement methodology using torso leads (eg, Mason-Likar) 
should not be used given the potential risk of discrepancies with ECGs acquired using 
standard limb lead placement. All scheduled ECGs should be performed after the participant
has rested quietly for at least 5 minutes in a supine position. 
To ensure safety of the participants, a qualified individual at the investigator site will make 
comparisons to baseline measurements. Additional ECG monitoring will occur if a) a 
postdose QTcF interval is increased by ≥60 msec from the baseline and is >450 msec; or b) 
an absolute QT value is ≥500 msec for any scheduled ECG.  If either of these conditions 
occurs, then 2 additional ECGs will be collected approximately 2 to 4 minutes apart to 
confirm the original measurement. If the QTc values from these repeated ECGs remain above 
the threshold value, then a single ECG must be repeated at least hourly until QTc values from 
2 successive ECGs fall below the threshold value that triggered the repeat measurement.
If a) a postdose QTcF interval remains ≥60 msec from the baseline and is >450 msec; or 
b) an absolute QT value is ≥500 msec for any scheduled ECG for greater than 4 hours (or 
sooner, at the discretion of the investigator); or c) QTcF intervals get progressively longer, 
the participant should undergo continuous ECG monitoring. A cardiologist should be 
consulted if QTcF intervals do not return to less than the criteria listed above after 8 hours of 
monitoring (or sooner, at the discretion of the investigator).
In some cases, it may be appropriate to repeat abnormal ECGs to rule out improper lead 
placement as contributing to the ECG abnormality. It is important that leads be placed in the 
same positions each time in order to achieve precise ECG recordings. If a machine-read QTc 
value is prolonged, as defined above, repeat measurements may not be necessary if a 
qualified medical provider’s interpretation determines that the QTcF values are in the 
acceptable range.
ECG values of potential clinical concern are listed in Appendix 7.


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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 28 calendar days after the last dose of study intervention 
should be repeated until the values return to normal or baseline or are no longer considered 
clinically significant by the investigator or medical monitor.
If such values do not return to normal/baseline within a period of time judged reasonable by 
the investigator, the etiology should be identified and the sponsor notified.
See Appendix 6 for suggested actions and follow-up assessments in the event of potential 
drug-induced liver injury.
Participants may undergo random urine drug testing at the discretion of the investigator. 
Drug testing conducted prior to dosing must be negative for participants to receive study 
intervention. 
8.2.5. COVID-19 Specific Assessments
Participants will be tested for SARS-COVID-19 infection by PCR prior to being admitted to 
the clinic for confinement and if they develop COVID-19 like symptoms. Additional testing 
may be required by local regulations or by the PI.
8.2.6. Pregnancy Testing
Pregnancy tests may be urine or serum tests, but must have a sensitivity of at least 
25 mIU/mL. Pregnancy tests will be performed in WOCBP at the times listed in the SoA. 
Following a negative pregnancy test result at screening, appropriate contraception must be 
commenced and a second negative pregnancy test result will be required at the baseline visit 
prior the participant’s receiving the study intervention. Pregnancy tests will also be done 
whenever 1 menstrual cycle is missed during the active treatment period (or when potential 
pregnancy is otherwise suspected) and at the end of the study. Pregnancy tests may also be 
repeated if requested by IRBs/ECs or if required by local regulations. If a urine test cannot be 
confirmed as negative (eg, an ambiguous result), a serum pregnancy test is required. In such 
cases, the participant must be excluded if the serum pregnancy result is positive.


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8.3. Adverse Events, Serious Adverse Events, and Other Safety Reporting
The definitions of an AE and an SAE can be found in Appendix 3.
AEs may arise from symptoms or other complaints reported to the investigator by the 
participant (or, when appropriate, by a caregiver, or surrogate), or they may arise from 
clinical findings of the Investigator or other healthcare providers (clinical signs, test results, 
etc.).
The investigator and any qualified designees are responsible for detecting, documenting, and 
recording events that meet the definition of an AE or SAE and remain responsible to pursue 
and obtain adequate information both to determine the outcome and to assess whether the 
event meets the criteria for classification as an SAE or caused the participant to discontinue 
the study (see Section 7.1). 
During the active collection period as described in Section 8.3.1, each participant/legal 
guardian/legally authorized representative 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 (eg, before undergoing 
any study-related procedure and/or receiving study intervention), through and including a 
minimum of 28 calendar days, after the last administration of the study intervention.
Follow-up by the investigator continues throughout and after the active collection period and 
until the AE or SAE or its sequelae resolve or stabilize at a level acceptable to the 
investigator.
For participants who are screen failures, the active collection period ends when screen failure 
status is determined.
If the participant withdraws from the study and also withdraws consent for the collection of 
future information, the active collection period ends when consent is withdrawn.
If a participant permanently discontinues or temporarily discontinues study intervention
because of an AE or SAE, the AE or SAE must be recorded on the CRF and the SAE 
reported using the CT SAE Report Form.
Investigators are not obligated to actively seek information on AEs or SAEs after the 
participant has concluded study participation. However, if the investigator learns of any SAE, 
including a death, at any time after a participant has completed the study, and he/she 


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considers the event to be reasonably related to the study intervention, the investigator must 
promptly report the SAE to Pfizer using the CT SAE Report Form.
8.3.1.1. Reporting SAEs to Pfizer Safety
All SAEs occurring in a participant during the active collection period as described in 
Section 8.3.1 are reported to Pfizer Safety on the CT SAE Report Form immediately upon 
awareness and under no circumstance should this exceed 24 hours, as indicated in 
Appendix 3. The investigator will submit any updated SAE data to the sponsor within 
24 hours of it being available.
8.3.1.2. Recording Nonserious AEs and SAEs on the CRF
All nonserious AEs and SAEs occurring in a participant during the active collection period, 
which begins after obtaining informed consent as described in Section 8.3.1, will be recorded 
on the AE section of the CRF.
The investigator is to record on the CRF all directly observed and all spontaneously reported 
AEs and SAEs reported by the participant.
Reporting of AEs and SAEs for participants who fail screening are subject to the CRF 
requirements as described in Section 5.4.
8.3.2. Method of Detecting AEs and SAEs
The method of recording, evaluating, and assessing causality of AEs and SAEs and the 
procedures for completing and transmitting SAE reports are provided in Appendix 3.
Care will be taken not to introduce bias when detecting AEs and/or SAEs. Open-ended and 
nonleading verbal questioning of the participant is the preferred method to inquire about 
AE occurrences.
8.3.3. Follow-Up of AEs and SAEs
After the initial AE or SAE report, the investigator is required to proactively follow each 
participant at subsequent visits/contacts. For each event, the investigator must pursue and 
obtain adequate information until resolution, stabilization, the event is otherwise explained, 
or the participant is lost to follow-up (as defined in Section 7.3).
In general, follow-up information will include a description of the event in sufficient detail to 
allow for a complete medical assessment of the case and independent determination of 
possible causality. Any information relevant to the event, such as concomitant medications 
and illnesses, must be provided.  In the case of a participant death, a summary of available 
autopsy findings must be submitted as soon as possible to Pfizer Safety. 
Further information on follow-up procedures is given in Appendix 3.


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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 toward the safety of participants and the safety of a 
study intervention under clinical investigation are met.
The sponsor has a legal responsibility to notify both the local regulatory authority and other 
regulatory agencies about the safety of a study intervention under clinical investigation. The 
sponsor will comply with country-specific regulatory requirements relating to safety 
reporting to the regulatory authority, IRBs/ECs, and investigators.
Investigator safety reports must be prepared for SUSARs according to local regulatory 
requirements and sponsor policy and forwarded to investigators as necessary.
An investigator who receives SUSARs or other specific safety information (eg, summary or 
listing of SAEs) from the sponsor will review and then file it along with the SRSD(s) for the 
study and will notify the IRB/EC, if appropriate according to local requirements.
8.3.5. Exposure During Pregnancy or Breastfeeding, and Occupational Exposure
Environmental exposure, occurs when a person not enrolled in the study as a participant 
receives unplanned direct contact with or exposure to the study intervention. Such exposure 
may or may not lead to the occurrence of an AE or SAE. Persons at risk for environmental 
exposure include healthcare providers, family members, and others who may be exposed. An 
environmental exposure may include exposure during pregnancy, exposure during 
breastfeeding, and occupational exposure.
Any such exposure to the study intervention under study are reportable to Pfizer Safety 
within 24 hours of investigator awareness.
8.3.5.1. Exposure During Pregnancy
An EDP occurs if: 

A female participant is found to be pregnant while receiving or after discontinuing 
study intervention.

A female is found to be pregnant while being exposed or having been exposed to 
study intervention due to environmental exposure. Below are examples of 
environmental EDP:

A female family member or healthcare provider reports that she is pregnant after 
having been exposed to the study intervention by ingestion.
The investigator must report EDP to Pfizer Safety within 24 hours of the investigator’s 
awareness, irrespective of whether an SAE has occurred. The initial information submitted 
should include the anticipated date of delivery (see below for information related to 
termination of pregnancy). 


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
If EDP occurs in a participant or a participant’s partner, the investigator must report 
this information to Pfizer Safety on the CT SAE Report Form and an EDP 
Supplemental Form, regardless of whether an SAE has occurred. Details of the 
pregnancy will be collected after the start of study intervention and until after the start 
of study interventions and until a minimum of 28 calendar days after 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 (eg, 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 (eg, environmental exposure). An example of environmental 
exposure during breastfeeding is a female family member or healthcare provider who 
reports that she is breastfeeding after having been exposed to the study intervention 
by ingestion.  
The investigator must report exposure during breastfeeding to Pfizer Safety within 24 hours 
of the investigator’s awareness, irrespective of whether an SAE has occurred. The 
information must be reported using the CT SAE Report Form. When exposure during 
breastfeeding occurs in the setting of environmental exposure, the exposure information does 
not pertain to the participant enrolled in the study, so the information is not recorded on a 
CRF. However, a copy of the completed CT SAE Report Form is maintained in the 
investigator site file.
An exposure during breastfeeding report is not created when a Pfizer drug specifically 
approved for use in breastfeeding women (eg, vitamins) is administered in accord with 
authorized use. However, if the infant experiences an SAE associated with such a drug, the 
SAE is reported together with the exposure during breastfeeding.
8.3.5.3. Occupational Exposure
The investigator must report any instance of occupational exposure to Pfizer Safety within 
24 hours of the investigator’s awareness using the CT SAE Report Form regardless of 
whether there is an associated SAE. Since the information about the occupational exposure 
does not pertain to a participant enrolled in the study, the information is not recorded on a 
CRF; however, a copy of the completed CT SAE Report Form must be maintained in the 
investigator site file.
8.3.6. Cardiovascular and Death Events
Not applicable.
8.3.7. Disease-Related Events and/or Disease-Related Outcomes Not Qualifying as AEs 
or SAEs
Not applicable.
8.3.8. Adverse Events of Special Interest
Not applicable.


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8.3.8.1. Lack of Efficacy
This section is not applicable because efficacy is not expected in the study population.
8.3.9. Medical Device Deficiencies
Not applicable.
8.3.10. Medication Errors
Medication errors may result from the administration or consumption of the study 
intervention by the wrong participant, or at the wrong time, or at the wrong dosage strength.
Exposures to the study intervention under study may occur in clinical trial settings, such as 
medication errors.
Safety Event
Recorded on the CRF
Reported on the CT SAE Report 
Form to Pfizer Safety Within 
24 Hours of Awareness
Medication errors 
All (regardless of whether 
associated with an AE)
Only if associated with an SAE
Medication errors include:

Medication errors involving participant exposure to the study intervention;

Potential medication errors or uses outside of what is foreseen in the protocol that do 
or do not involve the study participant.
Such medication errors occurring to a study participant are to be captured on the medication 
error page of the CRF, which is a specific version of the AE page.
In the event of a medication dosing error, the sponsor should be notified within 24 hours.
Whether or not the medication error is accompanied by an AE, as determined by the 
investigator, the medication error is recorded on the medication error page of the CRF and, if 
applicable, any associated AE(s), serious and nonserious, are recorded on the AE page of the 
CRF.
Medication errors should be reported to Pfizer Safety within 24 hours on a CT SAE Report 
Form only when associated with an SAE.


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8.4. Pharmacokinetics 
Plasma for analysis of EE and LN
Blood samples of approximately 6 mL (2 × 6 = 12 mL), to provide approximately 2.5 mL 
plasma for each EE and LN will be collected into appropriately labeled tubes containing 
K2EDTA for measurement of plasma concentrations of EE and LN as specified in the SoA. 
Instructions for the collection and handling of biological samples will be provided in the 
laboratory manual or by the sponsor. The actual date and time (24-hour clock time) of each 
sample will be recorded.
The actual times may change, but the number of samples will remain the same. All efforts 
will be made to obtain the samples at the exact nominal time relative to dosing. Collection of 
samples up to and including 10 hours after dose administration that are obtained within 
10% of the nominal time relative to dosing (eg, within 6 minutes of a 60-minute sample) will 
not be captured as a protocol deviation, as long as the exact time of the collection is noted on 
the source document and the CRF. Collection of samples more than 10 hours after dose
administration that are obtained ≤1 hour away from the nominal time relative to dosing will 
not be captured as a protocol deviation, as long as the exact time of the collection is noted on 
the source document and the CRF. 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 OC steroids (EE and LN). Samples collected for 
analyses of OC steroids (EE and LN) concentration may also be used to evaluate safety or 
efficacy aspects related to concerns arising during or after the study, for metabolite 
identification and/or evaluation of the bioanalytical method, 
 
 
Samples collected for measurement of plasma concentrations of OC steroids (EE and LN)
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.
CCI
CCI
CCI


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8.7. Immunogenicity Assessments
Immunogenicity assessments are not included in this study.
8.8. Health Economics
Health economics/medical resource utilization and health economics parameters are not 
evaluated in this study.
9. STATISTICAL CONSIDERATIONS
Detailed methodology for summary and statistical analyses of the data collected in this study 
is outlined here and further detailed in an 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 inferential statistics will be applied to the safety or PK data.
CCI


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9.2. Analysis Sets
For purposes of analysis, the following analysis sets are defined:
Population
Description
Enrolled 
All participants who sign the ICD. A participant will be 
considered enrolled if the informed consent is not withdrawn 
prior to participating in any study activity after screening.
Assigned to
investigational product
All participants who sign the ICD and meet all eligibility 
criteria.
Evaluable
All participants enrolled to investigational product and who
take at least 1 dose of investigational product. 
Safety
All participants enrolled to investigational product and who 
take at least 1 dose of investigational product.
9.3. Statistical Analyses
The SAP will be developed and finalized before any analyses are performed and will 
describe the analyses and procedures for accounting for missing, unused, and spurious data. 
This section is a summary of the planned statistical analyses of the primary and secondary 
endpoints.
9.3.1. Pharmacokinetic Analyses
The PK concentration population is defined as all participants that received at least 1 dose of 
investigational product and have at least 1 plasma concentration value reported in at least 
1 period. The PK parameter analysis population is defined as all participants that received at 
least 1 dose of investigational product and have at least 1 of the PK parameters of primary 
interest reported in at least 1 period.
PK parameters for EE and LN following alone and co-administration with PF-06650833 will 
be derived from the concentration-time profiles using non-compartmental methods as data 
permit. The PK parameters to be assessed in this study, their definition, and method of 
determination are outlined in Table 2. In all cases, actual PK sampling times will be used in 
the derivation of PK parameters.


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Table 2.
Plasma Pharmacokinetic Parameter Definitions
Parameter
Definition
Method of Determination
Cmax
Maximum plasma concentration 
during the dosing interval
Observed directly from data
Tmax
Time for Cmax
Observed directly from data as time of first occurrence
AUClast
Area under the plasma 
concentration-time profile from 
time 0 to the time of the last 
quantifiable concentration (Clast)
Linear/Log trapezoidal method
AUCinfa
Area under the plasma 
concentration-time profile from 
time 0 extrapolated to infinite 
time
AUClast + (Clast/kel),
where Clast is the predicted plasma concentration at the 
last quantifiable time point estimated from the log-linear 
regression analysis
CL/Fa
Apparent clearance
Dose/AUCtau
PTR
Peak-to-trough ratio
Cmax/Cmin
t½a
Terminal elimination half-life
Loge(2)/kel,
where kel is the terminal phase rate constant calculated by 
a linear regression of the log-linear concentration-time 
curve. Only those data points judged to describe the 
terminal log-linear decline will be used in the regression
a. If data permit
The plasma PK parameters in Table 2 will be summarized descriptively by treatment, as 
applicable, in accordance with Pfizer data standards. AUClast and Cmax for EE and LN
individual participant parameters will be plotted by treatment. Plasma concentrations will be 
listed and summarized descriptively by nominal PK sampling time and treatment. Individual 
participant and median profiles of the plasma concentration-time data will be plotted by 
treatment using actual and nominal times respectively. Median profiles will be presented on 
both linear-linear and log-linear scales.
To assess any effect of PF-06650833 on EE or LN exposures, natural log transformed 
AUClast and Cmax will be analyzed using a mixed effects model with treatment as a fixed 
effect and participant as a random effect. Estimates of the adjusted mean differences 
(Test-Reference) and corresponding 90% CIs will be obtained from the model and will be 
exponentiated to provide estimates of the ratio of adjusted geometric means (Test/Reference) 
and 90% CIs for the ratios.
The following assessment should be performed:

Effect of PF-06650833 on OC (EE or LN) exposures with OC alone (Period 1 Day 1
PK) as the Reference treatment and co-administration of PF-06650833 and OC 
(Period 2 Day 10 PK) as the Test treatment.
9.3.2. Safety Analyses
All safety analyses will be performed on the safety population.


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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.
9.3.2.1. Electrocardiogram Analyses
Changes from baseline for the ECG parameters QT interval, heart rate, QTc interval, PR 
interval, and QRS complex will be summarized by treatment and time.
The number (%) of participants with maximum postdose QTc values and maximum increases 
from baseline in the following categories will be tabulated by treatment (Table 3): 
Table 3.
Safety QTc 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, an attempt will be made to explore and characterize the relationship between 
plasma concentration and QT interval length using a PK/PD modeling approach. If a PK/PD 
relationship is found, the impact of participant factors (covariates) on the relationship will be 
examined.
 
9.4. Interim Analyses
No formal interim analysis will be conducted for this study. As this is an open-label study,
the sponsor may conduct unblinded reviews of the data during the course of the study for the 
purpose of safety assessment, facilitating PK/PD modeling, and/or supporting clinical 
development. 
CCI


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9.5. Sample Size Determination
Approximately 10 participants will be enrolled and dosed to achieve at least 8 participants
completing the study.
Table 4
and Table 5 presents the reference boundaries and width of the confidence intervals for a 
range of different estimated effects (estimates of the ratio for pairs of treatments: Test vs 
Reference).
 
 
 
CCI
CCI


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CCI


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


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


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Participants who are rescreened are required to sign a new ICD.
10.1.4. Data Protection
All parties will comply with all applicable laws, including laws regarding the implementation 
of organizational and technical measures to ensure protection of participant data.
Participants’ personal data will be stored at the study site in encrypted electronic and/or paper 
form and will be password-protected or secured in a locked room to ensure that only 
authorized study staff have access. The study site will implement appropriate technical and 
organizational measures to ensure that the personal data can be recovered in the event of 
disaster. In the event of a potential personal data breach, the study site will be responsible for 
determining whether a personal data breach has in fact occurred and, if so, providing breach 
notifications as required by law.
To protect the rights and freedoms of participants with regard to the processing of personal 
data, participants will be assigned a single, participant-specific numerical code. Any 
participant records or data sets that are transferred to the sponsor will contain the numerical 
code; participant names will not be transferred. All other identifiable data transferred to the 
sponsor will be identified by this single, participant-specific code. The study site will 
maintain a confidential list of participants who participated in the study, linking each 
participant’s numerical code to his or her actual identity and medical record ID. In case of 
data transfer, the sponsor will protect the confidentiality of participants’ personal data 
consistent with the clinical study agreement and applicable privacy laws.
10.1.5. Committees Structure
10.1.5.1. Data Monitoring Committee 
The study will not use a DMC.
10.1.6. Dissemination of Clinical Study Data
Pfizer fulfills its commitment to publicly disclose clinical study results through posting the 
results of studies on www.clinicaltrials.gov (ClinicalTrials.gov), the EudraCT, and/or 
www.pfizer.com, and other public registries in accordance with applicable local 
laws/regulations. In addition, Pfizer reports study results outside of the requirements of local 
laws/regulations pursuant to its SOPs.
In all cases, study results are reported by Pfizer in an objective, accurate, balanced, and 
complete manner and are reported regardless of the outcome of the study or the country in 
which the study was conducted.


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


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


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provide copies of the inspection findings to the sponsor or its agent. Before response 
submission to the regulatory authorities, the investigator will provide the sponsor or its 
agents with an opportunity to review and comment on responses to any such findings.
10.1.8. Source Documents
Source documents provide evidence for the existence of the participant and substantiate the 
integrity of the data collected. Source documents are filed at the investigator site.
Data reported on the CRF or entered in the eCRF that are from source documents must be 
consistent with the source documents or the discrepancies must be explained. The 
investigator may need to request previous medical records or transfer records, depending on 
the study. Also, current medical records must be available.
Definition of what constitutes source data and its origin can be found in the Source 
Document Locator.
Description of the use of the computerized system is documented in the Data Management 
Plan, which is maintained by the sponsor.
The investigator must maintain accurate documentation (source data) that supports the 
information entered in the CRF.
Study monitors will perform ongoing source data verification to confirm that data entered 
into the CRF by authorized site personnel are accurate, complete, and verifiable from source 
documents; that the safety and rights of participants are being protected; and that the study is 
being conducted in accordance with the currently approved protocol and any other study 
agreements, ICH GCP guidelines, and all applicable regulatory requirements.
10.1.9. Study and Site Start and Closure
The study start date is the date on which the clinical study will be open for recruitment of 
participants.
The first act of recruitment is the date of the first participant’s first visit and will be the study 
start date.
The sponsor designee reserves the right to close the study site or terminate the study at any 
time for any reason at the sole discretion of the sponsor. Study sites will be closed upon study 
completion. A study site is considered closed when all required documents and study 
supplies have been collected and a study-site closure visit has been performed.
The investigator may initiate study-site closure at any time upon notification to the sponsor 
or designee/CRO if requested to do so by the responsible IRB/EC or if such termination is 
required to protect the health of study participants.


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Reasons for the early closure of a study site by the sponsor may include but are not limited 
to:

Failure of the investigator to comply with the protocol, the requirements of the 
IRB/EC or local health authorities, the sponsor's procedures, or the ICH GCP 
guidelines;

Inadequate recruitment of participants by the investigator;

Discontinuation of further study intervention development.
If the study is prematurely terminated or suspended, the sponsor shall promptly inform the 
investigators, the ECs/IRBs, the regulatory authorities, and any CRO(s) used in the study of 
the reason for termination or suspension, as specified by the applicable regulatory 
requirements. The investigator shall promptly inform the participant and should assure 
appropriate participant therapy and/or follow-up.
Study termination is also provided for in the clinical study agreement. If there is any conflict 
between the contract and this protocol, the contract will control as to termination rights.
10.1.10. Publication Policy
The 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. 


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If publication is addressed in the clinical study agreement, the publication policy set out in 
this section will not apply.
10.1.11. Sponsor’s Qualified Medical Personnel
The contact information for the sponsor's appropriately qualified medical personnel for the 
study is documented in the study contact list located in the CTMS.
To facilitate access to appropriately qualified medical personnel for study-related medical 
questions or problems, participants are provided with an Emergency Contact Card (ECC) at 
the time of informed consent. The ECC contains, at a minimum, (a) protocol and study 
intervention identifiers, (b) participant’s study identification number, (c) site emergency 
phone number active 24 hours/day, 7 days per week, and (d) Pfizer Call Center number.
The ECC is intended to augment, not replace, the established communication pathways 
between the investigator, site staff, and study team. The ECC is to be used by healthcare 
professionals not involved in the research study only, as a means of reaching the investigator 
or site staff related to the care of a participant. The Pfizer Call Center number should only be 
used when the investigator and site staff cannot be reached. The Pfizer Call Center number is 
not intended for use by the participant directly; if a participant calls that number directly, 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 (Table 6) 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.
At screening, HBsAg and HBcAb will be tested:
a.
If both tests are negative, the participant is eligible for study inclusion;
b. If HBsAg is positive, the participant must be excluded from participation in the study;
c.
If HBsAg is negative and HBcAb is positive, HBsAb reflex testing is required:
i.
If HBsAb is negative, the participant must be excluded from participation in the 
study;
ii. If HBsAb is positive, the participant is eligible for study inclusion.
See Section 8.2.4 for more information on participant safety monitoring and discontinuation
regarding clinical lab tests.


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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/urea and creatinine
Glucose (fasting)
Calcium
Sodium
Potassium
Chloride
Total CO2 (bicarbonate)
AST, ALT
TBili
Alkaline phosphatase
Uric acid
Albumin
Total protein
CK
pH
Glucose (qual)
Protein (qual)
Blood (qual)
Ketones
Nitrites
Leukocyte esterase
Urobilinogen
Urine bilirubin
Microscopya
•
Urine drug screeningb
•
eGFR
•
Viral Screens: CMV, 
EBV, HSV 1&2, VZV
•
Pregnancy test (β-hCG)c
At screening only:
•
FSHd
•
HBsAg/HBcAb/HBsAb
•
HCVAbe
•
HIV
•
QFT-G Test IGRA
•
COVID-19 PCR test
a.
Only if urine dipstick is positive for blood, protein, nitrites, or leukocyte esterase.
b.
The minimum requirement for drug screening includes cocaine, THC, opiates/opioids, benzodiazepines, 
and amphetamines (others are site and study specific).
c.
Local serum testing will be standard for the protocol. Serum or urine β-hCG for female participants of 
childbearing potential.
d.
For confirmation of postmenopausal status only.
e.
All participants will undergo testing for HCVAb during Screening. Participants who are HCVAb 
positive will be reflex tested for HCV RNA. Participants who are HCVAb and HCV RNA positive are 
not eligible for the study. Participants who are HCVAb positive but HCV RNA negative will be 
considered eligible.
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.
 
 
 
 
 
Interferon Gamma Release Assay
QFT-G test will be performed during screening. Blood sampling may include 3 mL up to 
10 mL of blood. Test should be performed in accordance with the product specific processing 
and analyzing instructions.
CCI


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


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


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


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


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


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


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
New or updated information will be recorded in the originally submitted 
documents.

The investigator will submit any updated SAE data to the sponsor within 24 hours 
of receipt of the information.
10.3.4. Reporting of SAEs
SAE Reporting to Pfizer Safety via an Electronic Data Collection Tool

The primary mechanism for reporting an SAE to Pfizer Safety will be the 
electronic data collection tool.

If the electronic system is unavailable, then the site will use the paper SAE data 
collection tool (see next section) to report the event within 24 hours.

The site will enter the SAE data into the electronic system as soon as the data
become available.

After the study is completed at a given site, the electronic data collection tool will 
be taken off-line to prevent the entry of new data or changes to existing data.

If a site receives a report of a new SAE from a study participant or receives updated 
data on a previously reported SAE after the electronic data collection tool has been 
taken off-line, then the site can report this information on a paper SAE form (see 
next section) or to Pfizer Safety by telephone.
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 and Barrier Guidance
10.4.1. Male Participant Reproductive Inclusion Criteria
Not applicable.
10.4.2. Female Participant Reproductive Inclusion Criteria
A female participant is eligible to participate if she is not pregnant or breastfeeding, and at 
least 1 of the following conditions applies:

Is not a WOCBP (see definitions below in Section 10.4.3).
OR

Is a WOCBP and using a contraceptive method that is highly effective (with a failure 
rate of <1% per year), with low user dependency, as described below during the 
intervention period and for at least 28 days or 5 terminal half-lives plus 14 days 
(whichever duration is longer) after the last dose of study intervention, which 
corresponds to the time needed to eliminate any reproductive safety risk of the study 
intervention. The investigator should evaluate the effectiveness of the contraceptive 
method in relationship to the first dose of study intervention.
A WOCBP agrees not to donate eggs (ova, oocytes) for the purpose of reproduction during 
this period. The investigator should evaluate the effectiveness of the contraceptive method in 
relationship to the first dose of study intervention.
The investigator is responsible for review of medical history, menstrual history, and recent 
sexual activity to decrease the risk for inclusion of a woman with an early undetected 
pregnancy.
10.4.3. Woman of Childbearing Potential
A woman is considered fertile following menarche and until becoming postmenopausal 
unless permanently sterile (see below).
If fertility is unclear (eg, amenorrhea in adolescents or athletes) and a menstrual cycle cannot 
be confirmed before the first dose of study intervention, additional evaluation should be 
considered.
Women in the following categories are not considered WOCBP:
1. Premenopausal female with 1 of the following:

Documented hysterectomy;

Documented bilateral salpingectomy;

Documented bilateral oophorectomy.


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For individuals with permanent infertility due to an alternate medical cause other than 
the above, (eg, mullerian agenesis, androgen insensitivity), investigator discretion 
should be applied to determining study entry.
Note: Documentation for any of the above categories can come from the site 
personnel’s review of the participant’s medical records, medical examination, or 
medical history interview. The method of documentation should be recorded in the 
participant’s medical record for the study.
2. Postmenopausal female.

A postmenopausal state is defined as no menses for 12 months without an 
alternative medical cause. In addition:

A high FSH level in the postmenopausal range must be used to confirm a 
postmenopausal state in women under 60 years old and not using hormonal 
contraception or HRT. 

A female on HRT and whose menopausal status is in doubt will be required to 
use one of the 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. Intrauterine device.
2. Bilateral tubal occlusion (eg, bilateral tubal ligation).
3. Vasectomized partner. 

A vasectomized partner is a highly effective contraceptive method provided that 
the partner is the sole sexual partner of the WOCBP and the absence of sperm has 
been confirmed. If not, an additional highly effective method of contraception 
should be used. The spermatogenesis cycle is approximately 90 days.


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4. Sexual abstinence. 

Sexual abstinence is considered a highly effective method only if defined as 
refraining from heterosexual intercourse during the entire period of risk associated 
with the study intervention. The reliability of sexual abstinence needs to be 
evaluated in relation to the duration of the study and the preferred and usual 
lifestyle of the participant.


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.
CCI


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


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


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


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


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10.8. Appendix 8: Abbreviations
The following is a list of abbreviations that may be used in the protocol.
Abbreviation
Term

ongoing/continuous event
-hCG
a quantitative human chorionic gonadotropin
Abs
absolute
ADL
activities of daily living
AE
adverse event
ALC
absolute lymphocyte count
ALT
alanine aminotransferase
ANC
absolute neutrophil count
ARDS
acute respiratory distress syndrome
AST
aspartate aminotransferase
AUC
area under the concentration-time curve
AUC24
area under the concentration-time curve from time 0 to 24 hours
AUCinf
area under the plasma concentration-time profile from time 0 
extrapolated to infinite time
AUClast
area under the plasma concentration-time profile from time zero to 
the time of the last quantifiable concentration (Clast)
AUCtau
area under the plasma concentration-time profile from time 0 to 
time tau, the dosing interval
AV
atrioventricular
BBS
Biospecimen Banking System
BCRP
breast cancer resistance protein
BID
twice a day
BMI
body mass index
BP
blood pressure
bpm
beats per minute
BUN
blood urea nitrogen
14C
a radioactive isotope of carbon
Clast
last quantifiable concentration
Cmax
maximum plasma concentration during the dosing interval
Cmin
minimum observed concentration
CFR
Code of Federal Regulations
CI
confidence interval
CIA
collagen induced arthritis
CIOMS
Council for International Organizations of Medical Sciences
CK
creatine kinase
CKD-EPI
Chronic Kidney Disease Epidemiology Collaboration
CL/F
apparent clearance
CMV
cytomegalovirus


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Abbreviation
Term
CO2
carbon dioxide (bicarbonate)
COVID-19
coronavirus disease 2019
CRF
case report form
CRO
contract research organization
CRU
clinical research unit
CSR
clinical study report
CT
clinical trial
CTMS
clinical trial management system
CVw%
within-participant coefficient of variation
CYP
cytochrome P450
DDI
drug-drug interaction 
DILI
drug-induced liver injury
DMC
data monitoring committee
EBV
Epstein-Barr virus
EC
ethics committee
EC50
the concentration of a drug that gives half-maximal response
ECC
Emergency Contact Card
ECG
electrocardiogram
eCRF
electronic case report form
EDB
exposure during breastfeeding
EDP
exposure during pregnancy
EE
ethinyl estradiol
EFD
embryo-fetal developmental
eGFR
estimated glomerular filtration rate
EMA
European Medicines Agency
Emax
the maximum effect
EU
European Union
EudraCT
European Clinical Trials Database
F
bioavailability
Fa
fraction absorbed
FACS
fluorescent activated cell sorting
FSH
follicle-stimulating hormone
GCP
Good Clinical Practice
GGT
gamma-glutamyl transferase
GI
gastrointestinal
GLP
Good Laboratory Practice
HBcAb
hepatitis B core antibody
HBsAb
hepatitis B surface antibody
HBsAg
hepatitis B surface antigen
HCV
hepatitis C virus
CCI


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Abbreviation
Term
HCVAb
hepatitis C antibody
HIV
human immunodeficiency virus
HR
heart rate
HRT
hormone replacement therapy
HS
hidradenitis suppurativa
HSV
herpes simplex virus
IB
investigator’s brochure
IC50
the concentration of an inhibitor where the response (or binding) is 
reduced by half
ICD
informed consent document
ICH
International Council for Harmonisation of Technical 
Requirements for Pharmaceuticals for Human Use
ID
identification
IGRA
Interferon Gamma Release Assay
IND
investigational new drug 
INR
international normalized ratio
IP
investigational product
IPAL
Investigational Product Accountability Log
IQMP
integrated quality management plan
IR
immediate release
IRAK4
IL -1 receptor associated kinase 4
IRB
institutional review board
IV
intravenous
kel
terminal phase rate constant
K2EDTA
dipotassium ethylenediaminetetraacetic acid
LBBB
left bundle branch block
LFT
liver function test
LN
levonorgestrel
MAD
multiple ascending dose
MATE
multidrug and toxin extrusion protein
MCH
mean corpuscular hemoglobin
MCHC
mean corpuscular hemoglobin concentration
MCV
mean corpuscular volume
MR
modified release
mRNA
messenger ribonucleic acid
msec
millisecond
N/A
not applicable
NIMP
Non Investigational Medicinal Product
NOAEL
no-observed-adverse-effect level
OAT
organic anion transporter
OATP
organic anion-transporting polypeptide
OC
oral contraceptive


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Abbreviation
Term
OCT
organic cation transporter
PCR
polymerase chain reaction
PCRU
Pfizer Clinical Research Unit
PD
pharmacodynamic(s)
P-gp
P-glycoprotein
PI
principal investigator
PK
pharmacokinetic(s)
PO
by mouth
PPD
purified protein derivative
PT
prothrombin time
PTR
peak-to-trough ratio
PVC
premature ventricular contraction/complex
QD
once daily
QFT-G
QuantiFERON-TB Gold IN-Tube
QID
4 times a day
QTc
corrected QT
QTcF
corrected QT (Fridericia method)
qual
qualitative
RA
rheumatoid arthritis
RBC
red blood cell
RNA
ribonucleic acid
SAD
single ascending dose
SAE
serious adverse event
SAP
statistical analysis plan
SARS-CoV-2
severe acute respiratory syndrome coronavirus 2
SCr
serum creatinine
SD
standard deviation
SoA
schedule of activities
SOC
system organ class
SOP
standard operating procedure
SRSD
single reference safety document
ST-T
the ST segment and T-wave
SULT
sulfotransferase
SUSAR
suspected unexpected serious adverse reaction
t½
terminal elimination half-life
Tmax
Time for Cmax
TB
tuberculosis
TBili
total bilirubin
TBNK
lymphocyte subsets (T cells, B cells, and NK cells)
TEAE
treatment emergent adverse event
THC
tetrahydrocannabinol


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Abbreviation
Term
TLR
tool-like receptor
UGT
uridine diphosphate-glucuronsyltransferase
ULN
upper limit of normal
US
United States
VZV
varicella zoster virus
WBC
white blood cell
WOCBP
woman/women of childbearing potential
WONCBP
women of non-childbearing potential


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11. REFERENCES
NONE. 

SAP_001.pdf: 
        Protocol B7921026 (PF-06650833) Statistical Analysis Plan
PFIZER GENERAL BUSINESS 
Page 1
Protocol B7921026
A PHASE 1, OPEN LABEL, FIXED SEQUENCE STUDY TO ESTIMATE THE 
EFFECT OF MULTIPLE DOSE PF-06650833 ON THE PHARMACOKINETICS OF 
SINGLE DOSE ORAL CONTRACEPTIVE STEROIDS IN HEALTHY FEMALE
PARTICIPANTS
Statistical Analysis Plan 
(SAP)
Version:
1 
Date:
27 Oct 2021  


        Protocol B7921026 (PF-06650833) Statistical Analysis Plan
PFIZER GENERAL BUSINESS 
Page 2
TABLE OF CONTENTS
LIST OF TABLES.....................................................................................................................3
LIST OF FIGURES ...................................................................................................................3
APPENDICES ...........................................................................................................................3
1. VERSION HISTORY............................................................................................................4
2. INTRODUCTION .................................................................................................................4
2.1. Study Objectives, Endpoints, and Estimands............................................................4
2.2. Study Design .............................................................................................................5
3. ENDPOINTS AND BASELINE VARIABLES: DEFINITIONS AND 
CONVENTIONS ..................................................................................................................6
3.1. Primary Endpoints.....................................................................................................6
3.2. Secondary Endpoints.................................................................................................6
3.3. Tertiary/Exploratory Endpoint(s)..............................................................................6
3.4. Baseline Variables.....................................................................................................6
3.5. Safety Endpoints .......................................................................................................7
3.5.1. Adverse Events .............................................................................................7
3.5.2. Laboratory Data............................................................................................8
3.5.3. Vital Signs Data............................................................................................8
3.5.4. ECG Results..................................................................................................9
4. ANALYSIS SETS (POPULATIONS FOR ANALYSIS).....................................................9
5. GENERAL METHODOLOGY AND CONVENTIONS....................................................10
5.1. Hypotheses and Decision Rules ..............................................................................10
5.2. General Methods .....................................................................................................10
5.3. Methods to Manage Missing Data ..........................................................................11
5.3.1. Concentrations Below the Limit of Quantification ....................................11
5.3.2. Deviations, Missing Concentrations and Anomalous Values.....................11
5.3.3. Pharmacokinetic Parameters.......................................................................11
6. ANALYSES AND SUMMARIES ......................................................................................12
6.1. Primary Endpoint(s) ................................................................................................12
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6.1.1. Pharmacokinetic Endpoints ........................................................................12
6.2. Safety Summaries and Analyses .............................................................................14
6.2.1. Adverse Events ...........................................................................................14
6.2.2. Laboratory Data..........................................................................................14
6.2.3. Vital Signs ..................................................................................................15
6.2.4. Electrocardiograms.....................................................................................15
7. INTERIM ANALYSES.......................................................................................................15
8. REFERENCES ....................................................................................................................16
9. APPENDICES .....................................................................................................................17
LIST OF TABLES
Table 1.
Summary of Changes..................................................................................4
Table 2.
Study Design and Treatments.....................................................................5
Table 3.
Analysis Populations ..................................................................................9
Table 4.
Assignment of Reference and Test Treatments........................................10
Table 5.
Calculation and Safety Reporting by Treatment ......................................11
Table 6.
Noncompartmental PK Parameters...........................................................12
Table 7.
PK Parameters to be Summarized Descriptively by Treatment ...............13
LIST OF FIGURES
Figure 1.
Schematic of Study Design.........................................................................6
APPENDICES
Appendix 1. SAS CODE FOR ANALYSES...........................................................................17
Appendix 2. Categorical Classes for ECG and Vital Signs of Potential Clinical Concern .....18
Appendix 3. List of Abbreviations...........................................................................................19


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1. VERSION HISTORY
Table 1.
Summary of Changes
Version/
Date
Associated 
Protocol 
Amendment
Rationale
Specific Changes
1
27 Oct 2021
Original 
29 Jul 2021
N/A
N/A
NOTE: Italicized text within this document has been taken verbatim from the Protocol.
2. INTRODUCTION
This study will evaluate the effect of PF-06650833 on pharmacokinetics of oral contraceptive 
(OC) steroids, in order to select appropriate contraception requirements in Phase 2 studies.
 
This statistical analysis plan (SAP) provides the detailed methodology for summary and 
statistical analyses of the data collected in Study B7921026.  Any major modifications of the 
primary endpoint definition or its analysis will also be reflected in a protocol amendment.
2.1. Study Objectives, Endpoints, and Estimands
Objectives
Endpoints
Primary: 
Primary: 
•
To estimate the effect of multiple oral doses 
of PF-06650833 on the PK of a single dose 
of a combination OC in healthy female 
participants.
•
Cmax and AUClast of EE and LN.
Secondary: 
Secondary: 
•
To evaluate the safety of PF-06650833 
when co-administered with a single dose of 
a combination OC in healthy female 
participants.
•
Safety: laboratory tests, AEs reporting and 
vital signs.
Tertiary/Exploratory: 
Tertiary/Exploratory: 
•
To characterize the PK of a single dose of a 
combination OC with or without 
PF-06650833 in healthy female 
participants.
•
Tmax, and if data permit CL/F, t½ and AUCinf, 
of EE and LN.
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2.2. Study Design
This is a Phase 1, fixed-sequence, multiple-dose, open-label study of the effect of multiple 
dose PF-06650833 on single dose OC PK in healthy female participants. A total of 
approximately 10 healthy female participants will be enrolled in the study. The study will 
consist of 2 periods in a single fixed sequence. Participants will be screened within 28 days 
of the first dose of investigational product in Period 1. Participants will report to the CRU 
the day prior to Day 1 dosing in Period 1. Participants will remain in the CRU for a total of 
16 days and 15 nights. There will be no washout period.
On Period 1 Day 1, participants will be dosed with a single administration of OC in the form 
of 1 PORTIA® (EE and LN) or equivalent tablet, orally. OC (EE and LN) PK will then be 
assessed at pre-dose and over 48 hours, post OC dosing. Period 1 will be immediately 
followed by Period 2 with no washout, in which participants will be dosed orally with 
PF-06650833 400 mg MR QD for 9 days followed by administration of a single dose of OC 
on the morning of Day 10. OC PK will be assessed at pre-dose and for 48 hours following 
OC dosing. On Day 10, the morning dose of PF-06650833 and the single OC dose will be 
administered simultaneously within 5 minnutes. Dosing with PF-06650833 400 mg PO QD 
will continue until Day 11 (Table 2). Participants will be discharged on Day 12 only after 
review of safety laboratory by the PI. Figure 1 shows the schematic of Study Design.
Table 2.
Study Design and Treatments
Period 1
Washout
Period 2
Treatment R
None
Treatment T
Treatment R: Single dose of OC in the form of 1 PORTIA® (EE and LN) or equivalent oral tablet, containing 
EE 30 μg and LN 150 μg.
Treatment T: Single dose of combination OC in the form of 1 PORTIA® (EE and LN) or equivalent oral tablet, 
containing of EE 30 μg and LN 150 μg on the morning of Day 10 following 9 days of PF-06650833 dosed at 
400 mg PO QD. Dosing with PF-06650833 at 400 mg PO QD will continue through until Day 11.


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Figure 1.
Schematic of Study Design
3. ENDPOINTS AND BASELINE VARIABLES: DEFINITIONS AND 
CONVENTIONS
3.1. Primary Endpoints
Cmax and AUClast of EE and LN.
3.2. Secondary Endpoints

Laboratory tests.

Adverse events.

Vital signs.
3.3. Tertiary/Exploratory Endpoint(s)
Tmax, and if data permit CL/F, t½ and AUCinf, of EE and LN.
3.4. Baseline Variables
The following baseline variables will be summarized for each treatment. Details of summary
analyses are described in Section 6. 
Demographic characteristics:

Baseline age.

Gender (female vs. male).


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
Race (white, black, Asian, other).

Baseline body weight.

Baseline Body Mass.
The baseline data measured at Day 1 are:

Medical history & demography, medication history.

Physical Examinations.
For laboratory data, baseline for the "PF+OC" phase is defined as the last measurement 
collected before administering the first dose of OC at the beginning of Period 2 (ie, P2D10 
pre-dose).
For vital signs data, baseline for the "PF-only" phase is defined as the last measurement 
collected before administering the first dose of PF at the beginning of Period 2 (ie, P2D1 
pre-dose), and baseline for the "PF+OC" phase is defined as the last measurement collected 
before administering the first dose of OC at the beginning of Period 2 (ie, P2D10 pre-dose).
For ECG data, baseline for the "PF+OC" phase is defined as the last measurement collected 
before administering the first dose of OC at the beginning of Period 1 (ie, P1D1 pre-dose).
3.5. Safety Endpoints
The following data are considered in standard safety summaries (see protocol for collection 
days and list of parameters):

adverse events.

laboratory data.

vital signs data.

ECG results.
3.5.1. Adverse Events
An adverse event will be considered a Treatment-Emergent Adverse Event (TEAE) if the 
event started during the effective duration of treatment. All events that start on or after the 
first dosing day and time/start time, if collected, but before the last dose plus the lag time 
(28 days) will be flagged as TEAEs. The algorithm will not consider any events that started 
prior to the first dose date. Any events occurring following start of treatment or increasing in 
severity and occur in either of the following three phases: OC, PF-06650833 (Days 1-10 of 


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Period 2), OC+PF-06650833 (Days 10-12 of Period 2), will be counted as treatment 
emergent. Events that occur in a non-treatment period (for example, Follow-up) will be 
counted as treatment emergent and attributed to the previous treatment taken.
3.5.2. Laboratory Data
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 
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.
Plot of laboratory parameter(s) value and plot of change from baseline may be requested for 
parameters changing significantly from baseline.
3.5.3. Vital Signs Data
Supine measurements will be taken at times detailed in the Schedule of Activities given in 
the protocol.
The following vital signs endpoints will be determined:

The minimum and maximum systolic and diastolic blood pressures and the minimum 
and maximum pulse rates over all measurements taken post-dose.

The maximum increase and maximum decrease from baseline over all measurements 
taken post-dose for systolic and diastolic blood pressures and pulse rates.
The maximum increase from baseline will be calculated by firstly subtracting the baseline 
value from each post-dose measurement to give the change from baseline. The maximum of 
these values will then be selected, except in the case where a participant does not show an 
increase.  In such an instance, the minimum decrease should be taken.
Similarly, the maximum decrease from baseline will be determined by selecting the 
minimum value of the changes from baseline. In cases where a participant does not show a 
decrease, the minimum increase should be taken.
Plot of vital signs parameter(s) values and plot of change from baseline may be requested for 
parameters changing significantly from baseline.


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3.5.4. ECG Results
PR, QT, RR and QTc intervals, QRS and heart rate will be recorded at each assessment time 
indicated in the Schedule of Activities given in the protocol. QTcF will also be presented and 
will be derived using Fridericia’s heart rate correction formula.
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 maximum absolute value (post-dose) and the maximum increase from baseline for 
QTcF, PR, RR and QRS, over all measurements taken post-dose, will be determined.
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 will then be selected, except in the case where a participant does not show an 
increase. In such an instance, the minimum decrease should be taken.
 
4. ANALYSIS SETS (POPULATIONS FOR ANALYSIS)
Data for all participants will be assessed to determine if participants meet the criteria for 
inclusion in each analysis population prior to unblinding and releasing the database and 
classifications will be documented per standard operating procedures.
Table 3.
Analysis Populations
Population
Description
Enrolled
All participants who sign the informed consent document
(ICD). A participant will be considered enrolled if the informed 
consent is not withdrawn prior to participating in any study 
activity after screening.
Assigned to 
investigational product
All participants who sign the ICD and meet all eligibility 
criteria.
PK Concentration 
Analysis Set
All participants who receive at least 1 dose of investigational 
product and have at least 1 plasma concentration value reported 
in at least 1 period.
PK Parameter Analysis 
Set
All participants who receive at least 1 dose of investigational 
product and have at least 1 of the PK parameters of primary 
interest reported in at least 1 period.  
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Population
Description
Evaluable
All participants enrolled to investigational product and who 
take at least 1 dose of investigational product.
Safety
All participants enrolled to investigational product and who 
take at least 1 dose of investigational product. Participants will 
be analyzed according to the product they actually received.
5. GENERAL METHODOLOGY AND CONVENTIONS
5.1. Hypotheses and Decision Rules
There are no statistical hypotheses or statistical decision rules for PK and safety data.
5.2. General Methods
To assess any effect of PF-06650833 on EE or LN exposures, natural log transformed 
AUClast and Cmax will be analyzed using a mixed effects model with treatment as a fixed effect 
and participant as a random effect. Estimates of the adjusted mean differences 
(Test-Reference) and corresponding 90% CIs will be obtained from the model and will be 
exponentiated to provide estimates of the ratio of adjusted geometric means (Test/Reference) 
and 90% CIs for the ratios.
The following assessment should be performed:

Effect of PF-06650833 on OC (EE or LN) exposures with OC alone (Period 1 Day 1 
PK) as the Reference treatment and co-administration of PF-06650833 and OC 
(Period 2 Day 10 PK) as the Test treatment.
Data will be presented – ie, listed and summarized – by treatment/period and overall. 
Continuous data will be summarized comprising mean, median, standard deviation, 
minimum and maximum. Categorical and binary data that are summarized will be via 
percentages. Some measures will be summarized using graphical representations by 
treatment/period, where appropriate.
The assignment of the reference and test treatment for drug-drug interaction evaluation is 
shown in Table 4.
Table 4.
Assignment of Reference and Test Treatments
Reference Treatment 
(Observation Time)
Test Treatment 
(Observation Time)
OC (EE+LN)
(PERIOD 1/DAY 1)
PF-06650833 + OC (EE+LN)
(PERIOD 2/DAY 10)


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Table 5.
Calculation and Safety Reporting by Treatment
Treatment 
Code
Treatments
PK Calculation
Safety reporting
R
OC (EE and LN)
Day 1 PK in Period 
1
Period 1
T
OC (EE and LN) + 
PF-06650833
Day 10 PK in 
Period 2
Period 2
For summary statistics, median and mean plots by sampling time, the nominal PK sampling 
time will be used, for individual participant plots by time, the actual PK sampling time will 
be used.
5.3. Methods to Manage Missing Data
For the analysis of safety endpoints, the sponsor data standard rules for imputation will be 
applied.
5.3.1. Concentrations Below the Limit of Quantification
In all data presentations (except listings), concentrations below the limit of quantification 
(BLQ) will be set to zero.  (In listings BLQ values will be reported as “<LLQ”, where LLQ 
will be replaced with the value for the lower limit of quantification). For PK calculations, 
BLQ will be handled by the Pfizer standard processes.
5.3.2. Deviations, Missing Concentrations and Anomalous Values
In summary tables and plots of median profiles, statistics will be calculated having set 
concentrations to missing if 1 of the following cases is true:
1. A concentration has been collected as ND (ie not done) or NS (ie no sample).
2. A deviation in sampling time is of sufficient concern or a concentration has been 
flagged anomalous by the pharmacokineticist.
Note that summary statistics will not be presented at a particular time point if more than 
50% of the data are missing.
5.3.3. Pharmacokinetic Parameters
Actual PK sampling times will be used in the derivation of PK parameters.
If a PK parameter cannot be derived from a participant’s concentration data, the parameter 
will be coded as NC (ie not calculated).  (Note that NC values will not be generated beyond 
the day that a participant discontinues).


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In summary tables, statistics will be calculated by setting NC values to missing; and statistics 
will be presented for a particular treatment with ≥3 evaluable measurements. For statistical 
analyses (ie, analysis of variance), PK parameters coded as NC will also be set to missing; 
and analyses will not be performed for a particular parameter if more than 50% of the data 
are NC.
If an individual participantparticipant has a known biased estimate of a PK parameter (due 
for example to an unexpected event such as vomiting before all the compound is adequately 
absorbed in the body), this will be footnoted in summary tables and will not be included in 
the calculation of summary statistics or statistical analyses.
6. ANALYSES AND SUMMARIES
6.1. Primary Endpoint(s)
6.1.1. Pharmacokinetic Endpoints
The mixed effects model described in Section 5.2 will be applied to AUC and Cmax. The 
plasma PK parameters in Table 2 will be summarized descriptively by treatment, as 
applicable, in accordance with Pfizer data standards. AUClast and Cmax for EE and LN 
individual participant parameters will be plotted by treatment. Plasma concentrations will be 
listed and summarized descriptively by nominal PK sampling time and treatment. Individual 
participant and median profiles of the plasma concentration-time data will be plotted by 
treatment using actual and nominal times respectively. Median profiles will be presented on 
both linear-linear and log-linear scales.
Blood samples for PK analysis of EE and LN will be taken according to the Schedule of 
Activities given in the protocol.
The following PK parameters (shown in Table 6) will be calculated for EE and LN (if 
possible) from the concentration-time data using standard noncompartmental methods:
Table 6.
Noncompartmental PK Parameters
PK Parameter
Analysis Scale
EE
LN
Cmax
ln, R
A, D
A, D
Tmax
R
D
D
AUClast
ln, R
A, D
A, D
AUCinf*
ln, R
A, D
A, D
CL/F*
R
D
D
PTR
R
D
D
t1/2*
R
D
D
Key: A=analyzed using statistical model, D=displayed with descriptive statistics, ln=natural-log transformed, 
R=raw (untransformed), NA=not applicable; *=if data permits, Cmax= Maximum plasma concentration during 
the dosing interval; Tmax=Time for Cmax; AUClast=Area under the plasma concentration-time profile from time 


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zero to the time of the last quantifiable concentration (Clast); AUCinf =Area under the plasma concentration-time 
profile from time zero extrapolated to infinite time, and dose normalized AUCinf; CL/F=Apparent Clearance; 
PTR=Peak-to-trough ratio; t1/2=Terminal elimination half life.  
Table 7.
PK Parameters to be Summarized Descriptively by Treatment
Parameter
Summary Statistics
Cmax
AUClast
AUCinf *
CL/F *
PTR
N, arithmetic mean, median, cv%, standard deviation, minimum, 
maximum, geometric mean and geometric cv%.
Tmax
N, median, minimum, maximum.
t1/2 *
N, arithmetic mean, median, cv%, standard deviation, minimum, 
maximum.
* If data permit.
Box and whisker plots for individual participantparticipant parameters (Cmax, AUClast, and 
AUCinf ,) will be presented by treatment (R vs T as described in Table 4) and overlaid with 
geometric means. There will be a summary table each for OC (EE and LN) presenting all PK 
parameters. 
Supporting data from the estimation of t½ will be listed by treatment: terminal phase rate 
constant (kel); goodness of fit statistic from the log-linear regression (r2); and the first, last, 
and number of time points used in the estimation of kel.  This data may be included in the 
clinical study report.
Presentations for OC (EE and LN) concentrations will include:

A listing of all concentrations sorted by participant ID, period and nominal time 
postdose. The concentration listing will also include the actual times. Deviations from 
the nominal time will be given in a separate listing.

A summary of concentrations by treatment and nominal time postdose, where the set 
of statistics will include n, mean, median, standard deviation, coefficient of variation 
(cv), minimum, maximum and the number of concentrations above the lower limit of 
quantification.

Median concentration time plot (on both linear and semi-log scales) against nominal 
time post dose for reference vs test (treatment R vs T as described in Table 4). Test
and reference lines and points will be represented by different colors.


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
Mean (±90%CI) concentration time plot (on both linear and semi-log scales) against 
nominal time post dose for reference vs test (treatment R vs T). Test and reference 
lines and points will be represented by different colors.

Individual concentration time plot (on both linear and semi-log scales) against actual 
time post dose for reference vs test (R vs T Table 4). Test and reference lines and 
points will be represented by different colors.

Individual concentration time plots by treatment (on both linear and semi-log scales) 
against actual time postdose (there will be separate spaghetti plots for each treatment 
per scale).

Individual concentration time plots by participant (on both linear and semi-log scales) 
against actual time postdose [there will be separate plots for each participant 
(containing all treatments) per scale].
6.2. Safety Summaries and Analyses
All safety analyses will be performed on the safety population and summarized in accordance 
with Pfizer Data Standards. 
All clinical AEs, SAEs, TEAEs, withdrawal due to AEs, ECGs, vital signs and safety 
laboratory data will be reviewed and summarized on an ongoing basis during the study to 
evaluate the safety of participants. 
Safety data will be summarized descriptively through appropriate data tabulations, 
descriptive statistics, categorical summaries, and graphical presentations, where appropriate. 
Categorical outcomes (eg, AEs) will be summarized by participant counts and percentage. 
Continuous outcome (eg, blood pressure, pulse rate, etc.) will be summarized using N, mean, 
median, standard deviation, etc. Change from baseline (CFB) in laboratory data, and vital 
signs will also be summarized. Participant listings will be produced for the safety endpoints 
accordingly.
6.2.1. Adverse Events
Adverse events will be reported in accordance with the sponsor reporting standards.
6.2.2. Laboratory Data
Laboratory data will be listed and summarized by treatment in accordance with the sponsor 
reporting standards. Baseline is as defined in Section 3.5.2.


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6.2.3. Vital Signs
Absolute values and changes from baseline in supine systolic and diastolic blood pressure 
and pulse rate will be summarized by treatment in accordance with the sponsor reporting 
standards. Tables will be paged by parameter. Baseline is as defined in Section 3.5.3.
Mean changes from baseline with corresponding standard deviations for supine systolic and 
diastolic blood pressure and pulse rate for each treatment will be plotted against time 
post-dose. 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 absolute values and changes from baseline for vital signs will also be summarized 
descriptively by treatment using categories as defined in Appendix 1. Numbers and 
percentages of participants meeting the categorical criteria will be provided. All planned and 
unplanned post-dose timepoints will be counted in these categorical summaries. All values 
meeting the criteria of potential clinical concern will be listed.
6.2.4. Electrocardiograms
ECG
Absolute values in QT, heart rate, QTcB, QTcF, PR and QRS will be summarized by 
treatment in accordance with the sponsor reporting standards. Tables will be paged by 
parameter. Baseline is as defined in Section 3.5.4.
Maximum increase from baseline for QTcB, QTcF, heart rate, QT, PR and QRS will be 
summarized by treatment in accordance with the sponsor reporting standards. 
ECG endpoints (QTcB, QTcF, PR and QRS) will also be summarized descriptively by 
treatment, using categories as defined in Appendix 1 (for QTc these correspond to ICH 
E141). Numbers and percentages of participants meeting the categorical criteria will be 
provided. All planned and unplanned post-dose timepoints will be counted in these 
categorical summaries. All values meeting the criteria of potential clinical concern will be 
listed.
Listings of participants with any single post-dose value ≥500 msec will also be produced for 
QTcF.
7. INTERIM ANALYSES
No formal interim analysis will be conducted for this study. As this is an open-label study, the 
sponsor may conduct unblinded reviews of the data during the course of the study for the 
purpose of safety assessment, facilitating PK/PD modeling, and/or supporting clinical 
development.


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


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9. APPENDICES
Appendix 1. SAS CODE FOR ANALYSES
An example of the PROC MIXED code is provided below:
proc mixed data=tab.pk;
class trt participant;
model l&var= trt/ ddfm=KR;
random participant /participant=participant;
lsmeans trt /cl alpha=0.1;
estimate 'Test vs Reference' trt -1  1  /cl alpha=0.1;
ods 'Estimates' out=est&var;
ods 'lsmeans' out=ls&var;
ods 'covparms' out=cov&var;
ods 'tests3' out=tst&var;
run;
/* Letter assignments for treatments (trt) within the estimate statement above are as follows;
     (R (OC) = Reference; T (PF-06650833+OC) = Test)  */;


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Appendix 2. Categorical Classes for ECG and Vital Signs of Potential Clinical Concern
Categories for QTcF
Degree of Prolongation
Mild (msec)
Moderate (msec)
Severe (msec)
Absolute value
>450-480
>480-500
>500
Increase from baseline
30-60
>60
Categories for PR and QRS
PR (ms)
max. ≥300 
PR (ms) increase 
from baseline
Baseline >200 
and max. 
≥25% increase
Baseline ≤200 and 
max. ≥50% 
increase
QRS (ms)
max. ≥140
QRS (ms) increase 
from baseline
≥50% increase
Categories for Vital Signs
Systolic BP (mm Hg)
min. <90
Systolic BP (mm Hg) 
change from baseline
max. decrease ≥30
max. increase ≥30
Diastolic BP (mm Hg)
min. <50
Diastolic BP (mm Hg) 
change from baseline
max. decrease ≥20
max. increase ≥20
Supine pulse rate (bpm)
min. <40
max. >120
Measurements that fulfill these criteria are to be listed in the clinical study report.


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Appendix 3. List of Abbreviations
Abbreviation
Term
AUCinf
area under the plasma concentration-time profile from time 0 
extrapolated to infinite time
AUClast
area under the plasma concentration-time profile from time zero to the 
time of the last quantifiable concentration (Clast)
BLQ
below the limit of quantification
BP
blood pressure
Clast
last quantifiable concentration
Cmax
maximum plasma concentration during the dosing interval
CFB
change from baseline
CI
confidence interval
CL/F
apparent clearance
CRU
clinical research unit
CV
coefficient of variation
ECG
electrocardiogram
EE
ethinyl estradiol
ICD
informed consent document
ID
identification
kel
terminal phase rate constant
ICH
International Council for Harmonisation of Technical Requirements for 
Pharmaceuticals for Human Use
LLQ
lower limit of quantitation
LN
levonorgestrel
MR
modified release
NC
Not calculated
ND
not done
NS
no sample
OC
oral contraceptive
PD
pharmacodymic
PI
principal investigator
PK
pharmacokinetic
PO
by mouth
PTR
peak-to-trough ratio
QD
once daily
QTc
corrected QT
QTcF
corrected QT (Fridericia method)
r2
the goodness-of-fit statistic from the regression
SAP
statistical analysis plan
SAE
serious adverse event
Tmax
Time for Cmax


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Abbreviation
Term
t½
terminal elimination half-life
TEAE
treatment emergent adverse event