Clinical trial NCT04413617
Conditions: Rheumatoid Arthritis
Keywords: Rheumatoid Arthritis
Sponsor: Pfizer
Start date: 2020-07-29; Completion date: 2022-02-07
Enrollment: 460 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
Dual objectives of increased efficacy compared to currently available SoC RA drugs and maintaining a favourable benefit - risk relationship.

Detailed description:

Arms: arm 1: None arm 2: None arm 3: None arm 4: None arm 5: None
Interventions: intervention 1: PF-06650833 intervention 2: PF-06651600 intervention 3: Tofacitinib
Intervention descriptions: intervention 1: 400 mg intervention 2: 100 mg intervention 3: 11 mg

Protocol documents:
Prot_000.pdf: 
PF-06650833, PF-06651600, Tofacitinib (CP-690,550)
Protocol B7921023
Final Protocol Amendment 3, 10 February 2022
PFIZER CONFIDENTIAL
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A 24-WEEK RANDOMIZED, DOUBLE-BLIND, PARALLEL GROUP, ACTIVE 
COMPARATOR, MULTICENTER STUDY TO ASSESS THE EFFICACY AND 
SAFETY OF PF-06650833, PF-06651600 (RITLECITINIB) AND TOFACITINIB 
ALONE AND IN COMBINATION IN PARTICIPANTS WITH 
MODERATELY-SEVERELY ACTIVE RHEUMATOID ARTHRITIS WITH AN 
INADEQUATE RESPONSE TO METHOTREXATE
Investigational Product Number:
PF-06650833; PF-06651600; 
CP-690550 MR
Investigational Product Name:
N/A; ritlecitinib; tofacitinib (Xeljanz®)
United States (US) Investigational New 
Drug (IND) Number:
European Clinical Trials Database 
(EudraCT) Number:
2019-002676-14
Protocol Number:
B7921023
Phase:
Phase 2
Short Title: A Study to Assess the Efficacy and Safety of PF-06650833, PF-06651600
(ritlecitinib), and Tofacitinib Alone and in Combination in Active Rheumatoid Arthritis
This document and accompanying materials contain confidential information belonging to Pfizer.  Except as 
otherwise agreed to in writing, by accepting or reviewing these documents, you agree to hold this 
information in confidence and not copy or disclose it to others (except where required by applicable law) or 
use it for unauthorized purposes.  In the event of any actual or suspected breach of this obligation, Pfizer 
must be promptly notified.
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Protocol Amendment Summary of Changes Table
Document History
Document
Version Date
Summary of Changes and Rationale
Amendment 3
10 February 2022
The protocol is amended to include revisions to the 
estimands and statistics sections of the protocol (as 
well as administrative changes documented in 
PACLs) that were needed for reporting purposes 
and to support updates to the data analysis and 
reporting plan for programming.
•
Synopsis and Section 3 updated.
•
Synopsis text updated.
Rationale: per PACL text corrected to delete
repetitive sentence corresponding to 
folate/folinic acid discontinuation.
•
Section 2.1 updated.
Rationale: per PACL text corrected to indicate 
that both combination arms (not 1 combination) 
will be compared to tofacitinib.
•
Section 2.2.5.3 text corrected.   
Rationale: per PACL corrected the Investigator 
Brochure’s “b” to large cap.  
•
Synopsis and Section 3: clarified that the table 
of objectives, endpoints and estimands includes 
key estimands and additional supportive 
estimands will be described in the SAP.
Rationale: allows inclusion supportive 
estimands into SAP.
Modified the evaluation of estimands E1,E2,E3 
so that these use the intent to treat (treatment 
policy) approach. The approach compares 
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Final Protocol Amendment 3, 10 February 2022
PFIZER CONFIDENTIAL
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treatment efficacy across the treatment groups 
irrespective of the study participant's 
compliance with study treatment and use of 
concomitant medications. The effects of these 
post-randomization (intercurrent) events on the 
evaluation of treatment efficacy will be
explored in the sensitivity analyses. The 
sensitivity analyses will be described in SAP.
Rationale: make the analyses identical to the 
analyses planned in the forthcoming Phase 3 
study.
Replaced the estimation of the expected ratio of 
proportions in the analysis of secondary binary 
outcomes by the estimation of the expected 
difference of proportions. The comparison of 
the ratios of proportions of responders is 
retained for the key secondary outcome 
(DAS28-CRP remission at Week 24).
Rationale: This comparison is preferable for the 
outcomes (eg, ACR 90) where the observed 
proportions of responders may be low. 
•
Sections 2, 2.2 and 2.2.2 text corrected.
Rationale: per PACL corrected the error
“JAK3/TEC” to “JAK3” since tofacitinib does 
not inhibit TEC kinases.
•
Section 2.2.5.2 corrected text: ….(5) change in 
neutrophil counts; (6) decreased platelet count; 
(7) alterations in the lipid profile; and
(8) dermatologic effects (rash/acne);….. .
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Final Protocol Amendment 3, 10 February 2022
PFIZER CONFIDENTIAL
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Rationale: per PACLcorrected error in text.
•
Section 4.1 deleted “study intervention”. 
Rationale: per PACL text corrected.
•
Section 6.5.2.1 corrected “desosumab” to 
“denosumab”.
Rationale: per PACL text correction.
•
Section 9.1: Updated the description of key 
estimands (E1,E2,E3) replacing earlier version 
of the description.
Rationale: make the analyses identical to the 
ones planned for the forthcoming Phase 3 study. 
•
Section 9.2: Updated the text for the key 
secondary outcome so that it matches the 
updated definition of the key secondary 
estimand E2.
Rationale: support consistency with 
Sections 9.1, 9.4.1.
•
Section 9.3: Removed populations for the 
censored mITT and composite analysis. 
Rationale: these populations and corresponding 
data sets are no longer needed for the analyses 
described in the protocol.
•
Section 9.4.1: Updated the description of the 
efficacy analyses to match the updates in the 
estimands.
Rationale: support consistency with 
Sections 9.1, 9.4.1.
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Updated the statistical inference method used in 
the analysis of key secondary outcome. The 
exact method will replace the method based on 
normal approximation. 
Rationale: updated approach will be more 
precise if the numbers of responders at Week 24 
are small.
•
Section 9.4.2 removed 3 tier safety analysis
•
For consistency ‘Subject’ changed to ‘study 
participant’ throughout the protocol.
Amendment 2
07 July 2021
•
Synopsis, Study Design, Section 4.1 and 5.1 
(inclusion #7): methotrexate (MTX)
discontinuation and prohibition clarification.
Rationale: text clarification. 
•
Synopsis and Section 4.1: folinic acid intake
clarification.
Rationale: text clarification.
•
Synopsis and Section 3: clarified objectives, 
estimands and endponits text.
Rationale: text clarification. 
•
Section 1.3 Schedule of Activity, footnote “i”:
updated to include Rheumatoid Factor (RF) in 
the list of labs that may be repeated once during 
the screening period. 
Rationale: to correct omission of RF from the 
list of labs.
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•
Section 1.3 Schedule of Activity, footnote “k”:
revised to include a urine culture when urine 
microsopy is suggestive of infection. 
Rationale: to clarify procedure for collecting 
urinalysis samples. 
•
Section 2.2.5.2: PF-06651600 updated the 
clinical overview summary.
Rationale: to align with the PF-06651600 
Dec 2020 Investigator’s Brochure.
•
Section 2.2.5.3: Tofacitinib (CP-690550, 
Xeljanz®) updated the clinical overview 
summary.
Rationale: to align with the Tofacitinib 
Apr 2020 Investigator’s Brochure.
•
Section 2.3: added new risk text for tofacitinib.
Rationale: reflects emerging safety information 
from A3921133 provided as a Provision of 
Critical Safety Information to RAs, 
investigators, ECs.
•
Section 4.1: updated to clarify the study design.
Rationale: text clarification.
•
Section 4.2.3 title revised.
Rationale: to reflect changes to the study 
design.
•
Section 5.1, inclusion #4: clarified to allow 
participants to enroll into the study provided 
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that re-testing Erythrocyte Sedimentation Rate 
(ESR) result is >28 mm/h.
Rationale: text clarification.

Section 5.2, exclusion #3 (b, c, d, e) are added 
to clarify exclusion of participants with 
COVID-19. 
Rationale: this update is to clarified that 
participants with an active infection due to 
SARS-CoV-2 are excluded from randomization 
consistent with the exclusion for other active 
infections.

Section 5.2, exclusion #3 (f) updated.
Rationale: to clarify and add the criterion of 
60 days within “randomization” for exclusion of 
participants with infection requiring 
hospitalization, parenteral antimicrobial 
therapy.

Section 5.2, exclusion #3 (h): clarified the 
herpes zoster exclusion language. 
Rationale: text clarification.

Section 5.2: added exclusion criterion #21 to 
exclude participants with history of any 
medical condition associated with an increased 
risk of venothromboembolism (eg, paroxysmal 
atrial fibrillation) unless properly 
anti-coagulated.
Rationale: to minimize potential risk of 
participants developing a major adverse cardiac 
event.

Section 5.2, exclusion #24: clarified that 
participants with any known “history” of 
coagulopathy or hypercoagulation syndrome 
are excluded.


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Rationale: to clarify exclusion criteria 
clarification.

Section 5.2, exclusion #27: deleted the word 
“recent” in reference to prohibited DMARDs.
Rationale: corrected text.

Section 5.2, exclusion #33: clarified that 
participants with an electrocardiogram (ECG) 
performed prior to randomization that 
demonstrates atrial fibrillation are excluded 
unless subject is on a stable, therapeutic dose of 
non-excluded anti-coagulant. 
Rationale: to minimize potential risk of 
participants developing a major adverse cardiac 
event.

Section 6: text clarified. 
Rationale: text clarification.

Section 6.1.1, Table 1 updated to clarify that
ritlecitinib tablets are immediate release. 
Rationale: text clarification.

Section 6.4: added the word “treatment” that is 
missing from the study intervention compliance 
paragraph.
Rationale: corrected omission of text. 

Section 6.5.2.1: created new subsection related 
to concomitant medications used to increase 
bone mineral density. 
Rationale: clarification of text related to dosing 
of permitted medications.

Section 6.5.2.3: corrected a discrepancy in the 
wording of “background arthritis therapy”.
Rationale: text corrected. 


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•
Sections 6.5.3.3 and 6.5.3.4: updated to specify 
that the use of substrates of CYP3A4 and 
BCRP be avoided within 4 weeks or 
5 half-lives (whichever is longer) prior to the 
Randomization Visit (Visit 2) and during the 
trial.
Rationale: potential to increase exposure when 
co-administered with PF-06651600.
•
Section 7.1: clarified that when IP is 
permanently discontinued, the participant will 
enter the required 4-week FU period.
Rationale: text clarification.
•
Section 7.2: clarified that interruption in dosing 
of study treatment for more than 7 consecutive 
days may be due either to lack of compliance or 
in response to an AE. 
Rationale: clarified guidance about the 
definition of study treatment interruption.
•
Section 8.1.1.1: clarified the definition of 
blinded joint assessor.
Rationale: text clarification. 
•
Sections 8.1.2.1 and Appendix 10.10: clarified 
that the Disease Activity Scores DAS28-CRP 
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Rationale: provided detail about DAS28-CRP 
•
Section 8.2.5.3: clarified that the investigators 
will complete the “rash assessment CRF” not a 
questionnaire.
Rationale: text clarification.
•
Section 8.2.5.3: corrected and replaced the 
word “will” with “may” as the study team may 
consult an independent dermatologist to review 
all relevant data and summarize the data at the 
end of the study.
Rationale: text corrected.
•
Section 8.3.6: added new adjudication 
committees that will be used in the study. 
Rationale: to enhance assessment of targeted 
AEs.
•
Sections 8.3.7 and 8.4: corrected and replaced 
the word “immediately” with “within 
24 hours”.
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Rationale: to align with Pfizer May 2020 
protocol template updates. 

Section 8.4: corrected and replaced “until 
investigational products can no longer be 
detected systemically (at least 2 days)” with 
“for at least 5 half-lives or 28 calendar days 
after the overdose of investigational products 
(whichever is longer)”.
Rationale: to align with Pfizer May 2020 
protocol template updates.

Section 8.11: corrected and replaced the word 
“jaundiced participant” with “jaundiced 
person”.
Rationale: text corrected.  

Section 9.1: corrected the definition of the 
noncompliant participant.
Rationale: text corrected. 

Section 9.2: described the sample size 
estimation in the updated design. 
Rationale: to describe the sample size 
estimation in the updated design and clarify that 
additional participants may be enrolled into the 
study if the dropout rate of enrolled participants 
exceed 18% due to the COVID-19 pandemic. 

Section 9.3: corrected a discrepancy in the 
definition of non-responders.
Rationale: text corrected.

Section 10.2 Appendix 2: added “urine culture” 
test that is missing from Table 3 and updated 
footnote ‘e’.
Rationale: corrected Table 3.


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•
Section 10.2 Appendix 2: deleted ‘Microscopy’ 
test from Table 3.
Rationale: listed twice.  
•
Section 10.3.2:”Definition of the SAE, 
section e updated”. 
Rationale: to align with Pfizer May 2020 
protocol template updates.
•
Section 10.3.3: Recording/Reporting and 
Follow up of AEs and/or SAEs updated.
Rationale: text was accidently deleted.
•
Section 10.3.4: Reporting of SAEs.
Rationale: section reordered.
•
Section 10.4.4: deleted “injectable” from 
contraception highly effective methods that are 
user dependent.
Rationale: to align with Pfizer May 2020 
protocol template updates.
Rationale: text clarification.
•
Section 10.11, Appendix 11 updated.
Rationale: included a list of CYP3A4 substrates 
with NTI prohibited concomitant medications.
•
Section 10.12: adjusted the list of corticosteroid 
equivalents to a 7.5 mg dose of prednisone.
Rationale: corrected the list of corticosteroid 
equivalents. 
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
Section 10.13: Appendix 13 is added to the 
protocol.
Rationale: to provide guidance on the 
alternative study measures to be followed 
during public emergencies, including the 
COVID-19 pandemic.

Section 10.14: Appendix 14, abbreviation table 
updated.

JAK3 changed to JAK3/TEC throughout.
Rationale: text corrected.  
Amendment 1
08 April 2020
To comply with Health Canada Information
Request, the contraception requirement in 
Appendix 10.4.2 is updated to the use of two forms 
of contraception regardless of the user dependency
of the method(s) for participants enrolled at 
Canadian sites.  This includes at least one form of 
highly effective and one effective method of 
contraception. 
Original 
protocol
22 October 2019
Not applicable (N/A)
This amendment incorporates all revisions to date, including amendments made at the 
request of country health authorities and IRBs/ECs. 


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TABLE OF CONTENTS
LIST OF TABLES...................................................................................................................20
LIST OF FIGURES .................................................................................................................20
1. PROTOCOL SUMMARY...................................................................................................21
1.1. Synopsis ..................................................................................................................21
1.2. Schema ....................................................................................................................32
1.3. Schedule of Activities (SoA)...................................................................................33
2. INTRODUCTION ...............................................................................................................39
2.1. Study Rationale .......................................................................................................39
2.2. Background .............................................................................................................40
2.2.1. PF-06650833...............................................................................................41
2.2.2. Tofacitinib...................................................................................................41
2.2.3. PF-06651600...............................................................................................42
2.2.4. Nonclinical Overview.................................................................................42
2.2.5. Clinical Overview.......................................................................................43
2.2.5.1. PF-06650833 .............................................................................43
2.2.5.2. PF-06651600 .............................................................................44
2.2.5.3. Tofacitinib (CP-690550, Xeljanz®)...........................................45
2.3. Benefit: Risk Assessment........................................................................................46
3. OBJECTIVES, ESTIMANDS, AND ENDPOINTS ...........................................................47
4. STUDY DESIGN.................................................................................................................55
4.1. Overall Design.........................................................................................................55
4.1.1. Study Rationale...........................................................................................57
4.2. Justification for Dose ..............................................................................................58
4.2.1. Dose Rationale for PF-06650833 400 mg MR QD ....................................59
4.2.2. Dose Rationale for PF-06651600 100 mg QD ...........................................60
4.2.3. Dose Rationale for Tofacitinib 11 mg MR QD ..........................................61
4.2.4. Dose Rationale for PF-06650833 400 mg MR QD in Combination 
with PF-06651600 100 mg IR QD or Tofacitinib 11 mg MR QD...................61
4.3. End of Study Definition ..........................................................................................62
5. STUDY POPULATION......................................................................................................62
5.1. Inclusion Criteria.....................................................................................................62


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5.2. Exclusion Criteria....................................................................................................64
5.3. Randomization Criteria ...........................................................................................70
5.4. Lifestyle Considerations..........................................................................................70
5.4.1. Contraception..............................................................................................70
5.5. Screen Failures ........................................................................................................70
6. STUDY INTERVENTION..................................................................................................71
6.1. Study Intervention(s) Administered........................................................................71
6.1.1. Administration............................................................................................72
6.2. Preparation/Handling/Storage/Accountability ........................................................73
6.2.1. Preparation and Dispensing........................................................................74
6.3. Measures to Minimize Bias: Randomization and Blinding.....................................74
6.3.1. Allocation to Investigational Product .........................................................74
6.3.2. Breaking the Blind......................................................................................74
6.4. Study Intervention Compliance...............................................................................75
6.5. Concomitant Therapy..............................................................................................75
6.5.1. Rescue Treatment of RA ............................................................................75
6.5.2. Permitted Concomitant Medications ..........................................................76
6.5.2.1. Osteoporosis Drugs ...................................................................76
6.5.2.2. Hormonal Contraception...........................................................77
6.5.2.3. Background Arthritis Therapy ..................................................77
6.5.3. Prohibited Concomitant Medications .........................................................78
6.5.3.1. Strong and Moderate Inhibitors and Inducers of CYP3A4.......78
6.5.3.2. Strong Inhibitors/Inducers of BCRP .........................................78
6.5.3.3. Substrates of CYP3A4 ..............................................................78
6.5.3.4. Substrates of BCRP...................................................................78
6.5.3.5. Other Prohibited Concomitant Medications..............................78
6.5.4. Prohibited Background Rheumatoid Arthritis Therapies ...........................78
6.5.4.1. Disease Modifying Antirheumatic Drugs (DMARDs) .............78
6.5.4.2. Other Rheumatoid Arthritis Drugs............................................79
6.6. Dose Modification...................................................................................................80
6.7. Intervention After the End of the Study..................................................................80


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7. DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL...........................................................................80
7.1. Discontinuation of Study Intervention ....................................................................80
7.2. Participant Discontinuation/Withdrawal From the Study.......................................80
7.3. Lost to Follow-up....................................................................................................82
8. STUDY ASSESSMENTS AND PROCEDURES...............................................................83
8.1. Efficacy Assessments..............................................................................................84
8.1.1. American College of Rheumatology (ACR) Assessments.........................84
8.1.1.1. Tender/Painful Joint Count (68)................................................84
8.1.1.2. Swollen Joint Count (66)...........................................................85
8.1.1.3. Tender and Swollen Joint Counts (28)......................................85
8.1.1.4. Physician’s Global Assessment (PhGA) of Arthritis ................85
8.1.1.5. C-Reactive Protein (CRP).........................................................85
8.1.2. Composite Efficacy Assessments Derived from the ACR Core 
Dataset..............................................................................................................86
8.1.2.1. Disease Activity Score (DAS) Assessments .............................86
8.1.2.2. ACR Responder Analysis..........................................................86
8.1.4. Rater Qualifications....................................................................................88
8.1.5. Imaging Assessments/MRI of Hand/Wrist.................................................89
8.2. Safety Assessments .................................................................................................90
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8.2.1. Creatinine and estimated Glomerular Filtration Rate.................................90
8.2.2. Clinical Safety Laboratory Tests ................................................................90
8.2.3. Viral Surveillance .......................................................................................91
8.2.4. Medical History ..........................................................................................91
8.2.5. Physical Examinations................................................................................91
8.2.5.1. Complete Physical Examination ...............................................91
8.2.5.2. Targeted Physical Examination.................................................91
8.2.5.3. Dermatology/Skin .....................................................................92
8.2.6. Vital Signs ..................................................................................................93
8.2.7. Audiogram ..................................................................................................93
8.2.8. Electrocardiograms.....................................................................................94
8.2.9. Pregnancy Testing ......................................................................................94
8.3. Adverse Events and Serious Adverse Events..........................................................94
8.3.1. Time Period and Frequency for Collecting AE and SAE Information.......95
8.3.1.1. Reporting SAEs to Pfizer Safety...............................................95
8.3.1.2. Recording Nonserious AEs and SAEs on the CRF...................96
8.3.2. Method of Detecting AEs and SAEs ..........................................................96
8.3.3. Follow-up of AEs and SAEs.......................................................................96
8.3.4. Regulatory Reporting Requirements for SAEs...........................................96
8.3.5. Exposure During Pregnancy or Breastfeeding, and Occupational 
Exposure ..........................................................................................................97
8.3.5.1. Exposure During Pregnancy......................................................97
8.3.5.2. Exposure During Breastfeeding ................................................97
8.3.5.3. Occupational Exposure .............................................................97
8.3.6. Adjudication of Targeted Adverse Events..................................................97
8.3.6.1. Major Adverse Cardiovascular Events (MACE).......................98
8.3.6.2. Opportunistic and Serious Infections ........................................98
8.3.6.3. Elevated Liver Enzymes and Liver Injury ................................98
8.3.6.4. Malignancies .............................................................................98
8.3.6.5. Neurosensory Adverse Events ..................................................98
8.3.6.6. Interstitial Lung Disease (ILD) .................................................98
8.3.7. Medication Errors .......................................................................................98


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8.4. Treatment of Overdose............................................................................................99
8.6. Pharmacodynamics................................................................................................101
8.7. Genetics.................................................................................................................101
8.7.1. Specified Genetics ....................................................................................101
8.7.2. Banked Biospecimens for Genetics..........................................................101
8.8. Biomarkers ............................................................................................................101
8.8.1. Specified Gene Expression (RNA) Research ...........................................101
8.8.2. Specified Protein Research.......................................................................101
8.8.2.1. Anti-Citrullinated Protein Antibodies (ACPA).......................101
8.8.2.2. Rheumatoid Factor (RF)..........................................................101
8.8.2.3. Interferon Gamma-Induced Protein 10 (IP-10).......................102
8.8.2.4. Immunoglobulin Subtypes ......................................................102
8.8.2.5. Serum for Exploratory Analysis..............................................102
8.8.3. Specified Metabolomic Research .............................................................102
8.8.4. Banked Biospecimens for Biomarkers .....................................................102
8.9. Health Economics .................................................................................................102
8.10. Triggered Requirements......................................................................................103
8.11. Guidelines for Monitoring and Discontinuations................................................103
9. STATISTICAL CONSIDERATIONS ..............................................................................106
9.1. Estimands and Statistical Hypotheses...................................................................106
9.2. Sample Size Determination...................................................................................107
9.2.1. Power for the Efficacy Evaluation Based on the Primary Outcome ........107
9.2.2. Power for the Efficacy Evaluation Based on the Key Secondary 
Outcome.........................................................................................................107
9.3. Populations for Analysis .......................................................................................108
9.4. Statistical Analyses ...............................................................................................108
9.4.1. Efficacy Analyses .....................................................................................109
9.4.2. Safety Analyses ........................................................................................109
9.4.2.1. Electrocardiogram Analyses....................................................110
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9.5. Interim Analyses ...................................................................................................111
9.5.1. Data Monitoring Committee.....................................................................111
9.6. Safety Adjudication Committees ..........................................................................111
10. SUPPORTING DOCUMENTATION AND OPERATIONAL
CONSIDERATIONS........................................................................................................113
10.1. Appendix 1: Regulatory, Ethical, and Study Oversight Considerations.............113
10.1.1. Regulatory and Ethical Considerations ..................................................113
10.1.1.1. Reporting of Safety Issues and Serious Breaches of the 
Protocol or ICH GCP.......................................................................113
10.1.2. Financial Disclosure ...............................................................................114
10.1.3. Informed Consent Process ......................................................................114
10.1.4. Data Protection .......................................................................................115
10.1.5. Dissemination of Clinical Study Data ....................................................115
10.1.6. Data Quality Assurance ..........................................................................117
10.1.7. Source Documents..................................................................................118
10.1.8. Study and Site Closure............................................................................118
10.1.9. Publication Policy...................................................................................119
10.1.10. Sponsor’s Qualified Medical Personnel ...............................................119
10.2. Appendix 2: Clinical Laboratory Tests ...............................................................121
10.3. Appendix 3: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting ....................................................................122
10.3.1. Definition of AE .....................................................................................122
10.3.2. Definition of SAE...................................................................................123
10.3.3. Recording/Reporting and Follow-up of AEs and/or SAEs.....................124
10.3.4. Reporting of SAEs..................................................................................127
10.4. Appendix 4: Contraceptive Guidance and Collection of Pregnancy 
Information..............................................................................................................129
10.4.1. Male Participant Reproductive Inclusion Criteria..................................129
10.4.2. Female Participant Reproductive Inclusion Criteria...............................129
10.4.3. Woman of Childbearing Potential (WOCBP) ........................................130
10.4.4. Contraception Methods...........................................................................131
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10.5. Appendix 5: Genetics..........................................................................................134
10.6. Appendix 6: Liver Safety: Suggested Actions and Follow-up Assessments ......135
10.7. Appendix 7: ECG Findings of Potential Clinical Concern .................................137
10.8. Appendix 8: 2010 ACR/EULAR Classification Criteria for Rheumatoid 
Arthritis (RA) ..........................................................................................................139
10.9. Appendix 9: Criteria for Classification of Functional Status in Rheumatoid 
Arthritis....................................................................................................................141
10.10. Appendix 10: Disease Activity Score DAS (DAS28-CRP),
 
Assessments.............................................................................................................142
10.11. Appendix 11: Prohibited Concomitant Medications.........................................143
10.12. Appendix 12: Oral Corticosteroid Equivalents .................................................145
10.13. Appendix 13: Alternative Measures During Public Emergencies.....................146
10.13.1. Telehealth Visits...................................................................................146
10.13.2. Laboratory Testing................................................................................147
10.13.3. Electrocardiograms...............................................................................148
10.13.4. Study Intervention ................................................................................148
10.13.5. Adverse Events and Serious Adverse Events.......................................148
10.13.6. Independent Oversight Committees .....................................................148
10.14. Appendix 14: Abbreviations .............................................................................149
11. REFERENCES ................................................................................................................155
LIST OF TABLES
Table 1.
Dosing and Administration of Investigational Products...........................72
Table 2.
Management of Dermatological Events ...................................................92
Table 3.
Characterization of the Estimands..........................................................107
Table 4.
Protocol-Required Safety Laboratory Assessments ...............................121
LIST OF FIGURES
Figure 1.
Schema......................................................................................................57
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1. PROTOCOL SUMMARY 
1.1. Synopsis 
Short Title:
A STUDY TO ASSESS THE EFFICACY AND SAFETY OF PF-06650833,
PF-06651600, AND TOFACITINIB ALONE AND IN COMBINATION IN ACTIVE 
RHEUMATOID ARTHRITIS
Rationale
Rheumatoid arthritis (RA) is characterized by joint inflammation and destruction, 
progressive disability, and adverse psychological effects.  Disease-modifying antirheumatic 
drugs (DMARDs) are the standard treatments for RA.  However, despite the considerable list 
of approved treatments for RA, disease remission (or even low disease activity, [LDA]) is 
achieved in only a minority of patients and none completely cures the disease. Clearly, there 
is a need for therapeutics with enhanced efficacy that drive a higher proportion of patients to 
LDA and remission. It is also becoming evident, given the results with biologic and newer 
advanced therapeutic DMARDs administered alone or in combination with methotrexate 
(MTX), that such levels of activity may be difficult to achieve with drugs targeting a single 
pathway or cytokine. Combinations of drugs with complementary mechanisms of action 
offer the potential to achieve the goal of improved efficacy without incurring additional 
safety liabilities. 
The aim of the current study is to evaluate two different drug combinations to see if either 
can achieve the dual objectives of increased efficacy compared to currently available 
standard of care RA drugs while maintaining an acceptable safety profile (and therefore an 
overall positive benefit : risk relationship). All of the individual components of the 
combinations being explored in the current study have demonstrated efficacy in RA--either
showing clinical benefit in Phase 2 studies (PF-06650833 and PF-06651600) or having 
completed registration and approval (tofacitinib). The components of the combinations to be 
evaluated, PF-06650833 + tofacitinib and PF-06650833 + PF-06651600, have 
non-overlapping mechanisms of action. Moreover, PF-06650833 and PF-06651600 have 
appeared generally well-tolerated in their Phase 2 studies so have the potential for not having 
increased safety liabilities in combination with each other, or, for PF-06650833 with 
tofacitinib.


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Objectives, Estimands, and Endpoints
Objectives
Endpoints
Estimands***
Primary
Primary
Primary

To compare the efficacy 
of each of 2
combinations 
(PF-06650833 + 
PF-06651600, 
PF-06650833 + 
tofacitinib) individually 
to tofacitinib alone at 
Week 12 in participants 
with moderately -
severely active RA who 
have had an inadequate 
response to MTX.

Change from baseline in 
Disease Activity Score 
(DAS)28-C Reactive 
protein (CRP) at 
Week 12.

E1: 
Evaluates the difference 
across the treatment arms 
in the mean values of 
change from baseline of 
continuous outcome of 
interest. The treatment 
effect is evaluated in the 
population of study 
participants who are 
randomized and treated 
irrespective of their 
compliance  to the 
planned course of 
treatment or use of 
concomitant medications. 
Key Secondary
Key Secondary
Key Secondary

To compare the 
remission rates of each
of 2 combinations 
(PF-06650833 + 
PF-06651600, 
PF-06650833 + 
tofacitinib) individually 
to tofacitinib alone at 
Week 24 in participants 
with moderately -
severely active RA who 
have had an inadequate 
response to MTX.

DAS28-CRP remission 
(<2.6) at Week 24.

E2:
Evaluates the ratio  of the 
probability of response in 
the treatment arm of 
interest to the probability 
of response in the 
tofacitinib treatment arm.
The treatment effect is 
evaluated in the 
population of study 
participants who are 
randomized and treated 
irrespective of their 
compliance to the planned 
course of treatment or use 
of concomitant 
medications.


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Secondary
Secondary
Secondary

To assess the safety of 
PF-06650833, 
PF-06651600, and 
tofacitinib alone and of 
the combinations of 
PF-06650833 with 
PF-06651600 and 
tofacitinib in 
participants with 
moderately - severely 
active RA who have had 
an inadequate response 
to MTX.

Incidence and severity of 
adverse events, serious 
adverse events, and 
withdrawals due to 
adverse events.

Change from baseline in 
clinical laboratory values 
(chemistry, hematology 
parameters).

Change from baseline in 
vital signs (blood 
pressure, pulse rate and 
temperature 
measurements).

Incidences of severe and 
opportunistic infection 
AEs; herpes virus 
infection AEs; clinically 
significant categorical 
increases in hepatic 
enzymes Aspartate 
aminotransferase (AST), 
and Alanine 
aminotransferase (ALT) 
and total bilirubin, and 
potential cases meeting 
Hy’s Law criteria for 
increased risk of drug-
induced liver injury 
[DILI]; major adverse 
cardiovascular events 
(MACE), including 
pulmonary embolism 
(PE) and deep vein 
thrombosis (DVT), 
Cerebrovascular accident 
(CVA); Adverse events 
(AEs) for decreased renal 
function, acute kidney 
injury, clinically 
significant increases in 

There is no defined 
estimand for these 
endpoints. They will be 
analyzed using Pfizer data 
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serum creatinine (Scr) 
and decreases in 
estimated glomerular 
filtration rate (eGFR).
•
To evaluate other signs 
of clinical efficacy of all 
treatment arms in 
participants with 
moderately - severely 
active RA who have had 
an inadequate response 
to MTX. 
•
Change from baseline in 
DAS28-CRP at 
Week 24.
•
American College of 
Rheumatology (ACR)20, 
ACR 50, ACR 70, and 
ACR 90 responder rates 
at Week 12 and Week 
24. 
•
Change from baseline in 
the Tender/Painful and 
Swollen Joint Count at 
Week 12 and Week 24.
•
Change from baseline in 
the Physician’s Global 
Assessment (PhGA) of 
Arthritis at Week 12 and 
Week 24. 
•
E1 estimand for 
continuous and E3
estimand for binary 
efficacy outcomes.
•
E3: Evaluates the 
differences in probability 
of response of the 
treatment arm of interest 
in comparison to the 
tofacitinib treatment arm.
The treatment effect is 
evaluated in the 
population of study 
participants who are 
randomized and treated 
irrespective of their 
compliance to the planned 
course of treatment or use 
of concomitant 
medications.
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•
To collect blood for the 
potential exploratory 
analyses of 
pharmacodynamic 
activity of PF-06650833, 
PF-06651600, and 
tofacitinib alone and in 
combination with 
PF-06650833 in 
participants with 
moderately - severely 
active RA.
•
Change from baseline: 
anti-citrullinated protein 
antibodies (ACPA), 
rheumatoid factor (RF) 
and Ig levels.
•
Change from baseline of 
Interferon 
Gamma-Induced Protein 
10 (IP-10), if performed.
•
Endpoints may also 
include circulating 
proteins and protein 
fragments.
•
All continuous endpoints 
will be analyzed 
descriptively.  Other 
analyses may be done and 
will be described in the 
statistical analysis plan 
(SAP).
•
All other categorical 
endpoints will be analyzed 
descriptively. Other 
analyses may be done and 
will be described in the 
SAP.
•
To collect banked 
biospecimens for 
exploratory research, 
unless prohibited by 
local regulations or 
ethics committee 
decision.
•
Collection of banked 
biospecimens unless 
prohibited by local 
regulations or ethics 
committee decision.  
•
Not applicable.
•
To evaluate the effects 
of PF-06650833, 
PF-06651600, and 
tofacitinib alone and in 
combination on joint 
inflammation assessed 
by magnetic resonance 
imaging (MRI), in a 
•
Change from baseline in 
Rheumatoid Arthritis 
MRI Score (RAMRIS) 
and exploratory measures 
of joint inflammation
(eg, RAMRIQ, DCE), if 
performed, in hand MRI 
at Weeks 12 and 24.
•
All continuous endpoints 
will be analyzed 
descriptively.  Other 
analyses may be done and 
will be described in the 
statistical analysis plan 
(SAP).
•
All other categorical 
endpoints will be analyzed 
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subset of participants, if 
performed.
descriptively. Other 
analyses may be done and 
will be described in the 
SAP.
* 
Efficacy evaluations that are otherwise classified in the table as primary, key secondary o
 
*** The additional supportive estimands will be described in the SAP.
Overall Design
This is a Phase 2, 24-week, multicenter, randomized, double-blind, 5-arm, parallel group, 
active comparator study to evaluate the efficacy and safety profiles of 2 combinations of 
investigational products (IPs): PF-06650833 coadministered with PF-06651600 
(PF-06650833 + PF-06651600) and PF-06650833 coadministered with tofacitinib 
(PF-06650833 + tofacitinib), as well as the efficacy and safety of each IP individually in the 
absence of background MTX in participants with moderately - severely active RA who have 
had an inadequate response to MTX (MTX-IR).  
Both PF-06650833 and tofacitinib will be administered as modified release (MR) tablets to 
allow for once daily administration.  The study is powered to show statistical superiority of 
the combination to tofacitinib monotherapy at Week 12.
After an up to 28-day screening period, eligible participants will enter a 24-week active 
treatment period after being randomly assigned to one of the 5 treatment groups shown in
Section 1.2 Schema.
All doses will be administered orally once daily in a fasted state (about 4 hours after the last 
and 1.5 hours before the next meal). In order to maintain the blind and minimize bias, all 
participants will receive the same number and types of tablets each day as a mix of active and 
placebo tablets. MTX is to be discontinued (last MTX dose is to occur) during the week 
before randomization on Day 1 and be washed out during the active treatment phase.  The 
MTX washout is intended to reduce the potential for excessive immune suppression and 
additive safety liability. Participants whose regularly scheduled MTX dose would have been
on the day of randomization (Day 1) should not take that dose of MTX.  No further MTX 
dosing is permitted during the active dosing phase of the study.  Participants may restart 
MTX dosing beginning 14 days after the last dose of study intervention. Folate/folinic acid 
taken with MTX may also be discontinued in a manner consistent with local standard of care 
practice.
No changes in the background concomitant steroid dose is allowed during the study.  During 
the active dosing period, no “rescue” treatment is pre-specified. However, limited – duration 
increases in permitted analgesic medication (acetaminophen/paracetamol, nonsteroidal 
anti-inflammatory drugs [NSAIDs], opiates) will be permitted for acute worsening of arthritis 
pain (see Permitted Concomitant Medications, Section 6.5.1 and Section 6.5.2).  Participants, 
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who after at least a 12-week trial on the assigned investigational product have not achieved at 
least a minimal clinical response (as defined by the American College of Rheumatology 
[ACR] 20% response criteria [ACR20]) are to be discontinued from the study treatment and 
begin treatment for their RA according to local standard of care (SoC) practice. The 
Principal Investigator (PI) may also discontinue participants at any time during the study if in 
the PI’s opinion, worsening RA signs and symptoms unresponsive to limited-duration 
increases in analgesic medications requires more urgent advancement of RA treatment.
Additional treatment for participants meeting either of these criteria for discontinuation from 
the study will be provided by the investigator, and upon withdrawal from the study treatment, 
participants will enter a 4-week follow-up period and after which they will have End of 
Study (EOS)/follow-up (FU) visit.  Investigational product will not be provided after the 
participant completes the study.
Number of Participants
A maximum of up to approximately 450 participants will be randomized into the study to 
ensure at least up to approximately 370 participants complete the study through Week 12. 
Intervention Groups and Duration
Participants will be randomly assigned to 1 of the following 5 treatment groups in a 4:4:3:3:4 
ratio (see also study schematic design in Section 1.2): 

PF-06650833 400 mg MR + tofacitinib 11 mg MR.

PF-06650833 400 mg MR + PF-06651600 100 mg.

PF-06650833 400 mg MR.

PF-06651600 100 mg.

Tofacitinib 11 mg MR.
All participants will receive up to 24 weeks of study treatment. 
Data Monitoring Committee: 
An Independent Oversight Committee (IOC) will be constituted and be responsible for 
review of unblinded safety and laboratory data on a regularly scheduled, periodic basis
(eg, after 25%, 50% and 75% of participants have been randomized, and at specified times 
thereafter), as well as on an ad hoc basis at the request of the study team. The IOC may also 
have access to unblinded efficacy data from any interim analyses (if performed) for ongoing 
assessment of overall benefit: risk. 


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For this study, the IOC will be an Internal Review Committee (IRC) comprised of Sponsor 
personnel (at least one of whom is medically qualified and one of whom is a clinical 
statistician) not directly involved in study conduct or in interactions with site personnel or 
participants. The IRC will be responsible for ongoing monitoring of safety of participants in 
the study according to the Charter.  Any recommendations made by the IRC to alter the 
conduct of the study will be forwarded to the Executive Committee for final decisions. 
Pfizer will forward such decisions, which may include summaries of aggregate analyses of 
endpoint events and of safety data that are not endpoints, to regulatory authorities, as 
appropriate.
Statistical Methods
Detailed methodology for summary and statistical analyses of the data collected in this study 
will be documented in a statistical analysis plan (SAP) that will be maintained by the 
Sponsor. 
The primary endpoint is the mean change from baseline DAS28-CRP at Week 12.  The 
primary analysis will use a mixed model repeated measures (MMRM) model applied to all 
post-baseline data up through Week 12 to estimate the effect of the initially randomized 
treatment at Week 12.  The MMRM analysis will contain fixed effect terms for treatment, 
scheduled study visit, baseline DAS28-CRP, treatment by visit interaction, baseline by visit 
interaction.  The model will use an unstructured covariance matrix. The analysis will use the 
mITT analysis set up to Week 12 Missing data will not be imputed for this analysis.  The 
primary analysis comparing the combination arm to the tofacitinib monotherapy arm will be 
done using estimated least squares means at Week 12.  The comparison will be made at the 
one-sided significance level of 0.05 and no adjustment for multiplicity of comparisons will 
be attempted.
The key secondary endpoint is DAS28-CRP remission (DAS28-CRP <2.6) at Week 24. The 
key secondary analysis will estimate the relative risk of DAS28-CRP remission comparing 
each combination arm to the tofacitinib monotherapy arm.
This analysis will use the mITT analysis set and  the non-responder imputation method 
(NRI). The NRI treats missing value of the binary outcome as non-response with the 
exception of the two special cases of the reason for missing data. These special reasons 
include missingness related to the COVID infection (either patient illness or COVID-related 
problem of attending the visit) and missingness when subject attended the visit but some of 
the components for the calculation of the outcome (eg, ACR20) are missing. The 
observations that are missing for these special reasons will be excluded from the calculation 
of the probabilities of response at a given visit. Exact statistical inference will be used.  
The comparison will be made at the one-sided significance level of 0.05. No adjustment for 
multiplicity of comparisons will be attempted.


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One or more interim analyses (IA) may be performed for internal business decision-making 
or sample size reestimation (there is no intention a priori to terminate the study or a treatment 
arm based on the results of the IA).  The final number and timing of any IA, if performed, 
will be defined by the sponsor.
1.2. Schema
All doses are orally administered once daily under fasted conditions
Non-responders (defined as not meeting ACR20 response criteria) by Week 12 (or later) are to be 
discontinued from study.
MR=modified release; MTX=methotrexate; Rand=randomization; FU=follow-up; ACR=American College 
of Rheumatology.  
24 Weeks
ACR20 non-responders at 
Weeks 12, 16, and 20 are to be 
discontinued
12 Weeks
Weeks 
FU
<28 days 
Screening
Rand/
Stop
MTX
PF-06650833 400 mg MR + PF-06651600 100 mg
N =100
PF-06650833 400 mg MR + tofacitinib 11 mg MR
N =100
Tofacitinib 11 mg MR
N = 100
PF-06650833 400 mg MR
N= 75
PF-06651600 100 mg
N = 75


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1.3. Schedule of Activities (SoA)
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.
Protocol Activity
Screening
Treatment Period
FUb/EOS
EWb
Visit Identifier
1
2
3
4
5
6
7
8
9
10
Study Day/Weeka
Screening
Day 1/ 
Baseline
Day 
15 ±2
Day 
29 ±2
Day 
57 ±3
Day 
85 ±3
Day 
113 ±3
Day 
141 ±3
Day 169 End of 
Treatment ±3
Follow-upb
±3
Days
-28 to 0
Week 0
Week 2
Week 4
Week 8
Week 12
Week 16
Week 20
Week 24
Week 28
Informed consent
X
Inclusion/Exclusion Criteria
X
X
Demographics 
X
RA history, Prior RA medicationsc
X
Medical history and prior non RA 
medication historyd
X
Height  
X
Weight
X
X
X
Vital Signs (Pulse, blood pressure), 
temperaturee
X
X
X
X
X
Xe
X
X
X
X
X
Complete Physical Examinationf
X
X
X
Targeted Physical Examinationf
X
X
X
X
X
X
X
X
ECG (12 lead)g
X
X
X
X
X
X
X
X
Chest radiographh
X
Audiogramw
X
X
X
Magnetic resonance imaging (MRI) of 
handx
X
X
X
Laboratory Evaluations
Blood chemistry (fasting), Hematologyi
X
X
X
X
X
X
X
X
X
X
X
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Protocol Activity
Screening
Treatment Period
FUb/EOS
EWb
Visit Identifier
1
2
3
4
5
6
7
8
9
10
Study Day/Weeka
Screening
Day 1/ 
Baseline
Day 
15 ±2
Day 
29 ±2
Day 
57 ±3
Day 
85 ±3
Day 
113 ±3
Day 
141 ±3
Day 169 End of 
Treatment ±3
Follow-upb
±3
Days
-28 to 0
Week 0
Week 2
Week 4
Week 8
Week 12
Week 16
Week 20
Week 24
Week 28
Blood sample for viral surveillance
X
X
X
X
Urinalysis (including, protein creatinine, 
pH color, clarity, specific gravity) with 
microscopy (to be processed at central 
lab)i,k
X
X
X
X
X
X
X
X
X
X
X
Urine pregnancy testl
X
X
X
X
X
X
X
X
X
X
X
Contraception checkm
X
X
X
X
X
X
X
X
X
X
X
Serum FSH (WONCBP only) 
X
HBsAg, HbcAb, HBsAB and HCVAbn
X
HIV testingo
X
Tuberculosis testp
X
Banked biospecimen (whole blood, prep 
R1) for potential exploratory RNA 
Analysis
X
X
X
X
Banked biospecimen (serum, Prep B2) for 
exploratory protein biomarker analysis
X
X
X
X
Genomic banked biospecimens Prep D1 
for potential DNA analysisq
X
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Protocol Activity
Screening
Treatment Period
FUb/EOS
EWb
Visit Identifier
1
2
3
4
5
6
7
8
9
10
Study Day/Weeka
Screening
Day 1/ 
Baseline
Day 
15 ±2
Day 
29 ±2
Day 
57 ±3
Day 
85 ±3
Day 
113 ±3
Day 
141 ±3
Day 169 End of 
Treatment ±3
Follow-upb
±3
Days
-28 to 0
Week 0
Week 2
Week 4
Week 8
Week 12
Week 16
Week 20
Week 24
Week 28
Efficacy assessments
Tender/Painful Joint Count (68)
X
X
X
X
Swollen Joint Count (66)
X
X
X
X
Physician Global Assessment (PhGA) of 
Arthritisr VAS
X
X
X
X
Patient reported outcomes
Dispensing of Investigational Product 
Investigational Product Dispensing
X
X
X
X
X
X
Randomization (after all screening 
procedures are complete and reviewed)s
X
Administration of IPt
X
X
X
X
X
X
X
Review of participant diary (distribution 
and instructions on use of the diary on 
Week 0, review of participant dosing 
record at all other visits), IP accountability 
throughout the study
X
X
X
X
X
X
X
X
X
Prior/Concomitant treatment(s)
X
→
→
→
→
→
→
→
X
Serious and nonserious adverse event 
monitoring
X 
→
→
→
→
→
→
→
→
X
X
Discharge from the study
X
X
C
C
C
C
C
C
C
CC
C
C
CC
C
C
CC
C
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Abbreviations: →= ongoing/continuous event; 
; DNA = deoxyribonucleic acid; ECG = electrocardiogram; 
eGFR = estimated glomerular filtration rate; EOS = end of study; EW = early withdrawal;
 
 
 FSH = follicle stimulating hormone; 
FU = Follow-up; 
 
; HBcAb = hepatitis B core antibody; HBsAg = hepatitis B surface antigen; 
HBsAb = hepatitis B surface antibody; HCVAb = hepatitis C antibody; HIV = human immunodeficiency virus; 
 
IGRA = interferon-gamma release assay; 
; IP = investigational product; 
; MRI = Magnetic 
resonance imaging;
; PhGA = Physician Global Assessment; 
RA = rheumatoid arthritis; 
 RNA = ribonucleic acid; WONCBP = women of non-childbearing potential; 
 
VAS = Visual Analog Scale; w = week.
a.
Visits should occur when scheduled, within the time window indicated in the column headings.  On study drug dosing days, assessments (including joint 
counts and questionnaires), and predose blood collections are to be performed prior to dosing unless otherwise stated.  Additional unscheduled assessments 
should be performed as clinically indicated.
b.
Any participant who prematurely withdraws from the treatment period should undergo the procedures for an early withdrawal visit and return for follow up 
visits approximately 4 weeks after the last dose of study drug as medically indicated in the opinion of the PI.
c.
RA medications taken since diagnosis and before informed consent is signed (document non-drug treatment for RA in non-drug treatment CRF page).
d.
Medical history includes history of: alcohol and drug abuse; tobacco and related product use; herpes virus infection; vaccination (particularly for HZV);
major cardiovascular events including DVT, PE, and ischemic cerebral vascular accidents (CVA); skin rash; skin infection and any abnormalities that may 
predispose the subject to infection.
e.
Vital Signs include sitting/semi-supine blood pressure, pulse rate, and temperature (oral, temporal and tympanic, using the same methods throughout the 
study), measured after approximately 10 minutes of rest. At W12 pulse will also be collected at approximately 2 to 4 hrs post dose.  
f.
Complete physical exam (PE) of major body systems. Additional targeted (limited) PE may be performed during the study at the investigator’s discretion. 
Full and targeted physical examinations must include full body skin and neurologic examinations.  Skin examinations should include visual inspection of the 
breasts and external genitalia. Neurologic examination would include assessment of cerebellar function (see Section 8.2.5).
g.
An ECG may be performed at other times, at the discretion of the investigator, if there were findings during a previous examination or in the case of a 
new/open adverse event (AE). On Week 0, Week 2, Week 4, Week 8, Week 12 and Week 24 an ECG will be done before dosing.  
h.
Chest radiograph (posterior-anterior and lateral views are recommended; however local guidelines should be followed) is required at Screening.  A chest 
radiograph or other appropriate diagnostic imaging modality (ie, computerized tomography or MRI) performed within 12 weeks prior to screening and read 
by a qualified radiologist with no evidence of current, active TB or previous inactive TB, general infections, heart failure or malignancy may substitute for 
the chest X-ray taken at Screening.  Documentation of the official reading must be located and available in the source documentation.
i.
Laboratory tests may be repeated once during the screening period; the last value will be used to determine eligibility.  Single repeats of laboratory tests are 
inclusive of Blood Chemistry, Hematology, Rheumatoid Factor, 
 and 
Urinalysis. A delay in randomization up to 7 days for repeating labs will not be considered a protocol deviation. Fasting lipid profile will be assessed at 
Baseline, Week 12 and Week 24 (samples must be collected after a minimum 4-hour fasting), and includes: fasting total cholesterol, LDL, HDL and 
triglycerides.
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k.
Collect urine samples for central laboratory urinalysis and urine microscopy, and urine culture. Urine microscopy is to be performed on all urine samples.
Urine culture is indicated if the urinalysis is positive for blood, nitrite, leukocyte esterase and/or protein, the microscopic examination reveals numbers of 
neutrophils suggestive of infection, there is clinical suspicion of urinary tract infection, there is a decrease in renal function; or if otherwise clinically 
indicated.
l.
Required for women of childbearing potential that are not surgically sterilized or do not meet the definition of menopause as per the inclusion/exclusion 
criteria.  
m. Record all non-drug treatments, including non-drug contraception methods (eg, IUD placement), and contraception medications in medical history CRF 
page.
n.
Participants will be screened for hepatitis B virus infection and will be excluded if positive for hepatitis B surface antigen (HBsAg).  Participants with 
HBsAg negative testing but who test positive for hepatitis B core antibody (HBcAb) will be reflex tested for hepatitis B virus deoxyribonucleic acid (HBV 
DNA) and, if HBV DNA is negative, will be allowed to enroll in the study. Participants will be screened for hepatitis C virus (HCV Ab) and will be reflex 
tested for HCV ribonucleic acid (HCV RNA) if positive for HCV Ab.  Only participants with negative HCV Ab or HCV RNA, will be allowed to enroll in 
the study.
o.
Human immunodeficiency virus (HIV) testing is mandatory (unless local regulations prohibit mandatory testing); however, reporting of results should be 
handled per local regulations.
p.
Participants with a positive IGRA TB test performed within 12 Weeks prior to Screening are excluded except as noted below.  The specific IGRA method, 
or test, used should comply with local country-specific guidelines.  The type (name) and results of the IGRA TB test must be known and located in source 
documentation.  A participant who is currently being treated for either latent or active TB infection is to be excluded. Participants with a positive IGRA test 
who do not have a reliable history of adequate treatment with an effective regimen of anti-tuberculous combination therapy to which the TB strain is 
sensitive are excluded. Participants with a positive test and history of adequately treated active or latent TB should be referred to an appropriate specialist 
(eg, pulmonologist or infectious disease physician) for assessment for evidence of active TB. Participants with a positive IGRA who have been documented 
by this review not to have active TB may be enrolled in the study. The following are acceptable assays prior to screening: QuantiFERON® - TB Gold test 
(QFT-G), QuantiFERON® - TB Gold Plus test (QFT-G), QuantiFERON® - TB Gold In-Tube test (QFT-GIT) and T-SPOT® - TB test.
r.
Physician assessment should be performed without knowledge of PRO assessments.
s.
If the absolute neutrophil count (ANC) is ≤1500/mm3 at Screening, and the participant is eligible to enter the study, the ANC counts will need to be repeated 
(once) prior to the randomization visit, and the ANC must be ≥1500/mm3 for the participant to be eligible for randomization. A delay (<2 Weeks) in 
randomization for repeating labs will not be considered a protocol deviation. 
t.
Investigational product tablets will be administered to the participant in the clinic on the morning of clinic visits and all other dosing will be performed by 
the participant outside of the clinic.
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w.
Audiograms may be performed within a ±2-week window relative to the study visit.  
x.
MRIs, if performed, will be conducted in a subgroup of participants. Participants in the MRI subgroup will be recruited globally in the order of enrollment 
in the IVRS up to a maximum number as defined by the sponsor. Participants who refuse to undergo MRI may still be eligible for enrollment into the study.
Baseline MRIs should be acquired after all other eligibility criteria have been met and at least 1 week prior to randomization. After randomization, MRIs 
will be performed at Visit 6/Week 12 (±1 week), and Visit 9/Week 24 (-2 to +1 week). A delay in acquisition of the Baseline MRI up to 1 week (7 days)
after Randomization at Visit 2 (Week 0, Day 1) solely due to scheduling availability will not be considered a protocol deviation (PD). 
y.
Additional sample will be collected upon on presentation of infection.
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2. INTRODUCTION
PF-06650833 is a potent, selective, small molecule, reversible inhibitor of interleukin-1 
receptor-associated kinase 4 (IRAK4) that is currently under development for the treatment 
of RA and hidradenitis suppurativa (HS).
PF-06651600 is a potent, selective, covalent inhibitor of Janus kinase (JAK) 3/tyrosine 
kinase expressed in hepatocellular carcinoma (TEC) kinases that is currently being 
investigated in patients with RA, Alopecia Areata (AA), Vitiligo, Ulcerative Colitis (UC), 
and Crohn’s Disease (CD). 
Tofacitinib (CP-690,550), is a potent, selective inhibitor of the JAK family of kinases. In 
kinase assays, tofacitinib, inhibits JAK1, JAK2, JAK3, and to a lesser extent tyrosine kinase 
2 (TyK2). Tofacitinib (as of 05 May 2018) has been approved (as an Immediate Release 
tablet) for the treatment of RA in 90 countries (including the US, Japan, and the EU) and is 
marketed in 54 countries (including the US, Japan, and the EU) for the treatment of RA; 
tofacitinib has also been approved in 5 countries as a Modified Release (MR) (also referred 
to as Extended Release [XR]) formulation.
2.1. Study Rationale 
The aim of the current study is to evaluate 2 different drug combinations to see if either can 
achieve the dual objectives of increased efficacy compared to currently available standard of 
care RA drugs while maintaining an acceptable safety profile (and therefore an overall 
positive benefit : risk relationship).  All of the individual components of the combinations
being explored in the current study have demonstrated efficacy in Phase 2 studies in 
RA--either showing clinical benefit in Phase 2 studies (PF-06650833 and PF-06651600) or 
having completed registration and approval (tofacitinib).  The components of the 
combinations to be evaluated, PF-06650833 coadministered with tofacitinib (PF-06650833 + 
tofacitinib) and PF-06650833 coadministered with PF-06651600 (PF-06650833 + 
PF-06651600), have non-overlapping mechanisms of action.  Moreover, PF-06650833 and 
PF-06651600 have appeared generally well-tolerated in their Phase 2 studies so they have the 
potential for not having increased safety liabilities in combination with each other, or, for 
PF-06650833 with tofacitinib.
The study employs an active treatment period of 24 weeks to allow for a more robust 
assessment of remission rates, which generally require at least 6 months of drug treatment to 
manifest maximal drug activity.  The longer treatment period will also provide greater insight 
into the overall safety profiles of the assigned study treatments.  The study will be powered 
to show statistical superiority on DAS28-CRP of the combination to tofacitinib monotherapy 
at Week 12 and will include approximately 100 participants/arm for the combination and 
tofacitinib monotherapy arms, and approximately 75 participants/arm for the PF-06650833 
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2.2. Background 
Rheumatoid arthritis (RA) is a chronic, autoimmune disease characterized by joint 
inflammation and destruction, progressive disability, and adverse psychological effects.  
There are multiple therapeutic options for managing the pain and slowing the progression of
RA rheumatoid arthritis, but none completely cures the disease. Disease-modifying 
antirheumatic drugs (DMARDs) are the standard treatments for RA.  Conventional synthetic 
DMARDs (csDMARDs), such as MTX, are used either alone or in combination with newer 
biologic DMARDs.  They work to decrease pain and inflammation, to reduce or prevent joint 
damage, and to preserve the structure and function of the joints, but they uncommonly induce 
clinical remission.  Use of biologic DMARDs (bDMARDs), most commonly tumor necrosis 
factor alpha (TNF) inhibitors, is indicated when symptoms are not adequately controlled 
with csDMARDs. More recently, small molecule inhibitors of Janus kinases (JAK) have 
been introduced into the RA therapeutic armamentarium. Tofacitinib was the first JAK 
inhibitor approved as a DMARD for the treatment of RA. A number of other JAK inhibitors 
are now either approved or in the late stages of clinical development. Despite the 
considerable list of approved treatments for RA, the treatment goal of disease remission 
(or even low disease activity [LDA]) is achieved in only a minority of patients and none 
completely cures the disease. Clearly, there is a need for therapeutics with enhanced efficacy
that drive a higher proportion of patients to LDA and remission. It is also becoming evident 
given the results with biologic and newer advanced therapy DMARDs administered alone or 
in combination with MTX, that such levels of activity may be difficult to achieve with drugs 
targeting a single pathway or cytokine. Combinations of drugs with complementary 
mechanisms of action offer the potential to achieve the goal of improved efficacy without 
incurring additional safety liabilities.
IRAK4 is a serine, threonine kinase that serves as a key node in intracellular signaling 
downstream of the mydossome associated Toll Like Receptors (TLR 1, 2, 4, 5, 6, 7, 8, 9 and 
10) and the Interleukin (IL)-1 family receptors (IL-1R, IL-18R and IL-33R). TLR signaling 
has been implicated pre-clinically and clinically in RA, variously mediating inflammatory 
responses to damage associated molecular patterns (DAMPs), such as nucleic acids, 
extracellular matrix components, and citrulline-modified self-antigens, by cells of the 
immune system as well as synoviocytes. Inhibition of IRAK4 blocks the production of 
cytokines such as type I interferons (IFN), and the inflammatory cytokines IL-6, TNF, 
IL-1, and IL-12, that are key drivers of autoimmune and inflammatory diseases such RA.  
Significantly, as noted below, the role of innate immune signaling in RA through these 
pathways has recently been validated in a proof-of-concept study of the IRAK4 inhibitor 
PF-06650833 (on a background of MTX) in patients with moderately to severely active RA. 
The JAK family of kinases mediate pro-inflammatory signals induced by activation of type I 
and type II cytokine receptors.  Many of the cytokines involved in synovial inflammation in 
RA utilize JAK-dependent signal transduction pathways, particularly those involving JAK1 
and/or JAK3. This provides the rationale for targeting these cytokine signaling pathways in 
RA.  The therapeutic benefit of inhibiting JAK signaling in RA has been validated clinically 
with the development initially of tofacitinib, and, more recently, by the Phase 3 clinical data 
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2.2.1. PF-06650833
PF-06650833 is a highly selective, small molecule inhibitor of IRAK4 that is the first to have 
entered clinical development and successfully completed a Phase 2 clinical study in RA.
In preclinical experiments, PF-06650833 has been shown to inhibit inflammatory cytokine 
release induced by anti-citrullinated protein antibody – positive (ACPA+) RA serum in 
primary human macrophages and to inhibit IL-1 and TLR ligand-induced inflammatory 
mediators in synovial fibroblasts from RA patients. As described in greater detail below, in a
12-week proof-of-concept study in patients with active RA, PF-06650833 (on a background 
of MTX) showed activity in reducing the signs and symptoms of RA with a safety profile 
compatible with a positive benefit: risk relationship.
As an inhibitor of TLR signaling, PF-06650833 targets a different part of the immune system 
from the JAK inhibitors. Given the partial redundancy of innate immune signaling through 
IRAK4-independent TLR pathways and the lack of direct suppression of T- and B-cell 
signaling, PF-06650833 is unlikely to lead to over immunosuppression. Thus, a combination 
of PF-06650833 with either tofacitinib or PF-06651600 has the potential for complementary 
anti-inflammatory activity that could lead to additive or synergistic efficacy in patients with 
RA while having the potential to avoid increasing adverse effects due to excessive 
immunosuppression. 
The current study is designed to evaluate if either (or both) combination can achieve the dual 
objectives of superior efficacy while maintaining an acceptable safety profile.
Further details about PF-06650833 may be found in the current version of the single 
reference safety document (SRSD), which for PF-06650833, is the current version 
Investigator’s Brochure (IB).
2.2.2. Tofacitinib
Tofacitinib (CP-690,550) is a potent, selective inhibitor of the Janus kinase (JAK) family of 
kinases with a high degree of selectivity against other kinases in the human genome 
(Karaman et al, 2008).3  In kinase assays, tofacitinib, inhibits JAK1, JAK2, JAK3, and to a 
lesser extent tyrosine kinase 2 (TyK2).  In cellular settings where JAK kinases signal in pairs, 
tofacitinib preferentially inhibits signaling by heterodimeric receptors associated with JAK3 
and/or JAK1 with functional selectivity over receptors that signal via pairs of JAK2 
(Meyer et al, 2010).4 At the clinical dose of 5 mg twice daily (BID) of the IR formulation, 
tofacitinib provides high level suppression of IL-21, IL-15, IL-6, Interferon-alpha (IFN-), 
and Interferon-gamma (IFN-), as well as other cytokines. It also modestly inhibits JAK2 
which may explain some of its less desirable effects on hematopoiesis. Further details about 
tofacitinib may be found in the current version of the SRSD), which for this study is the 
current version of the tofacitinib IB.


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2.2.3. PF-06651600
PF-06651600 is an orally bioavailable small molecule that irreversibly inhibits JAK3/TEC
with selectivity over the other 3 JAK isoforms; JAK1, JAK2 and TyK2. PF-06651600 also 
inhibits irreversibly the TEC kinase family (Bruton’s tyrosine kinase, [BTK], bone marrow 
tyrosine kinase on chromosome X [BMX], interleukin-2-inducible T-cell kinase [ITK], TEC, 
and tyrosine kinase expressed in T cells [TXK]), with high selectivity over the broader 
kinome.  JAK3/TEC inhibition will lead to modulation of -common chain cytokine 
pathways, such as IL-7, IL-9, IL-15, and IL-21, some of which have been implicated in the 
pathophysiology of RA.  PF-06651600 is expected to spare inhibition of key
immuno-regulatory cytokines, such as IL-10, IL-27, and IL-35, which play a protective role.  
Inhibition of JAK2 cytokine signaling, implicated to be associated with adverse effects such 
as neutropenia, thrombocytopenia, and anemia (O'Shea et al, 2013),5 will also be spared. 
Additionally, PF-06651600 inhibits the cytotoxic function of CD8+ T cells and natural killer 
(NK) cells. Thus, PF-06651600 and tofacitinib have overlapping but distinct 
anti-inflammatory activities that have the potential for differential efficacy and safety profiles 
in RA. Further details may be found in the current version of the SRSD, which for this study 
is the current version of the PF-06651600 IB.
2.2.4. Nonclinical Overview
The nonclinical studies supporting the current clinical study include 3-month combination 
studies of PF-06650833 + PF-06651600 (Study 18GR138, a 3-Month Oral Gavage 
Combination Toxicity Study of PF-06650833 and PF-06651600 in Wistar Han Rat) and 
PF-06650833 + CP-690550 (tofacitinib) (Study 18GR099, 3-Month Oral Gavage Study of 
PF-06650833 and CP-690550 in Sprague-Dawley Rats) along with the nonclinical studies 
conducted with individual test articles (PF-06650833, PF-06651600, and tofacitinib 
[CP-690550]). These latter studies include safety pharmacology chronic toxicity studies 
sufficient to support chronic dosing of each of the individual investigational products, 
including with women of childbearing potential (WOCBP) using appropriate contraception. 
No new adverse effects were observed in the combination toxicity studies. Detailed 
nonclinical information may be found in the current versions of the Investigator’s Brochures 
(IBs) for PF-06650833, PF-06651600, and tofacitinib.
Conclusions for Nonclinical Safety
The nonclinical data package consisting of results from the combination toxicity studies 
conducted in rats administered PF-06650833 + CP-690550 (tofacitinib), or PF-06650833 + 
PF-06651600, and the results from toxicity studies for the individual test articles, support the 
clinical evaluation of these combinations. Details on the combination toxicity studies with 
PF-06650833 may be found in Section 5 of the current PF-06650833 IB. Further details for 
the individual IPs may be found in Section 5 of the current IB for each individual IP.


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2.2.5. Clinical Overview
2.2.5.1. PF-06650833
As of the date of this protocol, the safety, tolerability, and pharmacokinetic (PK) profiles of 
PF-06650833 have been evaluated in 5 Phase 1 studies in healthy participants. These have 
included single and repeat ascending dose studies, relative bioavailability studies, and a 
drug-drug interaction study (with PF-06651600).  PF-06650833 was generally well-tolerated 
in these studies with no dose-limiting adverse effect defined for escalating single doses of an 
immediate release (IR) formulation, up to 6000 mg with food, and for repeat dosing up to 
1000 mg IR four times a day (QID) and 300 mg of modified release (MR) tablets once daily, 
with a standard meal for 14 days. The most frequently reported Treatment Emergent 
Adverse Events (TEAEs) (>3 participants) in the repeat dose study were headache 
(9 participants), acne, abdominal pain, and nausea (3 participants each).  There were no 
deaths, severe Adverse Events (AEs), or Serious Adverse Events (SAEs) reported. There 
were no clinically significant Electrocardiogram (ECG) abnormalities, and no clinically 
significant changes in vital signs (blood pressure or pulse) or in laboratory test results, at any 
dose. Sporadic, asymptomatic, self-limited increases in aspartate aminotransferase (AST) 
and alanine aminotransferase (ALT) were observed without a clear relationship to dose or 
duration of treatment. Asymptomatic manifestations of atypical, needle-like crystals in the 
urine were reported intermittently in participants receiving immediate release doses 
>250 mg BID, and in the 300 mg MR once daily (QD) dose, as well as in 3 participants
receiving placebo.  No AEs related to the urine crystals were reported and the findings were 
not associated with any clinical or laboratory evidence of adverse effects on kidney function.
The efficacy and safety of PF-06650833 were evaluated in a Phase 2, dose-ranging, 
multicenter, randomized, double-blind, double dummy, placebo- and active-controlled, 
parallel group, 12-week study in participants with moderately to severely active, 
anti-anticitrullinated protein antibody positive (ACPA+) RA who have had an inadequate 
response to MTX. PF-06650833 doses of 20 mg, 60 mg, 200 mg, and 400 mg MR tablets 
administered once daily under fasted conditions compared to placebo were explored.
Tofacitinib 5 mg twice daily (BID) was included as an active control in this study (but no 
formal statistical comparisons with PF-06650833 were performed).
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The PK profile of PF-06650833 is discussed in Section 4.2.1.
Further details about the safety, tolerability, PK, and efficacy of PF-06650833 may be found 
in the current version of the PF-06650833 IB.
2.2.5.2. PF-06651600
As of 31 August 2020, PF-06651600 has been explored in 3 Phase 1 trials in healthy 
participants, and in 2 completed Phase 2 trials, in participants with RA and AA. There are 
ongoing Phase 2 studies in ulcerative colitis, Crohn’s Disease, alopecia areata, and vitiligo; a 
Phase 2b/3 study in alopecia areata, and a Phase 3 study in alopecia areata.
Based on the current clinical and nonclinical experience with PF-06651600 and other 
information from other JAK inhibitors (eg, Xeljanz® [tofacitinib], Jakafi® [ruxolitinib], 
baricitinib, GLPG0634, and VX-509), the potential risks for PF-06651600 include: (1) viral 
reactivation; (2) serious infections and opportunistic infections; (3) malignancy and 
lymphoproliferative disorders; (4) decreased lymphocyte counts; (5) change in neutrophil 
counts; (6) decreased platelet count; (7) alterations in the lipid profile; (8) dermatologic 
effects (rash/acne); and (9) thromboembolism.  Increased incidences of deep vein thrombosis 
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(DVT) and pulmonary embolism (PE) have recently been identified as potential risks for 
these other JAK inhibitors.  To date, no adverse drug reactions for ritlecitinib have been 
identified.
Additional information on the safety, tolerability, and efficacy of PF-06651600, including 
information about ongoing Phase 2/3 studies in other indications may be found in the current 
version of the PF-06651600 IB. 
2.2.5.3. Tofacitinib (CP-690550, Xeljanz®)
Tofacitinib is approved for treatment of RA, PsA, and UC, and is currently being 
investigated as a treatment for juvenile idiopathic arthritis (JIA) and ankylosing spondylitis 
(AS).  Tofacitinib was investigated for the treatment of psoriasis (approved in Russia only), 
prevention of acute renal allograft rejection, and CD; however, there are no ongoing or 
planned clinical trials for these indications at this time.
As stated in the current version (April 2020) of the tofacitinib Investigator’s Brochure, as of 
05 May 2019, it is estimated that 23,338 unique study participants have participated in 
tofacitinib clinical trials worldwide, with 19,597 study participants exposed to tofacitinib. 
Phase 1 studies are described in Section 6.1 and Phase 2, Phase 3 and Phase 4 studies are 
described in Section 6.2 of the current tofacitinib Investigator’s brochure.  From 
06 November 2012 through 05 May 2019, there have been approximately 
209,081 patient-years of exposure to tofacitinib from marketing experience. Approximately 
460 humans have applied at least 1 dose of topical tofacitinib in the completed Phase 2 
studies; there have not been any Phase 1 or Phase 3 studies for the dermal formulations.  The 
topical administration for dry eye disease as well as plaque psoriasis and atopic dermatitis is 
discussed separately in the Topical Formulation Section (Sections 2-6.2) of the current 
version of the tofacitinib Investigator’s brochure.  Currently, there are no ongoing or planned 
studies of topical formulations of tofacitinib.
Tofacitinib is an immunomodulator with important safety risks that include serious and other 
infections including tuberculosis and herpes zoster infections, and potential for malignancies 
including lymphoma, and potential for GI perforations.  Patients receiving tofacitinib may be 
at increased risk of Non-Melanoma Skin Cancer (NMSC).  Cardiovascular disease and
Interstitial Lung disease (ILD) are findings seen in RA patients receiving tofacitinib, and are 
recognized comorbidities for RA as well as being associated with other RA therapies.
Changes in laboratory values have also been observed with oral tofacitinib including a 
dose-dependent increase in LDL cholesterol and dose-dependent decreases in neutrophils and 
hemoglobin.  Other laboratory changes observed with oral tofacitinib treatment include 
decreases in lymphocytes and increases in transaminases, serum creatinine, and CK.
Laboratory changes observed with oral tofacitinib treatment are monitorable and manageable 
and recovery of laboratory changes upon discontinuation of oral tofacitinib treatment is 
characteristically observed.


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These topics are described in greater detail in Section 6.2.3 of the current version of the 
tofacitinib IB, including relevant differences in the clinical experience in the various 
indications in which tofacitinib has been studied.
Interpretation of these results and the possible risks associated with the administration of 
tofacitinib are summarized in Section 7 of the current version of the Tofacitinib IB.
Study A3921133 was an event-driven, postmarketing requirement study evaluating the safety 
of tofacitinib at 2 doses (5 mg BID and 10 mg BID) versus TNFi in participants with 
moderate to severe RA.  Participants who enrolled in this study were required to be 50 years 
of age or older with at least 1 cardiovascular risk factor and be on a stable background dose 
of MTX treatment.  On 05 February 2019, the Rheumatology Data Safety Monitoring Board 
(DSMB) for Study A3921133 communicated to Pfizer their observation of a statistically and 
clinically important difference in the occurrence of PE with the tofacitinib 10 mg BID 
treatment arm compared to the active tumor necrosis factor inhibitor (TNFi) control. VTE 
was subsequently considered to be an important identified risk for tofacitinib. In 
February 2021, based on initial review of the primary endpoint data deriving from 
Study A3921133 pertaining to the co-primary endpoint results for MACE (Major Adverse 
Cardiovascular Events) and malignancies excluding NMSC (Non-Melanoma Skin Cancer) 
for tofacitinib, relative to a TNFi, MACE has been identified as a new important potential 
risk and malignancies (excluding NMSC) remains as an important potential risk.
2.3. Benefit: Risk Assessment
Tofacitinib, as noted above and in the tofacitinib IB, has a number of important and 
potentially important safety risks that include serious and other infections, malignancies 
(excluding NMSC), a potential for GI perforations, blood and lymphatic system disorders, 
drug hypersensitivity, and MACE (including VTE).  Tofacitinib also has a number of 
monitorable effects on laboratory values, including both hematology and clinical chemistry 
parameters.  Given the totality of efficacy and safety data, the overall benefit: risk 
relationship for approved doses of tofacitinib (including, 5 mg IR BID and 11 mg MR QD) 
continues to remain favorable.
PF-06651600 is a selective inhibitor of a member of the JAK family and, therefore, may (or 
may not) have a safety profile distinct from other, less selective JAK inhibitors.  However, 
until more clinical trial data are available for it and other selective JAK inhibitors, a risk 
profile similar to other JAK inhibitors for which more data are available cannot formally be 
excluded.  Therefore, as noted above and in the PF-06651600 IB, based on the current 
clinical and nonclinical experience with PF-06651600 and other JAK inhibitors, the potential 
risks for PF-06651600 include: viral reactivation; serious infections and opportunistic 
infections; malignancy and lymphoproliferative disorders; decreased lymphocyte counts; 
change in neutrophil counts; decreased platelet count; alterations in the lipid profile; and
dermatologic effects (rash/acne); and thromboembolism.  Given the efficacy seen in the 
Phase 2 RA study and in Phase 2/3 studies in alopecia areata and vitiligo, the potential 
benefit: risk of PF-06651600 in RA at proposed doses appears favorable.


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To date, no safety risks or potentially important safety risks have been identified for 
PF-06650833. However, based on nonclinical and clinical data, and theoretical 
considerations derived from its mechanism of action as a modulator of innate immune 
signaling, effects of PF-06650833 on rates of infection, including serious and other 
infections, renal function, and liver transaminases are possible. The accumulated safety data 
and the efficacy demonstrated in the Phase 2 study in RA are consistent with a potentially 
favorable benefit: risk relationship for PF-06650833 in RA.
In light of accumulated nonclinical toxicity, and clinical safety and efficacy data for the 
individual components, the lack of new adverse effects being identified in the combination 
toxicity studies of PF-06650833 + PF-06651600 and of PF-06650833 + tofacitinib suggest 
that positive benefit: risk relationships will be maintained for these combinations in 
participants with moderately - severely active RA.
More detailed information about the known and expected benefits and risks, and reasonably 
expected adverse events (AEs) of PF-06650833, PF-06651600, and tofacitinib (Xeljanz®)
may be found in the current versions of the respective IB which are the SRSDs for this study.
3. OBJECTIVES, ESTIMANDS, AND ENDPOINTS
Objectives
Endpoints
Estimands***
Primary
Primary
Primary

To compare the efficacy 
of each of 2 combinations 
(PF-06650833 + 
PF-06651600, 
PF-06650833 + 
tofacitinib) individually to 
tofacitinib alone at 
Week 12 in participants 
with moderately - severely 
active RA who have had 
an inadequate response to 
MTX.

Change from baseline in 
Disease Activity Score 
(DAS)28-C Reactive 
protein (CRP) at 
Week 12.

E1: 
Evaluates the difference 
across the treatment arms 
in the mean values of 
change from baseline of 
continuous outcome of 
interest. The treatment 
effect is evaluated in the 
population of study 
participants who are 
randomized and treated 
irrespective of their 
compliance  to the 
planned course of 
treatment or use of 
concomitant medications. 


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Objectives
Endpoints
Estimands***
Key Secondary
Key Secondary
Key Secondary

To compare the remission 
rates of each of 2 
combinations 
(PF-06650833 + 
PF-06651600, 
PF-06650833 + 
tofacitinib) individually to 
tofacitinib alone at 
Week 24 in participants 
with moderately - severely 
active RA who have had 
an inadequate response to 
MTX.

DAS28-CRP remission 
(<2.6) at Week 24.

E2: 
Evaluates the ratio  of 
the probability of 
response in the treatment 
arm of interest to the 
probability of response 
in the tofacitininib 
treatment arm. The 
treatment effect is 
evaluated in the 
population of study 
participants who are 
randomized and treated 
irrespective of their 
compliance  to the 
planned course of 
treatment or use of 
concomitant 
medications.
Secondary
Secondary
Secondary

To assess the safety of 
PF-06650833, 
PF-06651600, and 
tofacitinib alone and of 
the combinations of 
PF-06650833 with 
PF-06651600 and 
tofacitinib in participants 
with moderately - severely 
active RA who have had 
an inadequate response to 
MTX.

Incidence and severity of
adverse events, serious 
adverse events, and 
withdrawals due to 
adverse events.

Change from baseline in 
clinical laboratory values 
(chemistry, hematology 
parameters).

Change from baseline in 
vital signs (blood 
pressure, pulse rate and 
temperature 
measurements).

Incidences of severe and 
opportunistic infection 
AEs; herpes virus 

There is no defined 
estimand for these 
endpoints.  They will be 
analyzed using Pfizer 
data standards as 
applicable.


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Objectives
Endpoints
Estimands***
infection AEs; clinically 
significant categorical 
increases in hepatic 
enzymes Aspartate 
aminotransferase (AST), 
and Alanine 
aminotransferase (ALT) 
and total bilirubin, and 
potential cases meeting 
Hy’s Law criteria for 
increased risk of 
drug-induced liver injury 
[DILI]; major adverse 
cardiovascular events 
(MACE), including 
pulmonary embolism 
(PE) and deep vein 
thrombosis (DVT), 
Cerebrovascular 
accident (CVA); 
Adverse events (AEs) 
for decreased renal 
function, acute kidney 
injury, clinically 
significant increases in 
serum creatinine (Scr) 
and decreases in 
estimated glomerular 
filtration rate (eGFR).

To evaluate other signs of 
clinical efficacy of all 
treatment arms in 
participants with 
moderately - severely 
active RA who have had 
an inadequate response to 
MTX. 

Change from baseline in 
DAS28-CRP at 
Week 24.

American College of 
Rheumatology (ACR)20, 
ACR 50, ACR 70, and 
ACR 90 responder rates 
at Week 12 and 
Week 24. 

Change from baseline in 
the Tender/Painful and 

E1 estimand for 
continuous and E3 
estimand for binary 
efficacy outcomes.
Evaluates the differences 
in probability of 
response of the treatment 
arm of interest in 
comparison to the 
tofacitinib treatment arm 
The treatment effect is 
evaluated in the 
population of study 


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Objectives
Endpoints
Estimands***
Swollen Joint Count at 
Week 12 and Week 24.
•
Change from baseline in 
the Physician’s Global 
Assessment (PhGA) of 
Arthritis at Week 12 and 
Week 24. 
participants who are 
randomized and treated 
irrespective of their 
compliance to the 
planned course of 
treatment or use of 
concomitant 
medications.
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CCI


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•
To collect blood for the 
potential exploratory 
analyses of 
pharmacodynamic activity 
of PF-06650833, 
PF-06651600, and 
tofacitinib alone and in 
combination with 
PF-06650833 in 
participants with 
•
Change from baseline: 
anti-citrullinated protein 
antibodies (ACPA), 
rheumatoid factor (RF) 
and Ig levels.
•
Change from baseline of 
Interferon 
Gamma-Induced 
Protein 10 (IP-10), if 
performed.
•
All continuous endpoints 
will be analyzed 
descriptively.  Other 
analyses may be done 
and will be described in 
the statistical analysis 
plan (SAP).
•
All other categorical 
endpoints will be 
analyzed descriptively. 
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Objectives
Endpoints
Estimands***
moderately - severely 
active RA.
•
Endpoints may also 
include circulating 
proteins and protein 
fragments.
Other analyses may be 
done and will be 
described in the SAP.
•
To collect banked 
biospecimens for 
exploratory research, 
unless prohibited by local 
regulations or ethics 
committee decision.
•
Collection of banked 
biospecimens unless 
prohibited by local 
regulations or ethics 
committee decision.  
•
Not applicable.
•
To evaluate the effects of 
PF-06650833, 
PF-06651600, and 
tofacitinib alone and in 
combination on joint 
inflammation assessed by 
magnetic resonance 
imaging (MRI), in a subset 
of participants, if 
performed.
•
Change from baseline in 
Rheumatoid Arthritis 
MRI Score (RAMRIS) 
and exploratory 
measures of joint 
inflammation
(eg, RAMRIQ, DCE), if 
performed, in hand MRI 
at Weeks 12 and 24.
•
All continuous endpoints 
will be analyzed 
descriptively.  Other 
analyses may be done 
and will be described in 
the statistical analysis 
plan (SAP).
•
All other categorical 
endpoints will be 
analyzed descriptively. 
Other analyses may be 
done and will be 
described in the SAP.
* 
Efficacy evaluations that are otherwise classified in the table as primary, key secondary or secondary are 
not viewed as exploratory.
**
The remission threshold definition for DAS28-ESR will be defined in the SAP.
*** The additional supportive estimands will be described in the SAP.
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4. STUDY DESIGN
4.1. Overall Design
This is a Phase 2, 24-week, multicenter, randomized, double-blind, 5-arm, parallel group, 
active comparator study to evaluate the efficacy and safety profiles of 2 combinations of 
investigational products (IPs): PF-06650833 coadministered with PF-06651600 
(PF-06650833 + PF-06651600) and PF-06650833 coadministered with tofacitinib 
(PF-06650833 + tofacitinib), as well as the efficacy and safety of each IP individually in the 
absence of background MTX in participants with moderately - severely active RA who have 
had an inadequate response to MTX (MTX-IR).  
The primary objective is to demonstrate superiority of at least 1 combination arm to 
tofacitinib monotherapy with the primary endpoint being change from baseline (CFB) in 
DAS28-CRP at Week 12.  A key secondary endpoint is remission rates of the combination 
and individual IPs at Week 24, as defined by DAS28-CRP <2.6.  The study is powered to 
show statistical superiority of the combination to tofacitinib monotherapy at Week 12. 
Up to approximately 450 participants are planned to be randomized globally into the study to 
ensure at least up to approximately 370 participants complete at least 12 weeks of active 
dosing (assuming a dropout rate of approximately 18%). Participants will be randomly 
assigned to 1 of the following 5 treatment groups in a 4:4 3:3:4 ratio: PF-06650833 + 
tofacitinib, PF-06650833 + PF-06651600, PF-06650833, PF-06651600, and tofacitinib (see 
also study schematic design in Section 1.2).
After an up to 28-day screening period, eligible participants will enter a 24-week active 
treatment period after being randomly assigned to one of the 5 treatment groups shown in 
Section 1.2.  Participants will be in this study for a total of approximately 32 weeks which 
includes the screening period, the 24-week active treatment period, and a 4-week drug-free 
follow-up period.
All doses will be administered orally once daily in a fasted state (about 4 hours after the last 
and 1.5 hours before the next meal). Both PF-06650833 and tofacitinib will be administered 
as modified release (MR) tablets to allow for once daily administration, whereas 
PF-06651600 will be administered as immediate release tablets. In order to maintain the 
blind and minimize bias, all participants will receive the same number and types of tablets 
each day as a mix of active and placebo tablets (see Table 1). MTX (and folate/folinic acid 
taken with MTX) will be discontinued at the time of randomization and washed out during 
the active treatment phase. The MTX washout is intended to reduce the potential for 
excessive immune suppression and additive safety liability. 
Folate/folinic acid taken with MTX may also be discontinued in a manner consistent with 
local standard of care practice. MTX is to be discontinued (last MTX dose is to occur) 
during the week before randomization on Day 1 and be washed out during the active 
treatment phase. No changes in the background concomitant steroid dose is allowed during 
the study. During the active dosing period, no “rescue” treatment is pre-specified. However, 
limited – duration increases in permitted analgesic medication (acetaminophen/paracetamol, 


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nonsteroidal anti-inflammatory drugs [NSAIDs], opiates) will be permitted for acute 
worsening of arthritis pain (see Permitted Concomitant Medications, Sections 6.5.1 and
6.5.2).  Participants, who, after at least a 12-week trial on the assigned investigational 
product have not achieved at least a minimal clinical response (as defined by the American 
College of Rheumatology [ACR] 20% response criteria [ACR20]) are to be discontinued 
from the study treatment and begin treatment for their RA according to local standard of care 
(SoC) practice.  The Principal Investigator (PI) may also discontinue participants at any time 
during the study if, in the PI’s opinion, worsening RA signs and symptoms unresponsive to 
limited-duration increases in analgesic medications requires more urgent advancement of RA 
treatment. Additional treatment for participants meeting either of these criteria for 
discontinuation from the study will be provided by the investigator, and upon withdrawal 
from the study treatment, participants will enter a 4-week follow-up period and after which 
they will have End of Study (EOS)/follow-up (FU) visit. IP will not be provided after the 
participant completes the study. 


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Figure 1.
Schema
4.1.1. Study Rationale
There are multiple therapeutic options for managing the pain and slowing the progression of 
RA, but none completely cures the disease.  Despite the considerable list of approved 
treatments for RA, the treatment goal of clinical remission (or LDA) is achieved in only a 
minority of patients.  Clearly, there is a need for therapeutics with enhanced efficacy that 
drive a higher proportion of patients to LDA and clinical remission.
The clinical hypothesis is that combinations of drugs with complementary mechanisms of 
action would offer the potential to achieve the goal of improved efficacy while still 
maintaining a positive benefit: risk profile.  As discussed above, it is becoming evident,
given the results with biologics and even with newer, advanced synthetic DMARDs 
administered alone or in combination with MTX, that “treat-to-target” levels of efficacy on 
All doses are orally administered once daily under fasted conditions
Non-responders (defined as not meeting ACR20 response criteria) by Week 12 (or later) are to be 
discontinued from study.
MR=modified release; MTX=methotrexate; Rand=randomization; FU=follow-up; ACR=American College of 
Rheumatology.  
4 
Weeks 
FU
<28 days 
Screening
Rand
/Stop
MTX
PF-06650833 400 mg MR + PF-06651600 100 mg
N =100
PF-06650833 400 mg MR + tofacitinib 11 mg MR
N =100
Tofacitinib 11 mg MR
N = 100
PF-06650833 400 mg MR
N= 75
PF-06651600 100 mg
N = 75
24 Weeks
ACR20 non-responders at 
Weeks 12, 16, and 20 are to be 
discontinued
12 Weeks


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remission and LDA rates may be difficult to achieve with drugs targeting a single pathway or 
cytokine.
The aim of the current study is to evaluate whether or not a combination of drugs with 
complementary mechanisms of action can achieve the dual objectives of increased efficacy 
compared to currently available standard of care RA drugs while maintaining an acceptable 
safety profile (and therefore an overall positive benefit: risk relationship). Both components 
(PF-06650833 and PF-06651600) of the combination being explored in the current study 
have demonstrated efficacy in Phase 2 studies in RA. Moreover, PF-06650833 and 
PF-06651600 appeared to be generally well-tolerated in their Phase 2 studies so they have the 
potential for not having increased safety liabilities in combination.
Depending on technical and logistical feasibility, the current study may include an 
exploratory imaging component consisting of hand magnetic resonance imaging (MRI)
procedures conducted in a subset of participants (up to approximately 60 participants per 
arm), as permitted by local regulatory and ethical guidelines. MRI offers the potential for an 
earlier, more sensitive, and more quantitative assessment of joint inflammation than afforded 
by traditional X-ray analyses. In the context of the current study, the MRI analyses may 
afford a heightened ability to detect and discriminate among the anti-inflammatory and 
disease-modifying effects of the study interventions and greater discriminatory power. The 
data will also help support development of this methodology for future studies and clinical 
development programs. Further details on the imaging methods will be provided separately 
(in the form of an imaging manual, or similar document).
Banked biospecimens will be collected for exploratory pharmacogenomic/ 
genomic/biomarker analyses and retained in the Biospecimen Banking System (BBS), which 
makes it possible to better understand the investigational product’s mechanism of action and 
to seek explanations for differences in, for example, exposure, tolerability, safety, and/or 
efficacy not anticipated prior to the beginning of the study.
4.2. Justification for Dose
Since this is the initial exploration of safety and efficacy for the proposed combination, 
maximal doses of the individual study drugs that could, based on prior clinical and 
preclinical experience, be expected to be safely administered during the 6-month active 
dosing period were selected, in order to increase the probability of achieving desired 
improvements in overall remission rates.

PF-06650833 400 mg MR QD + tofacitinib 11 mg MR QD.

PF-06650833 400 mg MR QD + PF-06651600 100 mg IR QD.

PF-06650833 400 mg MR QD.

PF-06651600 100 mg IR QD.


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•
tofacitinib 11 mg MR QD.  
4.2.1. Dose Rationale for PF-06650833 400 mg MR QD
PF-06650833 is considered to have an acceptable safety profile based on clinical studies to 
date in healthy participants and patients with moderately to severely active RA (see 
Section 2.2.1 and the PF-06650833 IB).  It was tested as an orally administered 
extemporaneously prepared immediate release formulation in doses up to 1000 mg four 
times-a-day (QID) for up to 14 days in healthy participants without a dose-limiting adverse 
effect being demonstrated.  
The efficacy, safety, and pharmacokinetics (PK) of PF-06650833 were evaluated in a
12-week study (Study B7921005) in participants with moderately – severely active RA at 
doses up to 400 mg MR administered QD in a fasted state. The dose of 400 mg MR tablets 
was efficacious in reducing the signs and symptoms of RA in this study as defined by change 
from baseline (CFB) in the Simplified Disease Activity Index (SDAI) at Week 12, the 
primary efficacy endpoint, that was statistically superior to placebo. 
 
As noted above, all doses of PF-06650833 in Study B7921005 were generally well-tolerated 
for 12 weeks in patients with RA with an overall safety profile consistent with a favorable 
benefit: risk relationship.
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Therefore, based on the accumulated, available clinical and comprehensive nonclinical 
toxicity data package for PF-06650833, a 400 mg MR QD dose is expected to be 
well-tolerated and have an acceptable safety profile while providing the best opportunity to 
maximize efficacy.
4.2.2. Dose Rationale for PF-06651600 100 mg QD
PF-06651600 is considered to have an acceptable safety profile based on clinical studies to 
date in healthy participants, and in patients with moderately to severely active RA which is
supplemented by emerging data in alopecia areata patients.  It was tested as an orally 
administered extemporaneously prepared IR formulation in doses up to 400 mg QD or 
200 mg BID for 14 days in healthy participants without a dose-limiting adverse effect being 
demonstrated.  
PF-06651600 was evaluated in participants with moderately to severely active RA at 
200 mg QD for 8 weeks in Study B7981006. Analysis of the primary efficacy endpoint
demonstrated a statistically significant change from baseline (CFB) in the simplified disease 
activity index (SDAI) at 8 weeks, that was superior to placebo. This dose was generally 
well-tolerated with an acceptable safety profile.  In addition, PF-06651600 was demonstrated 
to be efficacious with an acceptable safety profile in participants with moderate to severe AA
treated with an induction dose of 200 mg for 4 weeks followed by 50 mg QD for additional 
20 weeks.  
At the proposed dose of 100 mg QD of PF-06651600, the maximal dose supported by the 
nonclinical toxicity data, the γ-common chain cytokine pathways are expected to be 
selectively inhibited to approximately 64% and 49% based on in vitro IC50 values of 198 nM 
and 362 nM determined by inhibition of signal transducer and activator of transcription 
(STAT5 and STAT3 phosphorylation in lymphocytes, respectively.  Therefore, PF-06651600 
is predicted to be pharmacologically active at a 100 mg QD dose and is expected to be 
effective in reducing the signs and symptoms of RA.  
Given the overall safety profile of PF-06651600 in clinical studies and the comprehensive 
nonclinical toxicity package, a chronic dose of PF-06651600 of 100 mg QD should provide 
an acceptable safety and tolerability profile with a favorable benefit: risk relationship.  
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4.2.3. Dose Rationale for Tofacitinib 11 mg MR QD
As noted in Section 2.2.5.3 and as discussed extensively in the tofacitinib IB, the efficacy 
and safety of tofacitinib administered as an IR tablet have been extensively evaluated in 
multiple Phase 2, Phase 3, and post-marketing studies in patients with active RA.  It has a 
well-characterized safety and tolerability profile and has been shown to be efficacious as a 
DMARD in patients with moderately–severely active RA both alone and in combination with 
MTX. The 5-mg BID dose (IR formulation) has received market authorization in numerous 
countries globally and continues to maintain a favorable benefit: risk profile.  Tofacitinib 
11 mg MR has been evaluated in 7 Phase 1 studies, 1 Phase 3 study in Japanese RA patients 
(A3921215) and 1 Phase 4-3b/4 global study (A3921192).  The 7 healthy volunteer studies 
include 4 studies (A3921113, A3921131, A3921132, and A3921163) which evaluated PK of 
the pilot or initial commercial-scale formulations; a food effect (A3921180) and a single- and 
multiple-dose PK study with the proposed commercial formulation (A3921212); and an in 
vitro dissolution with in-vivo plasma drug concentrations (IVIVC) study (A3921195) which 
investigated the relationship between in vitro dissolution and in vivo PK performance of the 
MR formulations.
Given its QD administration, tofacitinib 11 mg MR was selected as an appropriate active 
comparator in the current study.
4.2.4. Dose Rationale for PF-06650833 400 mg MR QD in Combination with 
PF-06651600 100 mg IR QD or Tofacitinib 11 mg MR QD
The doses of PF-06651600 and tofacitinib used in combination with PF-06650833 will be the 
same as the doses used in their monotherapy arms.  As noted previously (Section 2.1), 
combinations of PF-06650833 + PF-06651600 or PF-06650833 + tofacitinib have the
potential for increased efficacy compared to tofacitinib monotherapy without increased safety 
liabilities due to increased pharmacology.  
Based on metabolic profiling, the exposure of PF-06651600 is not expected to change 
meaningfully when dosed in combination with PF-06650833.  Based on in vitro metabolic 
profiling of PF-06650833 and tofacitinib, their exposures when dosed in combination are not 
expected to change meaningfully.  
 
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Given observed and expected exposures of PF-06650833, PF-06651600, and tofacitinib, 
adequate safety margins, lack of new adverse effects or target organs in the nonclinical 
combination toxicity studies, and accumulated clinical safety data, the proposed 
coadministration of PF-06650833 400 mg MR QD + tofacitinib 11 mg MR QD and of 
PF-06650833 400 mg MR QD + PF-06651600 100 mg IR QD are expected to have 
acceptable safety and tolerability.  Moreover, the selected doses of the components of the 
combination have the highest potential to demonstrate superior efficacy.
4.3. End of Study Definition
A participant is considered to have completed the study if he/she has completed all phases of 
the study including the last visit.
The end of the study is defined as the date of the last visit of the last participant in the study.
5. STUDY POPULATION
This study can fulfill its objectives only if appropriate participants are enrolled.  The 
following eligibility criteria are designed to select participants for whom participation in the 
study is considered appropriate.  All relevant medical and nonmedical conditions should be 
taken into consideration when deciding whether a particular participant is suitable for this 
protocol.
Prospective approval of protocol deviations to recruitment and enrollment criteria, also 
known as protocol waivers or exemptions, is not permitted.
5.1. Inclusion Criteria
Participants are eligible to be included in the study only if all of the following criteria apply:
Age and Sex:
1. Male or female participants between the ages of 18 and 70 years, inclusive, at time of 
randomization (Visit 2). 
•
Refer to Appendix 4 for reproductive criteria for male (Section 10.4.1) and female 
(Section 10.4.2) participants.
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Type of Participant and Disease Characteristics:
2. Participants who are willing and able to comply with all scheduled visits, treatment 
plan (including washout of MTX at randomization), laboratory tests, lifestyle 
considerations, and other study procedures.
3. Diagnosis of RA and meeting the 2010 American College of Rheumatology 
(ACR)/European League Against Rheumatism (EULAR) classification criteria (see 
Appendix 8) for RA with a Total Score ≥6/10. The duration of time since diagnosis 
of RA should minimally be sufficient to meet the definition of MTX inadequate 
response (MTX-IR) (see Inclusion 7).
4. The participant has active disease at both Screening and Randomization, as defined 
by both:

≥6 joints tender or painful on motion, AND

≥6 joints swollen;
and fulfills 1 of the following 2 criteria at or before randomization:

High sensitivity C reactive protein (hsCRP) >7 mg/L at Screening (Visit 1) as 
performed by the central laboratory.  
OR

Erythrocyte sedimentation rate (ESR) (Westergren method) >28 mm/h.
Participants who do not meet this entry criterion but satisfy all other study entry 
criteria may have ESR or serum hsCRP concentration re-tested once within 14 days 
and, if the repeat hsCRP concentration is >7 mg/L or ESR >28 mm/h, will be eligible 
to enroll into the study provided all other inclusion/exclusion criteria are met.
5. Meets Class I, II or III of the ACR 1991 Revised Criteria for Global Functional Status 
in RA (see Appendix 9). 
6. Participants must be seropositive at the time of randomization (ACPA or RF 
positive).  


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7. Participants must have been taking oral MTX (or equivalent parenteral MTX) at an 
adequate dose (generally between 15 and 25 mg weekly [inclusive] unless 
documented to be intolerant to these doses) and for a sufficient duration (generally at 
least 3 months but may be as short as at least 8 weeks if consistent with local standard 
of care treatment guidelines) prior to Screening (Visit 1). To determine that the 
participant had an inadequate response to MTX, defined, for the purpose of this study, 
by the investigator’s and participant’s opinions that the participant did not experience 
adequate benefit from MTX plus the presence of sufficient residual disease activity to 
meet the entry criteria. Current treatment with methotrexate is not required for 
participant eligibility, provided documentation of prior inadequate response to or 
intolerance of MTX is available and provided in source documentation.
8. Participants receiving non-prohibited concomitant medications for any reason must 
be on a stable regimen, which is defined as not starting a new drug or changing 
dosage within 7 days or 5 half-lives (whichever is longer) prior to first study dose.
Weight: 
9. Body weight must be >40 kg. 
Informed Consent:
10. Capable of giving signed informed consent as described in Appendix 1
(Section 10.1), which includes compliance with the requirements and restrictions 
listed in the informed consent document (ICD) and in this protocol.
5.2. Exclusion Criteria
Participants are excluded from the study if any of the following criteria apply:
Medical Conditions:
1. Other acute or chronic medical or psychiatric condition including recent (within the 
past year) or active suicidal ideation or behavior or laboratory abnormality that may 
increase the risk associated with study participation or IP administration or may 
interfere with the interpretation of study results and, in the judgment of the 
investigator, would make the participant inappropriate for entry into this study.
2. Participants with a known immunodeficiency disorder or a first degree relative with a 
hereditary immunodeficiency.
3. Participants with any of the following infections or infections history:
a.
Any infection requiring treatment within 2 weeks prior to screening (Visit 1).
b. Active COVID-19 as defined by a positive test for SARS-CoV-2 or an exposure 
history with compatible symptoms (as defined by WHO).


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c.
Asymptomatic participants with an exposure history while under quarantine or 
pending results of a SARS-CoV-2 test (which if negative would allow the patient 
to be eligible).
d. Participants with a history of COVID-19 in the last 3 months unless asymptomatic 
for at least the last 30 days with a negative SARS-CoV-2 test in the last 7 days. 
Asymptomatic patients with a more remote (>3 months) history of COVID-19 do 
not need a confirmatory SARS-CoV-2 test to be eligible.
e.
Participants with COVID-19 who are symptomatic irrespective of the interval 
since infection.
f.
Any infection requiring hospitalization, parenteral antimicrobial therapy within 
60 days of randomization, or as otherwise judged by the investigator to be an 
opportunistic infection or clinically significant, within the past 6 months.
g. Infected joint prosthesis at any time with the prosthesis still in situ.
h. Recurrent (1 or more lifetime episodes after the initial episode) herpes zoster; or 
severe or disseminated (a single lifetime episode of either) herpes simplex. Note 
that for the purposes of this study the initial infection (eg, chicken pox) is 
considered the initial episode of herpes zoster. A recurrent episode of herpes 
zoster is any subsequent manifestation of active herpes zoster (eg, shingles).
i.
Participants will be screened for HIV (unless local regulations prohibit mandatory 
testing).  Participants who test positive for HIV will be excluded from the study.
4. Participants with positive hepatitis B surface antigen (HBsAg) will be excluded.  
Participants who are HBsAg negative but HBcAb positive will be reflex tested for 
hepatitis B virus deoxyribonucleic acid (HBV DNA) and, if HBV DNA is negative, 
will be allowed to enroll in the study, provided other inclusion/exclusion criteria are 
met if HBV DNA is positive, they will be screen failed.
5. Participants will be screened for hepatitis C virus (HCV Ab).  Participants with 
positive HCV Ab tests will be reflex tested for HCV ribonucleic acid (HCV RNA).  
Only participants with negative HCV Ab or HCV RNA, and normal liver function (as 
assessed by liver transaminases and bilirubin within protocol-permitted limits, and no 
other evidence of compromised liver synthetic ability (eg, albumin and coagulation 
tests within protocol-permitted limits]) will be allowed to enroll in the study, 
provided other inclusion exclusion criteria are met. 
6. Any history of either untreated or inadequately treated latent or active tuberculosis 
(TB) infection, current treatment for active or latent TB infection or evidence of 
currently active TB by chest x-ray, CT or MRI, residing with or frequent close 
contact with individual(s) with active TB.  Participants who have a positive Interferon 


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Gamma Release Assay during screening or within 12 weeks prior to randomization, 
except as noted below.

Participants with prior active or latent tuberculosis (except for multidrug-resistant 
TB) who have no current evidence of active disease and has completed an 
adequate course of therapy for active tuberculosis (a multi-drug regimen 
recognized by the World Health Organization to which the organism has 
demonstrated appropriate sensitivity), negative chest radiograph for active 
disease, and negative Interferon Gamma Release Assay (IGRA) are eligible.

Participants who have an indeterminate IGRA results may have the test repeated 
and, will be eligible if the repeat IGRA test is negative at time of randomization.
A positive test on repeat is exclusionary unless the participant meets the criteria 
below.

Participants who test positive for IGRA test (including borderline T-SPOT result) 
who do not have a reliable history of having received an adequate course of 
therapy for active or latent tuberculosis with a recognized effective combination 
drug regimen to which the TB organism was sensitive.

Participants who test positive for IGRA test (including borderline T-SPOT result), 
have a reliable history of having received an adequate course of therapy for active 
or latent tuberculosis with a recognized effective combination drug regimen to 
which the TB organism was sensitive, and in the opinion of the PI are at low risk 
of currently have active or latent TB infection may be referred to pulmonary or 
infectious disease specialist for consultation and may have the IGRA test repeated 
once.  Participants will be eligible if the repeat test is negative before the 
randomization. Alternatively, a participant with a positive IGRA may be eligible 
if the participant lives in a country/region without a high prevalence of multi-drug 
resistant TB (and has not recently traveled to a region with a high prevalence of 
MDR TB) and if the pulmonary or infectious disease specialist, after review of all 
relevant clinical and medical imaging data attests that the participant does not 
have active or latent TB infection.
7. History of a major organ transplant (eg, heart, lung, kidney and liver) or 
hematopoietic stem cell/marrow transplant.
8. History of severe allergic or anaphylactoid reaction to kinase inhibitors, or 
corticosteroid preparations.
9. Known history of diverticulitis or symptomatic diverticulosis, perineal abscess or 
fistulae.


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10. Participants with malignancy or history of malignancy (including lymphoma, 
leukemia, or lymphoproliferative disease), with the exception of participants with 
adequately treated or excised non-metastatic basal cell or squamous cell cancer of the 
skin or cervical carcinoma in situ.
11. Pre-existing chronic autoimmune disease (eg, inflammatory bowel disease, systemic 
lupus erythematosus, moderate-severe atopic dermatitis, dermatomyositis) other than 
RA.  Secondary Sjogren’s Syndrome (due to RA) may be included.
12. Participants with fibromyalgia will be excluded.
13. Major surgery within 4 weeks of screening or planned surgery scheduled to occur 
during the study.
14. Previous treatment with total lymphoid irradiation. 
15. Participants with any condition possibly affecting oral drug absorption 
(eg, bariatric/obesity surgery [such as gastric bypass or gastric banding], gastrectomy, 
or clinically significant diabetic gastroenteropathy).
16. Participants with an oral, tympanic, or temporal temperature of 38°C (100.4°F) or 
higher at baseline.
17. Participants may not receive any live/attenuated vaccine from 30 days prior to 
randomization during the course of the study, or for 30 days after the last dose of 
study medication. Participants who have current routine household contact with 
children who have received varicella or oral polio vaccine within 2 months of first 
study dose are also excluded.
18. History of any lymphoproliferative disorder (such as Epstein-Barr Virus 
[EBV]-related lymphoproliferative disorder, as reported in some participants on 
immunosuppressive drugs), history of lymphoma, leukemia, myeloproliferative 
disorders, multiple myeloma, or signs and symptoms suggestive of current lymphatic 
disease. 
19. Have hearing loss with progression over the previous 5 years, sudden hearing loss, or 
middle or inner ear disease such as otitis media, cholesteatoma, Meniere’s disease, 
labyrinthitis, or other auditory condition that is considered current, fluctuating or 
progressive.
20. History of any prior deep vein thrombosis (DVT) or pulmonary embolism [PE].
21. History of any medical condition associated with an increased risk of 
venothromboembolism (eg, paroxysmal atrial fibrillation) unless properly 
anti-coagulated.


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22. Recent (within 6 months of screening) myocardial infarction, coronary 
revascularization, or percutaneous angioplasty with or without placement of a 
coronary artery stent; acute coronary syndrome; chronic uncompensated heart failure 
or New York Heart Association Functional Class III or IV; left ventricular assist 
devices; implanted defibrillators.
23. Current severe chronic renal insufficiency or renal failure as defined by persistent (on 
repeated measurements) eGFR <60 mL/min per 1.73 m2 based on the Chronic Kidney 
Disease Epidemiology Collaboration (CKD-EPI) calculation.
24. Any known history of coagulopathy or hypercoagulation syndrome.
25. Presence of any of the following laboratory abnormalities at screening or within the 
3 months prior to first study dose:

Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) levels 
≥1.5 x the upper limit of normal (ULN).

Participants with a history of Gilbert's syndrome may have a direct bilirubin 
measured and would be eligible for this study provided the direct bilirubin is
≤ULN and other liver function assessments are normal.

Absolute neutrophil count of <1.5 x 109/L (<1500/mm3). Participants with cyclic 
(benign ethnic) neutropenia will be excluded.

Absolute lymphocyte count of <0.5 x 109/L (<500/mm3).

Absolute white blood cell (WBC) count of <3.0 x 109/L (<3000/mm3).

Hemoglobin <9.0 g/dL (90 g/L).

Platelet count ≤100 x 109/L (100,000 cells/mm3) or ≥1000 x 109/L 
(1,000,000 cells/mm3).

Thrombocytopenia, as defined by a platelet count <100 x 109/L (<100,000/mm3) 
at screening visit or within the 3 months prior to first study dose.
Screening laboratory tests with abnormal results may be repeated once to confirm 
abnormal results.  If results return to normal protocol acceptable limits within the 
4-week screening period, the participant may enter the study. 
26. Grade 3 or greater laboratory abnormality based on the Common Terminology 
Criteria for Adverse Events (CTCAE) version 5.0 toxicity scale, except for the 
following that are allowed:

Grade 3 prothrombin time (PT) secondary to warfarin treatment.


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
Grade 3 partial thromboplastin time (PTT) due to lupus anticoagulant and not 
related to liver disease or anti-coagulant therapy.
Prior/Concomitant Therapy:
27. Participants previously treated with a biologic DMARD (except for up to 25% of 
participants who may have been treated with 1, and only 1 prior TNF inhibitor) or any 
other targeted synthetic (ie, small molecule) approved DMARD treatment (eg, a JAK 
inhibitor), or participants currently treated with any other prohibited medications as 
specified in Section 6.5.3 will be excluded.
28. Prior use of tofacitinib or other JAK inhibitor in the context of a clinical trial is 
excluded.  Concomitant use of tofacitinib (other than as prescribed by the 
randomization scheme) or other JAK inhibitor is prohibited.
29. Prior use of PF-06650833 or PF-06651600 in the context of a clinical trial is 
excluded.
30. Participants who have previously been treated with other, non-TNFinhibiting 
biologic DMARDs [including, abatacept (Orencia®), tocilizumab (Actemra®), 
Sarilumab (Kevzara®), anakinra (Kineret®), rituximab (Rituxan®) or other selective B 
lymphocyte depleting agents, or other lymphocyte depleting agents/therapies (such as 
alemtuzab [CamPath®], natalizumab (Tysabri®), alkylating agents 
[eg, cyclophosphamide or chlorambucil], total lymphoid irradiation) are excluded 
from participation in the current study.
Prior/Concurrent Clinical Study Experience:
31. 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 IP used in this 
study (whichever is longer). 
32. As noted above and in Section 6.5.3, up to 25% of participants may have previously 
taken a TNF inhibitor (originator or biosimilar), which includes prior use in the 
context of a clinical trial, provided the clinical trial was the participant’s only 
exposure to a TNF inhibitor. If the participant was previously in a clinical trial for a 
TNF inhibitor and is known not to have been assigned to the TNF inhibitor (or other 
prohibited concomitant medication), then the participant may be eligible.
Diagnostic Assessments:
33. Any 12-lead electrocardiogram (ECG) performed prior to randomization that 
demonstrates clinically relevant abnormalities that may affect participant safety or 
interpretation of study results (eg, baseline corrected QT [QTc] interval >450 msec, 
complete left bundle branch block [LBBB], signs of an acute or indeterminate-age 
myocardial infarction, ST-T interval changes suggestive of myocardial ischemia, 


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second- or third-degree atrioventricular [AV] block, or serious bradyarrhythmias or 
tachyarrhythmias, any cardiac rhythm associated with increased risk of thrombosis or 
thromboembolism, eg atrial fibrillation, unless on a stable, therapeutic dose of 
non-excluded anti-coagulant).  If the baseline uncorrected QT interval is >450 msec, 
this interval should be rate-corrected using the Fridericia method and the resulting
corrected QT (Fridericia method) (QTcF) should be used for decision making and 
reporting.  If QTc exceeds 450 msec, or ventricular depolarization (QRS) duration
exceeds 120 msec, the ECG should be repeated 2 more times and the average of the 
3 QTc or QRS duration values should be used to determine the participant’s 
eligibility.  Computer-interpreted ECGs should be overread by a physician 
experienced in reading ECGs before excluding participants.
Other Exclusions:
34. Investigator site staff members directly involved in the conduct of the study and their 
family members, site staff members otherwise supervised by the investigator, or 
Pfizer employees, including their family members, directly involved in the conduct of 
the study.
5.3. Randomization Criteria 
Participants must meet all inclusion/exclusion criteria as well as all criteria for concomitant 
medications (including stability criteria) at time of randomization.
5.4. Lifestyle Considerations
5.4.1. Contraception
The investigator (or his or her designee), in consultation with the participant, will confirm 
that the participant has selected an appropriate method of highly effective 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).  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.
5.5. Screen Failures
Screen failures are defined as participants who consent to participate in the clinical study but 
are not subsequently randomly assigned to investigational product. A minimal set of screen 
failure information is required to ensure transparent reporting of screen failure participants to 
meet the Consolidated Standards of Reporting Trials (CONSORT) publishing requirements 
and to respond to queries from regulatory authorities. Minimal information includes 
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Participants who do not have all tests completed within the screening period or who 
temporarily do not meet study entry criteria for participation in this study (eg, screen failure 
due to treatment with antibiotics during the screening period, or for administrative reasons) 
may be re-screened 1 time under a new participant number; the participant’s prior ID number 
and reason for re-screening must be documented.
6. STUDY INTERVENTION
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.
For this study, the investigational product(s) are PF-06650833, PF-06651600, and tofacitinib 
administered as individual products, and the combination of PF-06650833 administered 
together with PF-06651600 and of PF-06650833 coadministered with tofacitinib.  
Investigational product will be administered only to participants who have provided informed 
consent.  Once a participant’s participation in the study has ended, investigational product 
will no longer be supplied to the participant by the investigative site and/or sponsor.
6.1. Study Intervention(s) Administered
Intervention 
Name
PF-06650833/
Tofacitinib/
Placebo for 
PF-06651600
PF-06650833/
PF-06651600/
Placebo for 
tofacitinib
PF-06650833/
Placebo for 
PF-06651600/
Placebo for 
tofacitinib
Placebo for 
PF-06650833/
PF-06651600/
Placebo for 
tofacitinib
Placebo for 
PF-06650833/
Placebo for 
PF-06651600/
tofacitinib
ARM
*1
2
3
4
5
Type
Drug
Dose 
Formulation
Tablets
Unit Dose 
Strength
200 mg/
11 mg/
0 mg
200 mg/
50 mg/
0 mg
200 mg/
0 mg/
0 mg
0 mg/
50 mg/
0 mg
0 mg/
0 mg/
11 mg
Dosage Level
400 mg QD/
11 mg QD/
0 mg QD
400 mg QD/
100 mg QD/
0 mg QD
400 mg QD/
0 mg QD/
0 mg QD
0 mg QD/
100 mg QD/
0 mg QD
0 mg QD/
0 mg QD/
11 mg QD
Route of 
Administration
Oral
Investigational 
Medicinal 
Product (IMP)
IMP


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Sourcing
Provided centrally by the Sponsor
Packaging and 
Labeling
Study intervention will be provided in blister packs in cartons containing one month of 
supplies.  Each blister pack and carton will be labeled as required per country 
requirement.
Current Name
tofacitinib is also called Xeljanz®
6.1.1. Administration
Participants will swallow the investigational products whole and will not manipulate or chew 
the investigational products prior to swallowing. IP will be provided in cartons containing 
4 blister cards of IP in individual blisters. A single dose (administration) of IP will consist of 
5 tablets provided as a row in a blister card Table 1. The row will contain different tablet 
types corresponding to the different study drugs and matching placebos. Participants are to 
take all tablets in 1 row of the blister card each day orally in a fasted state (at least 
approximately 4 h after the last and approximately 1.5 h before the next meal), but preferably 
should be taken consistently in the same manner, ideally in the AM before breakfast. Those 
participants who cannot take the dose in the morning due to work or other regularly 
occurring issue may take the dose later in the day provided the fasting requirements are met 
and the doses are taken at approximately the same time each day. Participants will record 
dosing in a dosing log (diary). 
Table 1.
Dosing and Administration of Investigational Products
Treatment 
Arm
Treatment group
(QD)
Treatment Assignment
(Blister Pack)
Matching Placebo
(Blister Pack)
Total 
Tablets 
per Day
1
PF-06650833 
(400 mg) + tofacitinib 
(11 mg)
2 x 200 mg PF-06650833 MR 
tablets AND
1 x 11 mg tofacitinib MR tablet
2 PF-06651600 IR 
matching placebo 
tablets
5
2
PF-06650833 (400 
mg) + PF-06651600 
(100 mg)
2 x 200 mg PF-06650833 MR 
tablets AND
2 x 50 mg PF-06651600 IR 
tablets
1 tofacitinib MR 
matching placebo 
tablet
5
3
PF-06650833
400 mg
2 x 200 mg PF-06650833 MR 
tablets
2 PF-06651600 IR 
and 1 tofacitinib MR 
matching placebo 
tablets
5
4
PF-06651600
100 mg
2 x 50 mg PF-06651600 IR 
tablets
2 PF-06650833 MR 
and 1 tofacitinib MR
matching placebo 
tablets
5
5
Tofacitinib
11 mg
1 x 11 mg tofacitinib MR tablet
2 PF-06650833 MR 
and 2 PF-06651600 
IR matching placebo 
tablets
5


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6.2. Preparation/Handling/Storage/Accountability
1. The investigator or designee must confirm appropriate temperature conditions have 
been maintained during transit for all study interventions received and any 
discrepancies are reported and resolved before use of the study intervention, as 
applicable for temperature-monitored shipments. 
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 temperature since previously documented for all 
site storage locations upon return to business.
3. The investigator, institution, or the head of the medical institution (where applicable) 
is responsible for study intervention accountability, reconciliation, and record 
maintenance (ie, receipt, reconciliation, and final disposition records).  All study 
interventions will be accounted for using an IP accountability form/record.
4. Further guidance and information for the final disposition of unused study 
interventions are provided in the IP manual.
5. Any storage conditions stated in the SRSD will be superseded by the storage 
conditions stated on the product label. 
6. Study interventions should be stored in their original containers and in accordance 
with their labels. 
7. See the IP manual, package insert, or equivalent for storage conditions of the study 
intervention.
8. Site staff will instruct participants on the proper storage requirements for take-home 
study intervention. 
9. 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.  It will not be considered a protocol deviation if Pfizer 
approves the use of the study intervention after the temperature excursion. Use of the 
study intervention prior to Pfizer approval will be considered a protocol deviation. 
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.


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10. The sponsor or designee will provide guidance on the destruction of unused study 
intervention (eg, at the site).  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, and all destruction must be adequately 
documented.
Additional details about accountability, storage, destruction, and excursion reporting can be 
found in the IP Manual.
6.2.1. Preparation and Dispensing
The IP will be provided as 4 weekly blister cards packaged and dispensed in cartons with 
tamper-evident seals.  It will be dispensed using an Interactive Response Technology (IRT) 
system at each dispensing visit specified in the SoA.  A qualified staff member will dispense 
the IP via the unique container number identified by the IRT system in the cartons provided, 
in quantities appropriate for the study visit schedule.  The participant/caregiver should be 
instructed to maintain the product in the carton and blister cards provided throughout the 
course of dosing and return the carton and blister cards to the site at the next study visit.
6.3. Measures to Minimize Bias: Randomization and Blinding
6.3.1. Allocation to Investigational Product
Allocation of participants to treatment groups will proceed through the use of an IRT system.  
The site personnel (study coordinator or specified designee) will be required to enter or select 
information including but not limited to their Login Identification (ID) and password, the 
protocol number, and the Single Subject Identification Number (SSID or Subject ID) 
assigned by the IRT system.  The site personnel will then be provided with a treatment 
assignment, randomization number, and dispensable unit (DU) or container number when IP 
is being supplied via the IRT system.  The IRT system will provide a confirmation report 
containing the SSID or Subject ID, randomization number and DU or container number 
assigned.  The confirmation report must be stored in the sites’ files. 
Investigational product will be dispensed at the study visits summarized in the SoA. 
Returned IP must not be redispensed to the participants.  The study-specific IRT Quick 
Reference Guide (QRG) and investigator Site Overview will provide contact information and 
further details on the use of the IRT system.
6.3.2. Breaking the Blind 
The IRT system will be programmed with blind-breaking instructions. In case of an 
emergency, the investigator has the sole responsibility for determining if unblinding of a 
participant’s treatment assignment is warranted. Participant safety must always be the first 
consideration in making such a determination. If the investigator decides that unblinding is 
warranted, the investigator should make every effort to contact the sponsor prior to 
unblinding a participant’s treatment assignment unless this could delay further management 


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of the participant. If a participant’s treatment assignment is unblinded, the sponsor must be 
notified within 24 hours after breaking the blind. The date and reason that the blind was 
broken must be recorded in the source documentation and case report form (CRF)/data 
collection tool (DCT).
6.4. Study Intervention Compliance
Participant compliance with completion of Diary and study intervention will be assessed at 
each visit. Participants interrupting study medication for more than 7 consecutive days, or 
participants who are less than 80% compliant with the dosage regimen for any 2 consecutive
visit periods should be withdrawn from the study treatment. Upon discontinuation of the 
study treatment, participants will enter a FU period of 4 weeks, after which they will 
complete the FU/EOS visit and will be withdrawn from the study.
If a dose is missed and the interval to the next dose is less than 8 hours, the missed dose 
should not be administered.
6.5. Concomitant Therapy
It is recommended that participants avoid changing other prescription or non-prescription 
drugs, vitamins, and dietary supplements within 7 days or 5 half-lives (whichever is longer) 
prior to the first dose of study medication and throughout the study.
All concomitant medication taken during the study must be recorded with indication, daily 
dose, and start and stop dates of administration.
Medications taken after informed consent is obtained but before the first dose of study 
medication, will be documented as prior medications.  Medications taken after the first dose 
of study drug has been administered will be documented as concomitant medications. 
Participants receiving non-prohibited concomitant medications for any reason must be on a 
stable regimen, which is defined as not starting a new drug or changing dosage within 7 days 
or 5 half-lives (whichever is longer) prior to first study dose.
6.5.1. Rescue Treatment of RA 
During the active dosing period, no “rescue” treatment is pre-specified. Rescue therapy for 
RA per se is not permitted during the study. Transient (up to 5 consecutive days) addition or 
increased doses of acetaminophen/paracetamol (dosed no more than 2.6 g/day if not on 
background acetaminophen/paracetamol), NSAIDs (up to maximal doses prescribed in the 
product label of package insert), or an opioid (not exceeding the potency equivalent of 20 mg 
of orally-administered morphine) is permitted for limited duration control of pain. If a 
participant is already taking stable background doses of acetaminophen/paracetamol, she/he 
may increase the dose up to 4 gm/day for up to 5 consecutive days.  Participants who require 
increased pain control medication for more than 5 consecutive days should be discontinued 
from the trial and treated for worsening RA as per local standard of care practice. 
Acetaminophen/paracetamol or NSAID may be taken for up to 5 days/week for headache, 
fever, or other acute, non-arthritis pain, provided the total dose (including background dose)


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of acetaminophen/paracetamol does not exceed 2.6 gm/day (or 4 g/d if on background 
acetaminophen/paracetamol) and the NSAID dose is limited to lowest recommended 
anti-pyretic dose. Rescue pain medications will not be provided by the sponsor.
Participants (to the extent possible) should not be dosed with increased doses of pain control 
medication during the 24 hours prior to interval study visits and 7 days prior to Week 0, 
Week 12, and Week 24 visits.  (Note: stable background doses of 
acetaminophen/paracetamol or opioids should NOT be discontinued in advance of study 
visits).
Although the use of additional/increased doses of pain control medications as described 
above is allowable, their use should be delayed, if possible, during the screening period and 
for at least the first 12 weeks following randomization.  The date and time of the 
additional/increased doses of pain control medication administration as well as the name and 
dosage regimen of these medications must be recorded in the CRF.
Participants, who after at least a 12-week trial on the assigned investigational product who 
have not achieved at least a minimal clinical response (as defined by the American College 
of Rheumatology [ACR] 20% response criteria [ACR20]) are to be discontinued from the 
study and treated for their RA according to local standard of care (SoC) practice.  The SoC 
treatment will not be provided by the sponsor.  The Principal Investigator (PI) may also 
discontinue participants at any time during the study if in the PI’s opinion, worsening RA 
signs and symptoms unresponsive to limited-duration increases in analgesic medications 
requires more urgent advancement of RA treatment. Additional treatment for participants 
meeting either of these criteria for discontinuation from the study will be provided by the 
investigator, and upon withdrawal from the study, participants will enter the follow-up phase 
of the study.
6.5.2. Permitted Concomitant Medications
It is recommended that study participants avoid changing other prescription or 
non-prescription drugs, vitamins, and dietary supplements within 7 days or 5 half-lives 
(whichever is longer) prior to the first dose of study medication and throughout the study.
Herbal medications with pharmaceutical properties must be discontinued at least 4 weeks 
before the first dose of study medication.
Study participants receiving non-prohibited concomitant medications for any reason must be 
on a stable regimen, which is defined as not starting a new drug or changing dosage within 
7 days or 5 half-lives (whichever is longer) prior to first study dose.
6.5.2.1. Osteoporosis Drugs
To the extent possible, dosing of concomitant medications indicated to increase bone mineral 
density (eg, bisphosphonates, denosumab) should not occur immediately before study visits, 
and in particular, Day 1 (randomization), Week 12, and Week 24 visits.  A minimal interval 
of approximately 4 weeks prior to a clinic visit is preferred (ie, dosing would occur just after 
a study visit).  Ideally, drugs dosed every 3 months would be administered just after the 


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Week 0 (Day 1), Week 12, and Week 24 visits; drugs dosed every 6 months should not be 
dosed during the active treatment period with doses administered before screening (and 
approximately 4 weeks prior to randomization) and after Week 24.  If a dose of drugs 
administered every 6 months must be given during the active dosing period, the dose should 
optimally be given after the Week 12 visit.
6.5.2.2. Hormonal Contraception
Hormonal contraceptives that meet the requirements of this study are allowed to be used in 
participants who are women of childbearing potential (WOCBP) (see Appendix 4).
6.5.2.3. Background Arthritis Therapy
The following concomitant medications may be continued during the study as background 
RA treatments, provided the dosage(s) do not change for the entire period from Screening 
through Discharge from the study and have been stable for the stipulated interval before 
Randomization.

Anti-malarials (eg, chloroquine, hydroxychloroquine) at doses consistent with their 
labeling.

Nonsteroidal Anti-inflammatory Drugs (NSAIDs), selective cyclooxygenase-2 
inhibitors ("COX-2 inhibitors") at a stable dose in accordance with local 
label/standard of care beginning at least 4 weeks prior to the first dose of study drug 
or “randomization”. Transient increased doses of NSAIDs are permitted for limited 
duration control of pain (see Section 6.5.1 for rescue treatment). Topical NSAIDs are 
allowed at any time during the study.

Acetaminophen/paracetamol at doses ≤2.6 grams per day.  Non-prohibited opioids at 
doses ≤the potency equivalent of 20 mg of orally-administered morphine at a stable 
dose beginning at least 4 weeks prior to the first dose of study drug or 
“randomization”. Since PF-06651600 may increase the exposure of drugs 
metabolized predominantly by CYP3A, participants using opiate analgesics should be 
cautioned about increased opiate side effects (eg, somnolence) and should be cautious 
about driving or using heavy machinery until the effects of IP administration is 
known. Doses of opioids may be reduced if needed to address the increase in opiate 
side effects.

Low dose oral corticosteroids (≤7.5 mg prednisone or equivalent [see Appendix 12
for potency equivalency] per day) at a stable dose beginning at least 4 weeks prior to 
the first dose of study drug or “randomization”. Reductions in oral corticosteroid 
dose are only allowed as needed to protect a participant’s safety. 


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6.5.3. Prohibited Concomitant Medications
6.5.3.1. Strong and Moderate Inhibitors and Inducers of CYP3A4 
Systemic therapy with medications that are strong or moderate CYP3A4 inhibitors, strong 
CYP3A inducers (some common examples are provided in Appendix 11) are prohibited 
within 4 weeks or 5 half-lives (whichever is longer) prior to the Randomization Visit 
(Visit 2) and during the trial. 
6.5.3.2. Strong Inhibitors/Inducers of BCRP
Systemic therapies with medications that are strong inhibitors of Breast Cancer Resistance 
Protein (BCRP) (some common examples are provided in Appendix 11) are prohibited 
within 4 weeks or 5 half-lives (whichever is longer) prior to the Randomization Visit 
(Visit 2) and during the trial. 
6.5.3.3. Substrates of CYP3A4
The exposure of CYP3A4 substrates may increase when co-administered with PF-06651600.
The use of drugs primarily metabolized and cleared by CYP3A4 should be either avoided
within 4 weeks or 5 half-lives (whichever is longer) prior to the Randomization Visit
(Visit 2) and during the trial or used with caution using clinical judgement. Please follow the 
respective approved prescribing guidelines (some common examples are provided in
Appendix 11).
6.5.3.4. Substrates of BCRP
The exposure of substrates of BCRP substrates may increase when co-administered with 
PF-06650833. The use of BCRP substrates listed in Appendix 11 is prohibited within
4 weeks or 5 half-lives (whichever is longer) prior to the Randomization Visit (Visit 2) and 
during the trial. Other BCRP substrates should be used with caution using clinical 
judgement. Please follow the respective approved prescribing guidelines (some common 
examples are provided in Appendix 11).
6.5.3.5. Other Prohibited Concomitant Medications
Herbal medications with pharmaceutical properties must be discontinued at least 4 weeks 
before the first dose of study medication.
Special restrictions regarding prior and concomitant RA drugs are outlined in the Section
below.
6.5.4. Prohibited Background Rheumatoid Arthritis Therapies
6.5.4.1. Disease Modifying Antirheumatic Drugs (DMARDs)
Conventional synthetic, biologic, or other advanced therapy DMARD concomitant 
medications are prohibited during the study. Specific washout requirements for non-
prohibited prior DMARDs are as follows: 


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
Biologic TNF inhibitors:

As noted in Section 5.1, up to 25% of participants may have previously received 
1 (and only 1) approved TNF-inhibiting biologic DMARD administered in 
accordance with its labeling recommendations.  The prior TNF-inhibiting biologic 
DMARD could have been discontinued due to its being deemed inadequately 
effective and/or not tolerated as defined, for the purpose of this study, by the 
investigator’s and participant’s opinions that the participant did not experience 
adequate benefit from the anti-TNF plus the presence of sufficient residual 
disease activity to meet the entry criteria.  The anti-TNF or biologic DMARD
biologic could also have been discontinued due to lack of continued access. The
anti-TNF or biologic DMARD should have been discontinued for a minimum of 
the washout period defined as follows (biosimilars of the below agents should be 
considered the same as the originators): 

entanercept (Enbrel®), adalimumab (Humira®): 6 weeks.

infliximab (Remicade®), golimumab (Simponi®): 10 weeks.

certolizumab pegol (Cimzia®): 12 weeks.

MTX

MTX is to be discontinued (last MTX dose is to occur) during the week before 
randomization on Day 1. Participants whose regularly scheduled MTX dose 
would occur on or up to Day -1 should take that dose. Participants whose 
regularly scheduled MTX dose would have been on the day of randomization 
(Day 1) should not take that dose of MTX. No further MTX dosing is permitted 
during the active dosing phase of the study. Participants may restart MTX dosing 
beginning 14 days after the last dose of IP (Week 26).
6.5.4.2. Other Rheumatoid Arthritis Drugs
The following concomitant background arthritis therapies are prohibited during the study:

Intravenous, and intra-articular corticosteroids.

Other csDMARDs, immunosuppressants/immunomodulators (including tacrolimus or 
other calcineurin inhibitors) and biologic response modifiers (including natalizumab 
or other anti-integrin biologics). 

Participants with prior use of tofacitinib or other JAK inhibitor are excluded.  
Concomitant use of tofacitinib or other JAK inhibitor (other than as prescribed by the 
randomization scheme) is prohibited.


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The following drugs are excluded during the study and for the prescribed washout period 
prior to the start of the study:

Auranofin (oral gold), aurothioglucose (injectable gold), aurothiomalate (injectable 
gold) must be discontinued for 8 weeks prior to the first dose of the study medication.

Sulfasalazine, d-penicillamine, bucillamine, mizoribin, azathioprine, cyclosporine, 
tacrolimus, and staphylococcal protein A immuno-absorbant pheresis columns 
(eg, PROSORBA® device/column) must be discontinued for 4 weeks prior to the first 
dose of study medication.

Leflunomide (Arava®) must be discontinued 8 weeks prior to the first dose of study 
medication if no elimination procedure is followed.  Alternately, it should be 
discontinued with the following elimination procedure at least 4 weeks prior to the 
first dose of study medication:

Cholestyramine at a dosage of 8 grams three times daily for at least 24 hours, or 
activated charcoal at a dosage of 50 grams 4 times a day for at least 24 hours 
(US Product Insert (USPI), Elimination Procedure to significantly lower 
leflunomide drug levels).
6.6. Dose Modification
This protocol does not allow alteration from the currently outlined dosing schedule.
6.7. Intervention After the End of the Study
No intervention will be provided to study participants at the end of the study.
7. DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL
7.1. Discontinuation of Study Intervention
In rare instances, it may be necessary for a participant to discontinue IP permanently.  If IP is 
permanently discontinued, the participant will enter the required 4-week FU period, after 
which the participant will not remain in the study unless the participant is being 
treated/followed for an adverse event and agrees to the non-drug follow-up.
Note that discontinuation of IP does not represent withdrawal from the study. 
7.2. Participant Discontinuation/Withdrawal From the Study
A participant may withdraw from the study at any time at his/her own request or may be 
withdrawn at any time at the discretion of the investigator for safety, behavioral, compliance, 
or administrative reasons.


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At the time of discontinuing from the study, if possible, an early withdrawal (EW) 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 randomized and then are 
prematurely withdrawn from the study.  Participants should be questioned regarding their 
reason for withdrawal.  The participant will be permanently discontinued both from the study 
intervention and from the study at that time.
If a participant withdraws from the study, he/she may request destruction of any remaining 
samples, but data already generated from the samples will continue to be available, and may 
be used to protect the integrity of existing analyses.  The investigator must document any 
such requests in the site study records.
If the participant withdraws from the study and also withdraws consent (see below) 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.
When a participant withdraws from the study because of an SAE, the SAE must be recorded 
on the CRF and reported on the Clinical Trial (CT) SAE Report.
Lack of completion of all or any of the withdrawal/early termination procedures will not be 
viewed as protocol deviations so long as the participant’s safety was preserved.
The Sponsor’s clinical team should be consulted as soon as possible if a participant is being 
considered for or has been discontinued from study treatment for an adverse event or other 
safety issue.
Participants interrupting study medication for more than 7 consecutive days (either due to 
lack of compliance or in response to an AE), or patients who are less than 80% compliant 
with the dosage regimen for any 2 consecutive visit periods should be withdrawn from the 
study. Upon discontinuation of the study treatment, participants will enter a FU period of 
4 weeks, after which they will complete the FU/EOS visit and will be withdrawn from the 
study.
Any participant who meets discontinuation criteria as specified in Section 8.10 should be 
discontinued from the study.
ECG Changes 
A participant who meets either of the bulleted criteria based on the average of triplicate ECG 
readings will be withdrawn from the study. 

QTcF >500 msec.


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
Change from baseline: QTc >60 msec.
If a clinically significant finding is identified (including, but not limited to, changes from 
baseline/randomization 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.
See the SoA for data to be collected at the time of intervention discontinuation and follow-up 
and for any further evaluations that need to be completed.
Withdrawal of Consent: 
Participants who request to discontinue receipt of study treatment 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 investigational product 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.
Participants who discontinue receipt of treatment due to lack of response will be discontinued
from this study and will be treated for their RA according to local standard of care (SoC) 
practice.  Upon discontinuation of the study treatment, participants will enter a FU period of 
4 weeks, after which they will complete the FU/EOS visit and will be withdrawn from the 
study.
Participants who discontinue receipt of treatment due to AE will be discontinued from this 
study and followed until the event is considered resolved or the participant is considered 
clinically stable. 
7.3. Lost to Follow-up 
A participant will be considered lost to follow-up if he or she repeatedly fails to return for 
scheduled visits and is unable to be contacted by the study site.
The following actions must be taken if a participant fails to return to the clinic for a required 
study visit:


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
The site must attempt to contact the participant and reschedule the missed visit as 
soon as possible and counsel the participant on the importance of maintaining the 
assigned visit schedule and ascertain whether or not the participant wishes to and/or 
should continue in the study.

Before a participant is deemed lost to follow-up, the investigator or designee must 
make every effort to regain contact with the participant (where possible, 3 telephone 
calls and, if necessary, a certified letter to the participant’s last known mailing 
address or local equivalent methods). These contact attempts should be documented 
in the participant’s medical record.

Should the participant continue to be unreachable, he/she will be considered to have 
withdrawn from the study. 
Discontinuation of specific sites or of the study as a whole is handled as part of Appendix 1.
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.
Immediate safety concerns should be discussed with the sponsor immediately upon 
occurrence or awareness to determine if 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.
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.


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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.
Blood samples may be taken for safety assessments at times specified by Pfizer, provided the 
total volume taken during the study does not exceed 550 mL during any period of 
60 consecutive days.
8.1. Efficacy Assessments
8.1.1. American College of Rheumatology (ACR) Assessments 
The specific components of the ACR Assessments (ACR Core Dataset) that will be used in 
this study are:
1. Tender/Painful Joint count (TJC) (68).
2. Swollen Joint Count (SJC) (66).
4. Patient’s Global Assessment (PtGA) of Arthritis.
5. Physician’s Global Assessment (PhGA) of Arthritis.
6. C-Reactive Protein (CRP), measured by high sensitivity methodology (hsCRP).
Components of the ACR Core Dataset will be collected at the visits indicated in the SoA.
Details regarding the physician-conducted and laboratory assessments are provided below.
Details on the participant-provided assessments are described in Section 8.1.3.  
The responder according to 
this definition has the TJC68 ≤1 SJC66 ≤1, CRP ≤1 mg/dL and PtGA ≤10 (on 1-100 scale).
8.1.1.1. Tender/Painful Joint Count (68)
Sixty-eight (68) joints will be assessed by a blinded joint assessor (ie, someone not otherwise
involved in the conduct of the study, and not having interactions with study participants or 
site personnel directly involved in the study) to determine the number of joints that are 
considered tender or painful.  The response to pressure/motion on each joint will be assessed 
using the following scale: Present/Absent/Not Done/Not Applicable (to be used for artificial 
or missing joints).  Artificial joints will not be assessed.
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The 68 joints to be assessed are:

Upper Body: temporomandibular, sternoclavicular, acromioclavicular;

Upper Extremity: shoulder, elbow, wrist (includes radiocarpal, carpal and 
carpometacarpal considered as 1 unit), metacarpophalangeals (MCP I, II, III, IV, V), 
thumb interphalangeal (IP), proximal interphalangeals (PIP II, III, IV, V), distal 
interphalangeals (DIP II, III, IV, V);

Lower Extremity: hip, knee, ankle, tarsus (includes subtalar, transverse tarsal and 
tarsometatarsal considered as one unit), metatarsophalangeals (MTP I, II, III, IV, V), 
great toe interphalangeal (IP), proximal and distal interphalangeals combined (PIP II, 
III, IV, V).
8.1.1.2. Swollen Joint Count (66)
The blinded joint assessor will also assess joints for swelling using the following scale: 
Present/Absent/Not Done/Not Applicable (to be used for artificial or missing joints). 
Sixty-six (66) joints will be assessed for swelling, the same as those listed above for 
tenderness/pain, except that the right and left hip joints are not included in the swollen joint 
count.  Artificial joints will not be assessed.
8.1.1.3. Tender and Swollen Joint Counts (28)
The twenty-eight tender/painful and swollen joint counts are a subset of the 68/66 tender and 
swollen joint counts and includes the following joints: shoulders, elbows, wrists, 
metacarpophalangeal joints (MCP), proximal interphalangeal joints (PIP), and knees.  The 
28 tender/painful join count will be calculated by Pfizer from the 68 tender/painful joint 
count assessed by the blinded joint assessor as described in Section 8.1.1.
The 28 swollen joint count uses the same joints as the 28 tender/painful joint count, and will 
be calculated by Pfizer from the 66 swollen joint count assessed for swelling by the blinded 
joint assessor as described in Section 8.1.2.
8.1.1.4. Physician’s Global Assessment (PhGA) of Arthritis
The investigator will assess how the patient’s overall arthritis appears at the time of the visit.  
This is an evaluation based on the patient’s disease signs, functional capacity and physical 
examination, and should be independent of the Patient’s Global Assessment of Arthritis.  The 
investigator’s response will be recorded using a 100 mm visual analog scale (VAS).
8.1.1.5. C-Reactive Protein (CRP)
Samples for analysis of high sensitivity CRP (hsCRP) will be collected at the visits specified 
in the SoA. The samples will be shipped to and analyzed by a central laboratory.  After 
randomization, the investigator and Pfizer Study Personnel directly involved in the conduct 
of the trial will be kept blinded of the results of this test.


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8.1.2. Composite Efficacy Assessments Derived from the ACR Core Dataset
The ACR core data set are used in various combinations to produce composite scores or 
indices which are used as more wholistic assessments of disease activity and study efficacy 
endpoints. The details of these composite efficacy endpoints are provided in the sections 
below.
8.1.2.1. Disease Activity Score (DAS) Assessments
The Disease Activity Score (DAS) assessment is a continuous composite measure of TJC, 
SJC, PhGA, and an acute phase reactant that is either CRP 
. The DAS is derived 
using differential weighting given to each component.  DAS28 is a measure based on 
assessment of 28 joints for tenderness and swelling (tender and swollen joint counts). 
DAS28 will be calculated with 4 components (TJC, SJC, PtGA, and either CRP
 
[DAS28-CRP 
]).  The formulae for calculation of DAS28-CRP, 
are presented in the Appendix 10.  
Remission and low disease activity were defined as scores <2.6 and ≤3.2, respectively for 
DAS28-CRP.
8.1.2.2. ACR Responder Analysis
The American College of Rheumatology’s definition for calculating improvement in RA 
(ACR20) is calculated as a 20% improvement in tender and swollen joint counts and 
20% improvement in 3 of the 5 remaining ACR-core set measures: patient and physician 
global assessments, pain, disability, and an acute-phase reactant which for this study will be 
CRP or ESR.  Similarly, ACR50, ACR70, and ACR 90 are calculated with the respective 
percent improvement.
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8.1.4. Rater Qualifications 
Clinical evaluations of RA (eg, tender/painful joint assessments) will be performed by an 
experienced and qualified rheumatologist (board certified or equivalent).  An experienced 
and qualified non-rheumatologist physician or experienced medical professional with 
experience in the conduct of RA clinical trials may be permitted to perform the clinical 
evaluations of RA when designated by primary site investigator.  The evaluator must be able 
to document competency in performing the efficacy assessment scales (eg, through prior 
training with certification, or at least 3 years’ experience performing the assessments in 
Industry-sponsored clinical trials) prior to performing these evaluations.  To assure 
consistency and reduce variability, the same evaluator must assess all rheumatology 
clinical evaluations for any individual participant throughout the study whenever 
possible; a back-up experienced and qualified, protocol-trained evaluator will only be 
allowed and documented in case of emergency or special situations when the designated 
evaluator is unable to perform the evaluation. The raters who administer specific study 
assessments will be documented in a centralized location and all site staff who administer 
ratings will be verified in the site study documentation during the conduct of the study. 
Sixty-eight (68) joints will be assessed by a blinded joint assessor (not otherwise involved in 
the conduct of the study, and not have other interactions with study participants or site 
personnel directly involved in the study) to determine the number of joints that are 
considered tender or painful.
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8.1.5. Imaging Assessments/MRI of Hand/Wrist
Depending on logistical and feasibility considerations, MRIs of the hand may be performed 
in a subset of participants (up to approximately 60 participants per arm) who agree to be 
included in this aspect of the study as allocated according to the study randomization scheme.  
Participants who refuse to undergo MRI may still be eligible for enrollment into the study.
Participants in the MRI subgroup will be recruited globally in the order of enrollment in the 
Integrated Voice Response System (IVRS) up to a maximum number as defined by the 
sponsor.
If the substudy is conducted, a baseline MRI of a single hand and wrist will be performed 
during screening period after all other eligibility criteria have been met and at least 1 week 
prior to randomization (Visit 2).  Follow-up MRIs will be performed at Visit 6/Week 12 
(±1 week), and Visit 9/Week 24 (-2 to +1 week), as specified in the imaging guidelines 
(which for these procedures will supersede the SoA).  A delay in acquisition of the Baseline 
MRI up to 1 week (7 days) after Randomization at Visit 2 (Week 0, Day 1) solely due to 
scheduling availability will not be considered a protocol deviation. At all visits, MRI will be 
performed on the same hand and wrist, both before, during and after intravenous 
administration of a gadolinium contrast agent.  All images will be evaluated by centralized 
reviewers blinded to the treatment designation.  MRI assessments will include evaluation of 
synovitis, bone marrow edema, and bone erosions using the RAMRIS and RAMRIQ scoring 
methods. RAMRIS is a semi-quantitative scoring system to evaluate longitudinal changes in 
RA patients.  RAMRIQ is a quantitative version of the RAMRIS scoring system.  When 
image quality permits, dynamic contrast enhanced-MRI (DCE-MRI) analysis will also be 
evaluated. Procedures for obtaining MRI images and evaluating images will be described in 
separate imaging guidelines and an image review charter.  The imaging guidelines will be 
provided to investigators and radiology personnel prior to initiation of the study. Details of 
the statistical analyses of the results will be provided in the statistical analysis plan (SAP).
Management of Incidental Findings
An incidental finding is one unknown to the participant that has potential health or 
reproductive importance, which is discovered unexpectedly in the course of a research study, 
but is unrelated to the purpose and beyond the aims of the study.
MRI images will be reviewed by a central review facility.  The purpose of this review is to 
evaluate images for synovitis, bone marrow edema, and bone erosions.  Central image review 
is not a complete medical review of the participant.  If, during the central review process, an 
unexpected observation is identified and this finding could, in the opinion of the central 
reviewer, have a significant health or reproductive consequence, this finding may be shared 
with the study sponsor for disclosure to the principal investigator (PI).  All follow-up testing 
and final diagnosis will be left to the discretion of the medical professionals at the site or 
those with an existing physician-participant relationship.  The PI will be responsible for 
reporting any AEs identified from incidental findings as described in the AE reporting 
section.  Identification of such incidental findings during the central review process should 


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not be expected, and the site maintains responsibility for performing a general safety review 
of all images as per site protocols.
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 concerns.
Safety will be assessed by the spontaneous reporting of AEs, physical examinations, vital 
signs, ECGs, and clinical laboratory results in all participants who received at least 1 dose of 
study medication.  Investigators and Pfizer Clinicians will review individual participant data 
throughout the conduct of the trial to ensure participant’s well-being.
8.2.1. Creatinine and estimated Glomerular Filtration Rate
Estimated GFR will be calculated via the 2012 Chronic Kidney Disease Epidemiology 
Collaboration (CKD-EPI) creatinine, for reporting purposes. Investigators may also use 
other methods for following renal function if eGFR from the central laboratory is not readily 
available.
Serum creatinine will be measured and creatinine based eGFR will be calculated at times 
specified in the SoA in order to facilitate calculation of eGFR and assess renal function.at 
these time points.  
8.2.2. Clinical Safety Laboratory Tests
See Appendix 2 for the list of clinical safety laboratory tests to be performed and the SoA for 
the timing and frequency.
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 2 weeks after the last dose of study intervention should be 
repeated until the values return to normal or baseline (prior the participant’s receiving the 
investigational product) 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.
All protocol-required laboratory assessments, as defined in Section 10.2, must be conducted 
in accordance with the laboratory manual and the SoA.


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If laboratory values from non-protocol-specified laboratory assessments performed at the 
institution’s local laboratory require a change in participant management or are considered 
clinically significant by the investigator (eg, SAE or AE or dose modification), then the 
results must be recorded in the CRF.
8.2.3. Viral Surveillance
A blood sample for potential viral load surveillance will be collected as indicated in the SoA. 
Assessment may include EBV and cytomegalovirus (CMV). 
8.2.4. Medical History
Medical history, including history of alcohol, tobacco and drug abuse; RA history, including 
disease duration and extent of disease; major cardiovascular events including DVT, PE, and 
ischemic cerebral vascular accidents (CVA); history of herpes virus infection, vaccination 
(particularly for HZV); skin rash; skin infection and any abnormalities that may predispose 
the subject to infection and smoking history will be collected at Screening. Height and 
weight will be measured without the participant wearing shoes.  Height (inches or 
centimeters) and weight (lbs or kg) will be measured up to 1 decimal place and recorded in 
the source document per the SoA. 
8.2.5. Physical Examinations
8.2.5.1. Complete Physical Examination
A standard/complete physical examination will be performed by a qualified physician 
(Doctor of Medicine [MD], or equivalent) or other experienced medical professional
(eg, Doctor of Osteopathic (DO)), Nurse Practitioner, Physician’s Assistant) at the visits 
identified in SoA. The following parameters and body systems will minimally be examined 
and any abnormalities described: General appearance, skin (eg, presence of rash), Head, Eye, 
Ear, Nose and Throat (HEENT), lungs (auscultation), heart (auscultation for presence of 
murmurs, gallops, rubs, peripheral edema), abdominal (palpation and auscultation), 
neurologic (including cranial nerves, reflexes, motor and sensory function and assessment of 
cerebellar function such as gait, coordination, ataxia) and, lymph nodes.
8.2.5.2. Targeted Physical Examination
At all other visits, as defined in the SoA, an abbreviated physical examination will be 
performed that will minimally include the following: skin, lungs, heart, abdomen and lymph 
nodes.  Additional organ systems may be examined at the investigator decision.  Any 
clinically significant changes from the baseline examination should be recorded as AEs.  
Body temperature also will be collected at these visits.  Both full and targeted physical 
examinations must include a full body skin and neurologic examinations (neurologic 
examination would include assessment of cerebellar function).  Skin examinations should 
include a visual inspection of the breasts and external genitalia.


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8.2.5.3. Dermatology/Skin
Skin lesions will be evaluated as defined in the National Cancer Institute Common Toxicity 
Criteria for Adverse Events v5.0 and managed as shown below in Table 2.
Table 2.
Management of Dermatological Events
Dermatologic Event (CTCAE v 5.0)
Course of Management
Acne/Acneiform Rash/Maculopapular Rash
Grade 1/2
1. Investigator’s discretion for withdrawing IP.
2. Execute reasonable monitoring.
3. Consider treatment with topical agents such as 
clindamycin or corticosteroids.
Grade 3
1. Discontinue IP.
2. Monitor to resolution (defined as a Return to Baseline 
status).
3. Consider treatment with topical agents such as 
clindamycin or corticosteroids.
Pruritus
Grade 1 Mild or localized
1. Investigator’s discretion for withdrawing IP.
2. Execute reasonable monitoring.
3. Consider treatment with topical agents such as 
clindamycin or corticosteroids.
Grade 2 Intense or widespread
1. Discontinuation of the IP may not be required unless 
condition is sustained >4 days or at the investigator’s 
discretion.
2. Execute reasonable monitoring.
3. Consider treatment with topical agents such as 
clindamycin or corticosteroids.
Grade 3 Intense or widespread and interfering 
with activities of daily living
1. Permanently discontinue IP.
2. Monitor to resolution (Return to Baseline).
3. Consider treatment with topical agents such as 
clindamycin or corticosteroids.
In any event of an unexplained rash, a blood sample for viral surveillance will be collected 
for the analysis of viral load including but not limited to CMV, EBV, Herpes Simplex Virus 
type 1 (HSV1), HSV2, and varicella-Zoster Virus (VZV).  For a suspected infectious rash, a 
swab (for microbiological assessment) of the affected area will also be taken for culture and 
sensitivity to assess for any bacterial or fungal pathogens.  For any occurrence of a suspected 
herpetiform rash (eg, herpes zoster and herpes simplex) an additional swab of the affected 
area will be collected for confirmation.  Details for these collections will be provided in the 
laboratory manual.
Investigators will complete the rash assessment CRF and take appropriate photographs of the 
rash in order to provide information necessary for a dermatologist’s assessment of the event.


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All participants reporting an unexplained skin rash should be referred to a local dermatologist 
according to local guidelines for formal comprehensive dermatologic evaluation.  A 4 mm 
punch biopsy should be taken and sent to the local laboratory for histological investigation of 
the rash in order to gain insight into potential etiology of the rash.  If the rash is present on 
the face or other cosmetically exposed area, biopsy can be at the discretion of the 
dermatologist.  All events of rash should be treated according to international and local 
guidelines for the treatment of rash, eg, where appropriate, topical corticosteroids and/or 
agents such as antibiotics or antivirals could be prescribed. 
All treatment-related reports of rash will be followed up until resolution or clinically stable or 
agreement with Pfizer.  Upon resolution of a Grade 1 or 2 rash/pruritus, including confirmed 
herpes zoster, participants may be re-challenged with IP at the discretion of the investigator.  
Re-challenge is not permitted with Grade 3 rash/pruritus.
All de-identified dermatologic consultation reports, biopsy results, culture results, 
photographs, and any additional relevant test results will be forwarded to Pfizer/designee for 
review within 30 days of receipt by the PI.
An independent dermatologist contracted by Pfizer may review all relevant data and 
summarize the data at the end of the study. 
8.2.6. Vital Signs
Oral, tympanic, or temporal artery temperature (using the same methods throughout the 
study); pulse rate; and blood pressure will be assessed.
Vital signs will be measured with the participant in a sitting/semi-supine position after at
least 10 minutes of rest and will include temperature, systolic and diastolic blood pressure, 
and pulse.  Three readings of blood pressure and pulse rate will be taken.  The first reading 
should be rejected.  The second and third readings should be averaged to give the 
measurement to be recorded in the CRF. At W12 pulse will also be collected at 
approximately 2 to 4 hrs post dose.  
8.2.7. Audiogram
All participants will have an audiogram at times specified in the SoA.  Audiograms may be 
performed within a ±2 week window relative to the study visit.  When possible, the 
participant should have the audiogram performed at the same evaluation center during the 
study. Audiogram should be performed at the Early Termination (ET) visit unless the 
previous audiogram was less than 16 weeks prior to this.
If there is a clinically meaningful, treatment related decline in hearing from baseline
screening the subject will be followed off treatment with appropriate testing at regular 
intervals, until hearing returns to baseline (prior to the participant’s receiving the 
investigational product) or is determined to be clinically stable.
The information from the audiogram will be entered into the data collection tool.


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Any de-identified audiogram results/reports and any additional relevant test results 
(if applicable) may be requested to be forwarded to Pfizer (and/or designee) at any time 
during the study. Further details will be provided to investigators prior to the start of the 
study.
8.2.8. Electrocardiograms
Single 12-lead ECGs will be obtained on all participants at times specified in the SoA.  All 
scheduled ECGs should be performed after the participant has rested quietly for at least 
10 minutes in a supine position. ECG results (heart rate, PR interval, RR interval, QRS 
duration, QT interval, rhythm, waveform abnormalities, or other clinically significant 
findings) will be recorded in the CRF. Any clinically significant changes from the 
baseline/Day 1 (Visit 2) ECG may potentially be AEs (Appendix 7) and should be evaluated 
further, as clinically warranted.  ECG values of potential clinical concern are listed in
Appendix 7.
If QTc interval exceeds 450 msec, or QRS duration exceeds 120 msec, the ECG should be 
repeated 2 more times and the average of the 3 QTc or QRS values should be used to 
determine the participant’s eligibility.
If a postdose QTc interval remains ≥30 msec from the baseline and is >450 msec; or an 
absolute QTc value is ≥500 msec for any scheduled ECG for greater than 4 hours (or sooner,
at the discretion of the investigator), QRS duration exceeds 120 msec, or QTc intervals get 
progressively longer, the participant should undergo continuous ECG monitoring.  A 
cardiologist should be consulted if QTc intervals do not return to less than the criterion listed 
above after 8 hours of monitoring (or sooner, at the discretion of the investigator). 
8.2.9. 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 
(Visit 2) prior the participant’s receiving the investigational product.  Pregnancy tests will 
also be done at every study visit, and 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 institutional review boards 
(IRBs)/ethics committees (ECs) or if required by local regulations.  If a urine test cannot be 
confirmed as negative (eg, an ambiguous result), a serum pregnancy test is required.  In such 
cases, the participant must be excluded if the serum pregnancy result is positive.
8.3. Adverse Events and Serious Adverse Events
The definitions of an AE and an SAE can be found in Section 10.3.
AEs will be reported by the participant (or, when appropriate, by a caregiver, surrogate, or 
the participant's legally authorized representative).


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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 it 
meets the criteria for classification as an SAE or that caused the participant to discontinue the 
study (see Section 7). 
In addition, the investigator may be requested by Pfizer Safety to obtain specific follow-up 
information in an expedited fashion.
8.3.1. Time Period and Frequency for Collecting AE and SAE Information
The time period for actively eliciting and collecting AEs and SAEs (“active collection 
period”) for each participant begins from the time the participant provides informed consent, 
which is obtained before the participant’s participation in the study (ie, before undergoing 
any study-related procedure and/or receiving investigational product), through and including 
a minimum of 28 calendar days, except as indicated below, after the last administration of the 
investigational product.
For participants who are screen failures, the active collection period ends when screen failure 
status is determined.
Medical occurrences that begin before the start of study intervention but after obtaining 
informed consent will be recorded on the Medical History/Current Medical Conditions 
section of the case report form (CRF), not the AE section.
Follow-up by the investigator continues throughout and after the active collection period and 
until the event or its sequelae resolve or stabilize at a level acceptable to the investigator, and 
Pfizer concurs with that assessment.
Investigators are not obligated to actively seek AEs or SAEs after conclusion of the study 
participation.  However, if the investigator learns of any SAE, including a death, at any time 
after a participant has been discharged from the study, and he/she considers the event to be 
reasonably related to the study intervention or study participation, the investigator must 
promptly notify the sponsor.
8.3.1.1. Reporting SAEs to Pfizer Safety
All SAEs occurring in a participant during the active collection period 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.
SAEs occurring in a participant after the active collection period has ended are reported to 
Pfizer Safety if the investigator becomes aware of them; at a minimum, all SAEs that the 
investigator believes have at least a reasonable possibility of being related to investigational 
product must be reported to Pfizer Safety.


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8.3.1.2. Recording Nonserious AEs and SAEs on the CRF
During the active collection period, both nonserious AEs and SAEs are recorded on the CRF.
8.3.2. Method of Detecting AEs and SAEs
The method of recording, evaluating, and assessing causality of AEs and SAEs and the 
procedures for completing and transmitting SAE reports are provided in Appendix 3.
Care will be taken not to introduce bias when detecting AEs and/or SAEs.  Open-ended and 
nonleading verbal questioning of the participant is the preferred method to inquire about 
AE occurrences.
8.3.3. Follow-up of AEs and SAEs
After the initial AE/SAE report, the investigator is required to proactively follow each 
participant at subsequent visits/contacts. For each event, the investigator must pursue and 
obtain adequate information until resolution, stabilization, the event is otherwise explained, 
or the participant is lost to follow-up (as defined in Section 7.3).
In general, follow-up information will include a description of the event in sufficient detail to 
allow for a complete medical assessment of the case and independent determination of 
possible causality.  Any information relevant to the event, such as concomitant medications 
and illnesses, must be provided.  In the case of a participant death, a summary of available 
autopsy findings must be submitted as soon as possible to Pfizer Safety. 
Further information on follow-up procedures is given in Appendix 3.
8.3.4. Regulatory Reporting Requirements for SAEs
Prompt notification by the investigator to the sponsor of an SAE is essential so that legal 
obligations and ethical responsibilities towards the safety of participants and the safety of a 
study intervention under clinical investigation are met.
The sponsor has a legal responsibility to notify both the local regulatory authority and other 
regulatory agencies about the safety of a study intervention under clinical investigation.  The 
sponsor will comply with country-specific regulatory requirements relating to safety 
reporting to the regulatory authority, institutional review boards (IRBs)/ethics committees 
(ECs), and investigators.
Investigator safety reports must be prepared for suspected unexpected serious adverse 
reactions (SUSARs) according to local regulatory requirements and sponsor policy and 
forwarded to investigators as necessary.
An investigator who receives an investigator safety report describing an SAE or other 
specific safety information (eg, summary or listing of SAEs) from the sponsor will review 
and then file it along with the investigator’s brochure and will notify the IRB/EC, if 
appropriate according to local requirements.


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8.3.5. Exposure During Pregnancy or Breastfeeding, and Occupational Exposure
Exposure to the investigational product under study during pregnancy or breastfeeding and 
occupational exposure are reportable to Pfizer Safety within 24 hours of investigator 
awareness.
8.3.5.1. Exposure During Pregnancy
Details of all pregnancies in female participants will be collected after the start of study 
intervention and until 4 weeks after the last dose of study medication (Week 28).
If a pregnancy is reported, the investigator should inform the sponsor within 24 hours of 
learning of the pregnancy and should follow the procedures outlined in Appendix 4.
Abnormal pregnancy outcomes (eg, spontaneous abortion, fetal death, stillbirth, congenital 
anomalies, ectopic pregnancy) are considered SAEs.
8.3.5.2. Exposure During Breastfeeding
Scenarios of exposure during breastfeeding must be reported, irrespective of the presence of 
an associated SAE, to Pfizer Safety within 24 hours of the investigator’s awareness, using the 
CT SAE Report Form.  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’s administration, the SAE is reported together with the exposure during breastfeeding.
8.3.5.3. Occupational Exposure
An occupational exposure occurs when, during the performance of job duties, a person 
(whether a healthcare professional or otherwise) gets in unplanned direct contact with the 
product, which may or may not lead to the occurrence of an AE.
An occupational exposure is reported 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 does not pertain to a participant enrolled in the study, the 
information is not recorded on a CRF; however, a copy of the completed CT SAE Report 
Form is maintained in the investigator site file.
8.3.6. Adjudication of Targeted Adverse Events
Certain targeted adverse events, as enumerated below, will be subject to adjudication by an 
adjudication/review committee. These events will be forwarded for adjudication either by 
the study team or by its designee. Documents or additional information related to the event 
may be requested from sites and may vary with the event requiring adjudication and may 
include (but not be limited to): hospital discharge summaries, operative reports, clinic notes, 
diagnostic tests, pathology reports, autopsy reports and death certificate information, as 
applicable. Details on the adjudication process, will be provided in an adjudication
committee charter.


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8.3.6.1. Major Adverse Cardiovascular Events (MACE)
All major adverse cardiovascular events requiring hospitalization and deaths will be recorded 
as SAEs and additional data solicited in the CRF. Venous thromboembolic events (VTE) 
such as deep vein thrombosis (DVT) and pulmonary embolism (PE) will be adjudicated and 
will have additional information requested on separate CRF pages.
8.3.6.2. Opportunistic and Serious Infections
AEs of opportunistic or serious infections will be adjudicated and will have additional 
information requested on separate CRF pages.
8.3.6.3. Elevated Liver Enzymes and Liver Injury
AEs for elevated liver enzymes (AST, ALT, total bilirubin) and liver injury will be 
adjudicated and will have additional information requested on separate CRF pages.
8.3.6.4. Malignancies
All AEs of malignancies will be adjudicated and will have additional information requested.
8.3.6.5. Neurosensory Adverse Events
Neurosensory adverse events will be adjudicated and will have additional information 
requested.
8.3.6.6. Interstitial Lung Disease (ILD)
AEs of ILD will be adjudicated and will have additional information requested.
8.3.7. Medication Errors
Medication errors may result from the administration or consumption of the investigational 
product by the wrong participant, or at the wrong time, or at the wrong dosage strength.
Exposures to the investigational product 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 investigational product;


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•
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 an AE page of the 
CRF. 
Medication errors should be reported to Pfizer Safety within 24 hours on a CT SAE Report 
Form only when associated with an SAE.
8.4. Treatment of Overdose
For this study, any dose of investigational product greater than 1 row of tablets in the IP 
dosing card or multiple tablets within 1 or more columns of the IP blister card within a 
24-hour (-2 hours) time period will be considered an overdose.  
Sponsor does not recommend specific treatment for an overdose. Treatment of overdose 
should consist of general supportive measures.
In the event of an overdose, the investigator/treating physician 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 investigational products
(whichever is longer).
4. Document the quantity of the excess dose as well as the duration of the overdose in 
the CRF.
5. Overdose is reportable to Safety only when associated with an SAE.
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.
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8.6. Pharmacodynamics
Pharmacodynamic (PD) parameters (other than CRP and ESR, ACPA and RF, described 
above) are not evaluated in this study.
8.7. Genetics
8.7.1. Specified Genetics
Genetics (specified analyses) are not evaluated in this study.
8.7.2. Banked Biospecimens for Genetics
A 4-mL blood sample optimized for DNA isolation Prep D1 will be collected as local 
regulations and IRBs/ECs allow. 
Banked biospecimens may be used for research related to drug response and RA.  Genes and 
other analytes (eg, proteins, ribonucleic acid [RNA], nondrug metabolites) may be studied 
using the banked samples. 
Unless prohibited by local regulations or IRB/EC decision, participants will be asked to 
indicate on the consent document whether they will allow their banked biospecimens to also 
be used to design and conduct research in order to gain a further understanding of other 
diseases and to advance science, including development of other medicines for patients.  This 
component of the sampling banking is optional for participants; they may still participate in 
the study even if they do not agree to the additional research on their banked biospecimens.  
The optional additional research does not require the collection of any further samples. 
See Appendix 5 for information regarding genetic research.  Details on processes for 
collection and shipment of these samples will be provided in the lab manual.
8.8. Biomarkers
8.8.1. Specified Gene Expression (RNA) Research 
Specified gene expression (RNA) research is not included in this study.
8.8.2. Specified Protein Research 
Details on processes for collection and shipment of these sample(s) can be found in the lab 
manual.
8.8.2.1. Anti-Citrullinated Protein Antibodies (ACPA)
Blood samples of approximately 3-ml will be collected as specified in the SoA.  The 
sample(s) may be analyzed for anti-citrullinated protein antibodies.
8.8.2.2. Rheumatoid Factor (RF)
Blood samples of approximately 3-mL will be collected as specified in the SoA.  The 
sample(s) may be analyzed for Rheumatoid Factor.


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8.8.2.3. Interferon Gamma-Induced Protein 10 (IP-10)
Blood samples of approximately 3-ml will be collected as specified in the SoA. The 
sample(s) may be analyzed for IP-10 protein.
8.8.2.4. Immunoglobulin Subtypes
Separate blood samples for immunoglobulin subtype analyses of approximately 6-ml will be 
collected as specified in the SoA. Serum sample(s) will be evaluated for IgG, IgA, IgM, and 
IgE.
8.8.2.5. Serum for Exploratory Analysis
Blood samples of approximately 6-ml will be collected and as specified in the SoA. Serum 
sample(s) may be analyzed for circulating proteins and protein fragments.  
Samples may be stored at a facility selected by the sponsor for a maximum of 15 years (or 
according to local regulations) following the last participant’s last visit for the study.
8.8.3. Specified Metabolomic Research 
Specified metabolomic research is not included in this study.
8.8.4. Banked Biospecimens for Biomarkers
10-mL serum (Prep B2) samples will be collected as local regulations and IRB/ECs allow as 
specified in the SoA.  
2.5-mL whole blood (Prep R1) samples will be collected as local regulations and IRB/ECs 
allow as specified in the SoA.  
Banked biospecimens may be used for research related to drug response and RA.  Genes and 
other analytes (eg, proteins, RNA, nondrug metabolites) may be studied using the banked 
samples. 
Unless prohibited by local regulations or IRB/EC decision, participants will be asked to 
indicate on the consent document whether they will allow their banked samples to also be 
used to design and conduct research in order to gain a further understanding of other diseases 
and to advance science, including development of other medicines for patients.  This 
component of the sampling banking is optional for participants; they may still participate in 
the study even if they do not agree to the additional research on their banked samples.  The 
optional additional research does not require the collection of any further samples.
See Appendix 5 for information regarding genetic research.  Details on processes for 
collection and shipment of these samples can be found in the lab manual. 
8.9. Health Economics
Health economics/medical resource utilization and health economics parameters are not 
evaluated in this study.


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8.10. Triggered Requirements 
Triggered requirements are specified in the Table in Section 8.11.
8.11. Guidelines for Monitoring and Discontinuations
Condition
Action
Renal function
Any serum creatinine increase >50% over the 
average of screening (most recent value prior to 
baseline) and baseline values OR an absolute 
increase in serum creatinine >0.3 mg/dL 
(>26.5 µmol/L) over the average of screening (most 
recent value prior to baseline) and baseline values.
The participant should return to the study site for 
prompt retesting, ideally within 3-5 days.
If the second assessment (after the 1st observations 
of ≥0.3 mg/dL (or ≥26.5 µmol/L) in serum 
creatinine relative to study participants’ own 
baseline measurement) is ≥0.4 mg/dL (or 
≥35.4 µmol/L), the subject should be discontinued 
from the study and adequate, immediate, supportive 
measures taken to correct apparent acute kidney 
injury. Participant followed until resolution or 
deemed medically stable by PI.
Liver Function
2 sequential AST or ALT elevations ≥3 x ULN with 
a total bilirubin value ≥2 x ULN.
Treatment with all study drugs will be discontinued 
and the participant withdrawn from this study. 
Participant followed until resolution or deemed 
medically stable by PI.
2 sequential AST or ALT elevations ≥3 x ULN with 
an elevated INR.
Treatment with all study drugs will be discontinued 
and the participant withdrawn from this study.
Participant followed until resolution or deemed 
medically stable by PI.
2 sequential AST or ALT elevations ≥3 x ULN 
accompanied by symptoms consistent with hepatic 
injury.
Treatment with all study drugs will be discontinued 
and the participant withdrawn from this study. 
Participant followed until resolution or deemed 
medically stable by PI.
2 sequential AST or ALT elevations ≥5 x ULN, 
regardless of Total Bilirubin or accompanying 
symptoms.
Treatment with all study drugs will be discontinued 
and the participant withdrawn from this study. 
Participant followed until resolution or deemed 
medically stable by PI.
Any single AST and/or ALT elevation >3 times 
the upper limit of normal (ULN).*
The participant should return to the study site for 
prompt retesting, ideally within 3-5 days.* 
* The participant must return to the study site for prompt retesting and include the following tests: albumin, 
creatine kinase (CK), total bilirubin, direct and indirect bilirubin, GGT, PT/INR, and alkaline phosphatase. 
Additional investigations include a detailed history, occupational exposure, sexual history, travel history, 
history of contact with a jaundiced person, surgery, blood transfusion, history of liver or allergic disease, 
work exposure, history of ethanol, recreational drug and dietary supplement consumption.  Testing for acute 
hepatitis A, B or C infection and biliary tract imaging may be considered.  A participant with a total 
bilirubin value ≥2 × ULN concurrently may need to return to the investigational site and be evaluated as 
soon as possible, preferably within 48 hours from awareness of the abnormal results (refer to Appendix 6).


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Condition
Action
Hematology
Neutrophil counts <1000 cells/mm3.
The participant should return to the study site for 
prompt retesting, ideally within 3-5 days.
Platelet counts <100,000 platelets/mm3.
The participant should return to the study site for 
prompt retesting, ideally within 3-5 days.
Lymphocyte counts <500 lymphocytes/mm3.
The participant should return to the study site for 
prompt retesting, ideally within 3-5 days.
Any single hemoglobin value <8.0 g/dL or one that 
drops ≥2 g/dL below baseline. 
The participant should return to the study site for 
prompt retesting, ideally within 3-5 days.
Two sequential hemoglobin values <8.0 g/dL or a 
decrease of more than 30% from baseline value.
Treatment with all study drugs will be discontinued 
and the participant withdrawn from this study.  
Participant followed until resolution or deemed 
medically stable by PI.
Two sequential platelet counts 
<75,000 platelets/mm3.
Treatment with all study drugs will be discontinued 
and the participant withdrawn from this study. 
Participant followed until resolution or deemed 
medically stable by PI.
2 sequential neutrophil counts <1000 cells/mm3
Treatment with all study drugs will be discontinued 
and the participant withdrawn from this study.  
Participant followed until resolution or deemed 
medically stable by PI.
Confirmed lymphocyte counts 
<500 lymphocytes/mm3 by repeat testing.
Treatment with all study drugs will be discontinued 
and the participant withdrawn from this study. 
Participant followed until resolution or deemed 
medically stable by PI.
Infections
Serious infections defined as any infection (viral, 
bacterial, or fungal) requiring parenteral 
antimicrobial therapy or hospitalization for treatment 
or meeting other criteria that require the infection to 
be classified as a serious adverse event. 
Treatment with all study drugs will be discontinued 
and the participant withdrawn from this study.
Participant followed until resolution or deemed 
medically stable by PI.
Opportunistic infection judged significant by 
investigator.
Treatment with all study drugs will be discontinued 
and the participant withdrawn from this study.
Participant followed until resolution or deemed 
medically stable by PI.
Other
Participants who have a flare of RA requiring 
treatment with prohibited concomitant medication 
are to be discontinued from the study treatment.
Treatment with all study drugs will be discontinued
and participants will be treated for their RA 
according to local standard of care (SoC) practice. 
Upon discontinuation of the study treatment, 
participants will enter a FU period of 4 weeks, after 
which they will complete the FU/EOS visit and will 
be withdrawn from the study.


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Condition
Action
Participants who require additional/increased doses 
of pain control medication for more than 
5 consecutive days for treatment of increased RA 
symptoms should be discontinued from the study 
treatment.
Treatment with all study drugs will be discontinued
and participants will be treated for their RA 
according to local standard of care (SoC) practice. 
Upon discontinuation of the study treatment, 
participants will enter a FU period of 4 weeks, after 
which they will complete the FU/EOS visit and will 
be withdrawn from the study.
Participants who at any time from Week 12 to 
Week 24 do not manifest a minimal clinical response 
as defined by meeting ACR20 criteria.
Treatment with all study drugs will be discontinued 
and participants will be treated for their RA 
according to local standard of care (SoC) practice.  
Upon discontinuation of the study treatment, 
participants will enter a FU period of 4 weeks, after 
which they will complete the FU/EOS visit and will 
be withdrawn from the study.
Venous thromboembolic events (including DVT,
PE).
Withdraw the participant from the study treatment
and follow participant until the event is confirmed. 
Participants suspected of having VTE should be 
questioned for VTE risk factors and have 
appropriate diagnostic testing (such as d-dimers, 
lupus anticoagulant, PT/PTT, platelet counts and 
imaging as deemed appropriate by the PI or 
consultant) to confirm the VTE event. If the VTE 
event is confirmed, investigational product is to be 
withdrawn permanently and the participant 
followed until the event is considered resolved or 
the participant is considered clinically stable by the 
PI.
Other major cardiovascular events [MACE] 
(eg, acute coronary syndrome, ischemic stroke).
Permanently withdraw the participant from study 
treatment until the event is confirmed. 
Participants suspected of having other MACE 
should be questioned for risk factors and have 
appropriate diagnostic testing as deemed 
appropriate by the PI or consultant. Participants 
with confirmed other MACE should be 
permanently discontinued once the event is 
considered resolved or the participant is considered 
clinically stable by the PI.
Malignancies excluding adequately treated non 
melanoma skin cancer (NMSC) and cervical 
carcinoma in situ.
Treatment with all study drugs will be discontinued 
and, if possible, the participant will enter a 4-week 
follow-up period following which the participant 
should be withdrawn from this study.
Increased lipid parameters (total cholesterol, LDL 
cholesterol, HDL cholesterol, triglycerides).
Monitor and treat according to local guidance 
(eg, diet and behavior modification, statin therapy).
Pregnancy or refusal to use appropriate 
contraception.
Permanently withdraw the participant from the 
study and follow any pregnancy to resolution.


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Condition
Action
Use of prohibited concomitant medications.
See Section 6.5.3 Concomitant Medications of the 
protocol for specific actions. Discontinue 
concomitant medications, if possible and monitor 
the participant. If concomitant medications are 
needed to treat participants then treatment with all 
study drugs will be temporarily or permanently 
discontinued. Upon permanently discontinuation of 
the study treatment, participants will enter a FU 
period of 4 weeks, after which they will complete 
the FU/EOS visit and will be withdrawn from the 
study.
Anaphylactic or other serious allergic reaction.
Immediately discontinue study drug and institute 
appropriate therapy.  Participant followed until 
resolution or deemed medically stable by PI.
Symptoms suggestive of a lupus-like syndrome.
Discontinue study drug and institute appropriate 
therapy. Participant followed until resolution or 
deemed medically stable by PI.
9. STATISTICAL CONSIDERATIONS
Detailed methodology for summary and statistical analyses of the data collected in this study 
is outlined here and further detailed in a statistical analysis plan (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. Estimands and Statistical Hypotheses
The characterization of the key estimands E1,E2,E3 that are used in the analyses are 
described in the Table 3. The additional supportive estimands will be described in the SAP. 
The study objectives, endpoints and estimands are described in the Section 3.  
The primary (key secondary) hypothesis is that the efficacy in the combination treatment arm 
based on the primary (key secondary) endpoint is not superior to the efficacy of tofacitinib 
treatment. The primary hypothesis needs to be rejected at the one-sided significance level of 
0.05 for the declaration of the superior efficacy of the particular combination treatment arm. 
No adjustment for the multiplicity (n=2) comparisons of the combination treatment arms 
with the tofacitinib treatment arm will be applied.


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Table 3.
Characterization of the Estimands
Notation 
for the 
Estimand
Population 
Targeted by the 
Scientific Question
Type of 
Endpoint  
Population-level 
Summary for a 
Given Treatment
Metric for 
Comparison 
between the 
Treatment Groups  
Account for the 
Intercurrent 
Events
E1 
All treated study 
participants
Continuous
Mean change from 
baseline 
Difference of mean 
changes from 
baseline
None  
E2
All treated study 
participants
Binary
Probability of 
response
Ratio of 
probabilities of 
response.
None  
E3 
All treated study 
participants
Binary
Probability of 
response
Difference of 
probabilities of 
response
None  
Other estimands may be used for assessing the robustness of results, if performed they will 
be documented in the statistical analysis plan.
 
9.2. Sample Size Determination
9.2.1. Power for the Efficacy Evaluation Based on the Primary Outcome
A sufficient number of participants will be screened to achieve up to approximately 
100 participants randomly assigned to the 2 combination arms and the tofacitinib 
monotherapy arms (the 3 arms used in primary and key secondary hypothesis testing), and up 
to approximately 75 participants to the PF-06650833 and PF-06651600 monotherapy arms.  
The dropout rate by Week 12, the time of the primary analysis, is expected to be no greater 
than approximately 18%, providing up to approximately 82 participants in the tofacitinib and 
combination arm used for the primary hypothesis testing with full 12-week data.  If this 
drop-out rate is exceeded due to COVID-19, the proportion of participants discontinued due 
to COVID-19 may be replaced. The standard deviation of baseline-adjusted 
CFB DAS28-4(CRP) is approximately 1.20 based on prior RA studies run by the Sponsor.  A 
pairwise comparison of a combination arm contrasted with the tofacitinib monotherapy arm 
using a one-sided alpha=0.05 testing level, with an assumed between-arm difference of 0.5 
has a power of approximately 84%.
9.2.2. Power for the Efficacy Evaluation Based on the Key Secondary Outcome
A test of the key secondary hypothesis is based on  the comparison of the proportions of 
study participants with DAS-28-CRP remission at Week 24. In the analysis of binary 
outcomes we will use the non-responder imputation treating missing value of the binary 
outcome as non-response with the exception of the two special cases of the reason for 
missing data. These  special reasons for missing data include missingness related to the 
COVID infection (either patient illness or COVID-related problem of attending the visit) and 
missingness when subject attended the visit but some of the components for the calculation 
of the outcome (eg, ACR20) are missing. The observations that are missing for these special 
reasons will be excluded from the calculation of the probabilities of response at a given visit. 
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This strategy will make a proportion of study participants with missing values at Week 24 
very small as most of the study participants with missing observations will be assigned a 
non-responder status. Based on historical data the remission rate for the tofacitinib 
monotherapy arm is assumed to be 26%. In the absence of missing observation at Week 24 a 
pairwise comparison of a combination arm with the tofacitinib monotherapy arm using a one 
sided alpha=0.05 testing level with an assumed relative remission ratio (combinations 
remission percentage/tofacitinib monotherapy remission percentage) of 1.7 (equivalently a 
combination arm remission rate of 44.2%) has a power of approximately 84%.
9.3. Populations for Analysis
For purposes of analysis, the following populations are defined:
Defined Population for 
Analysis
Description
Modified Intent to Treat
(mITT)
Observations for participants randomly assigned to 
investigational product who take at least 1 dose of 
investigational product.  Participants will be analyzed 
according to the randomized intervention
Safety analysis set
Observations for participants randomly assigned to 
investigational product who take at least 1 dose of 
investigational product.  Participants will be analyzed 
according to the product they actually received.
PD data set 
Observations for participants randomly assigned to 
investigational product and who take at least 1 dose of 
investigational product and have at least 1 of PD parameters 
of interest. Participants will be analyzed according to the 
randomized intervention.
9.4. Statistical Analyses
The SAP will be developed and finalized before database lock and will describe the 
participant populations to be included in 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.
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9.4.1. Efficacy Analyses
Endpoint
Statistical Analysis Methods
Primary:
Change from 
Baseline 
DAS28-CRP 
at Week 12
A Mixed Model Repeated Measures (MMRM) approach to estimate the 
mean change from baseline of DAS28-CRP at Week 12 using data at all 
visits post-baseline up to Week 12 to estimate the effect of the initially 
randomized treatment at Week 12. The analysis will use the mITT 
analysis set Missing data will not be imputed for this analysis. The 
MMRM analysis will contain fixed effect terms for treatment, scheduled 
study visit, baseline DAS 28-CRP, treatment by visit interaction, 
baseline by visit interaction. The model will use an unstructured 
covariance matrix. The primary analysis, comparing the combination 
arm to the tofacitinib monotherapy arm will be done using estimated 
least squares means for each treatment arm at Week 12. The comparison 
will be made at the one-sided significance level of 0.05 and no 
adjustment for multiplicity of comparisons will be attempted.
Key 
Secondary: 
DAS28-CRP 
Remission at 
Week 24
A landmark analysis at Week 24 will estimate the relative risk of 
DAS 28-CRP remission comparing each combination arm to the 
tofacitinib monotherapy arm.  This analysis will use the mITT analysis 
set and the non-responder imputation method (NRI). The NRI treats
missing value of the binary outcome as non-response with the exception 
of the two special cases of the reason for missing data. These special 
reasons are missingness related to the COVID infection (either patient 
illness or COVID-related problem of attending the visit) and missingness 
when subject attended the visit but some of the components for the 
calculation of the outcome (eg, ACR20) are missing. The observations 
that are missing for these special reasons will be excluded from the 
calculation of the probabilities of response at a given visit. 
Exact statistical inference will be used. The comparison will be made at 
the one-sided significance level of 0.05 and no adjustment for 
multiplicity of comparisons will be attempted. 
Other 
Secondary 
 
 
Will be described in the SAP finalized before database lock.
9.4.2. Safety Analyses
All safety analyses will be performed on the safety population derived from all participants 
enrolled.
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Endpoint
Statistical Analysis Methods
Primary
The safety data will be summarized in accordance with Pfizer Data 
Standards. All participants who receive at least 1 dose of IP (safety 
population) will be included in the safety analyses. All safety data will be 
summarized descriptively through appropriate data tabulations, descriptive 
statistics, categorical summaries, and graphical presentations. Safety 
endpoints for the study include:

Treatment-emergent AEs and SAEs;

Withdrawals from active treatment due to AEs;

Serious infections, defined as any infection (viral, bacterial, and 
fungal) requiring hospitalization or parenteral antimicrobials;

Safety laboratory tests (eg, hematology [including coagulation panel], 
chemistry and lipid profiles);

Vital signs;

ECG.
Change from baseline on laboratory data, vital signs and ECG will be 
additionally summarized. Participant listings will also be produced for 
these safety endpoints.
9.4.2.1. 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: 
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, the number of participants with uncorrected QT values >500 msec will be 
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9.5. Interim Analyses
One or more interim analyses (IA) may be performed for internal business decision-making 
or sample size reestimation (there is no intention a priori to terminate the study or a treatment 
arm based on the results of the IA).  The final number and timing of any IA, if performed, 
will be defined by the sponsor.
If an IA is performed, an Interim Analysis Committee/Executive Committee will be 
constituted that will include members of senior Pfizer leadership. Before any interim 
analysis is initiated, the details of the objectives, decision criteria, dissemination plan, and 
method of maintaining the study blind as per Pfizer’s SOPs will be documented and 
approved in an Interim Analysis Committee/Executive Committee charter.  In addition, the 
analysis details must be documented and approved in an interim analysis SAP or final SAP. 
The study team will remain blinded to all interim results.
9.5.1. Data Monitoring Committee 
An Independent Oversight Committee (IOC) will be constituted and be responsible for 
review of unblinded safety and laboratory data on a regularly scheduled, periodic basis
(eg, after 25%, 50% and 75% of participants have been randomized, and periodically
thereafter), as well as on an ad hoc basis at the request of the study team. The IOC may also 
have access to unblinded efficacy data from any interim analyses (if performed) for ongoing 
assessment of overall benefit: risk. For this study, the IOC will be an Internal Review 
Committee (IRC) comprised of Sponsor personnel (at least one of whom is medically 
qualified and one of whom is a clinical statistician) not directly involved in study conduct or 
in interactions with site personnel or participants.
The IRC will be responsible for ongoing monitoring of safety of participants in the study 
according to the Charter.  Any recommendations made by the IRC to alter the conduct of the 
study will be forwarded to the Executive Committee for final decisions. Pfizer will forward 
such decisions, which may include summaries of aggregate analyses of endpoint events and 
of safety data that are not endpoints, to regulatory authorities, as appropriate.
9.6. Safety Adjudication Committees
The identification of events requiring submission to an adjudication/review committee may 
be made by the study site and communicated to Pfizer or designee. Events requiring review, 
including opportunistic infections, cardiovascular, and malignancy events may also be 
identified by the Pfizer Study Team or designee during the review of subject data listings or 
by site monitors during routine monitoring of subject’s study records. The Pfizer Study 
Team or designee will notify the study site of any events should they identify. 
The Pfizer Study Team or designee will provide a listing of specific documents needed to 
support event adjudication by the Adjudication/Review Committees.  Obtaining and 
submitting the documentation will be the responsibility of the study site.  Event 
documentation will vary with the event requiring adjudication and may include (but not be 


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limited to): hospital discharge summaries, operative reports, clinic notes, diagnostic tests, 
pathology reports, autopsy reports and death certificate information, as applicable.
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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 Council for International Organizations of Medical 
Sciences (CIOMS) International Ethical Guidelines;

Applicable International Council for Harmonisation (ICH) Good Clinical Practice 
(GCP) guidelines;

Applicable laws and regulations, including applicable privacy laws.
The protocol, protocol amendments, ICD, investigator’s brochure (IB), and other relevant 
documents (eg, advertisements) must be reviewed and approved by the sponsor and 
submitted to an IRB/EC by the investigator and reviewed and approved by the IRB/EC 
before the study is initiated.
Any amendments to the protocol will require IRB/EC approval before implementation of 
changes made to the study design, except for changes necessary to eliminate an immediate 
hazard to study participants.
The investigator will be responsible for the following:

Providing written summaries of the status of the study to the IRB/EC annually or 
more frequently in accordance with the requirements, policies, and procedures 
established by the IRB/EC;

Notifying the IRB/EC of SAEs or other significant safety findings as required by 
IRB/EC procedures;

Providing oversight of the conduct of the study at the site and adherence to 
requirements of 21 Code of Federal Regulations (CFR), ICH guidelines, the IRB/EC, 
European regulation 536/2014 for clinical studies (if applicable), and all other 
applicable local regulations.
10.1.1.1. Reporting of Safety Issues and Serious Breaches of the Protocol or ICH GCP
In the event of any prohibition or restriction imposed (ie, clinical hold) by an applicable 
regulatory authority in any area of the world, or if the investigator is aware of any new 
information that might influence the evaluation of the benefits and risks of the investigational 
product, 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 ICH GCP that the investigator becomes aware 
of.
10.1.2. Financial Disclosure
Investigators and subinvestigators will provide the sponsor with sufficient, accurate financial 
information as requested to allow the sponsor to submit complete and accurate financial 
certification or disclosure statements to the appropriate regulatory authorities. Investigators 
are responsible for providing information on financial interests during the course of the study 
and for 1 year after completion of the study.
10.1.3. Informed Consent Process
The investigator or his/her representative will explain the nature of the study to the 
participant or his/her legally authorized representative and answer all questions regarding the 
study.
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, Health Insurance Portability and Accountability Act 
(HIPAA) requirements, where applicable, and the IRB/EC or study center.
The investigator must ensure that each study participant is fully informed about the nature 
and objectives of the study, the sharing of data related to the study, and possible risks 
associated with participation, including the risks associated with the processing of the 
participant’s personal data. 
The participant must be informed that his/her personal study-related data will be used by the 
sponsor in accordance with local data protection law. The level of disclosure must also be 
explained to the participant.
The participant must be informed that his/her medical records may be examined by Clinical 
Quality Assurance auditors or other authorized personnel appointed by the sponsor, by 
appropriate IRB/EC members, and by inspectors from regulatory authorities.
The investigator further must ensure that each study participant is fully informed about his or 
her right to access and correct his or her personal data and to withdraw consent for the 
processing of his or her personal data.
The medical record must include a statement that written informed consent was obtained
before the participant was enrolled in the study and the date the written consent was obtained.
The authorized person obtaining the informed consent must also sign the ICD.
Participants must be reconsented to the most current version of the ICD(s) during their 
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A copy of the ICD(s) must be provided to the participant.
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 shall 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 natural persons 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. In case of data 
transfer, the sponsor will protect the confidentiality of participants’ personal data consistent 
with the clinical study agreement and applicable privacy laws.
10.1.5. Dissemination of Clinical Study Data
Pfizer fulfills its commitment to publicly disclose clinical study results through posting the 
results of studies on www.clinicaltrials.gov (ClinicalTrials.gov), the European Clinical Trials 
Database (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 standard operating procedures (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 US Basic 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.  US Basic 
Results are generally submitted for posting within 1 year of the primary completion date 
(PCD) for studies in adult populations or within 6 months of the PCD for studies in pediatric 
populations.
PCD is defined as the date that the final participant was examined or received an intervention 
for the purposes of final collection of data for the primary outcome, whether the clinical 
study concluded according to the prespecified protocol or was terminated.
EudraCT
Pfizer posts European Union (EU) Basic Results on EudraCT for all Pfizer-sponsored 
interventional studies that are in scope of EU requirements.  EU Basic Results are submitted 
for posting within 1 year of the PCD for studies in adult populations or within 6 months of 
the PCD for studies in pediatric populations.
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 US Basic Results document is 
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 European Medicines Agency (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 contribute to the scientific understanding of the 
disease, target, or compound class. Pfizer will make available data from these trials 
24 months after study completion.  Patient-level data will be anonymized in accordance with 
applicable privacy laws and regulations.  CSRs will have personally identifiable information 
redacted.


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Data requests are considered from qualified researchers with the appropriate competencies to 
perform the proposed analyses. Research teams must include a biostatistician. Data will not 
be provided to applicants with significant conflicts of interest, including individuals 
requesting access for commercial/competitive or legal purposes.
10.1.6. Data Quality Assurance
All participant data relating to the study will be recorded on printed or electronic CRF unless 
transmitted to the sponsor or designee electronically (eg, laboratory data). The investigator is 
responsible for verifying that data entries are accurate and correct by physically or 
electronically signing the CRF.
The investigator must maintain accurate documentation (source data) that supports the 
information entered in the CRF.
The investigator must ensure that the CRFs are securely stored at the study site in encrypted 
electronic and/or paper form and are password protected or secured in a locked room to 
prevent access by unauthorized third parties.
The investigator must permit study-related monitoring, audits, IRB/EC review, and 
regulatory agency inspections and provide direct access to source data documents.  This 
verification may also occur after study completion.  It is important that the investigator(s) 
and their relevant personnel are available during the monitoring visits and possible audits or 
inspections and that sufficient time is devoted to the process.
Monitoring details describing strategy (eg, risk-based initiatives in operations and quality 
such as risk management and mitigation strategies and analytical risk-based monitoring), 
methods, responsibilities, and requirements, including handling of noncompliance issues and 
monitoring techniques (central, remote, or on-site monitoring), are provided in the 
monitoring plan.
The sponsor or designee is responsible for the data management of this study, including 
quality checking of the data.
Study monitors will perform ongoing source data verification to confirm that data entered 
into the CRF by authorized site personnel are accurate, complete, and verifiable from source 
documents; that the safety and rights of participants are being protected; and that the study is 
being conducted in accordance with the currently approved protocol and any other study 
agreements, ICH GCP, and all applicable regulatory requirements.
Records and documents, including signed ICDs, pertaining to the conduct of this study must 
be retained by the investigator for 15 years after study completion unless local regulations or
institutional policies require a longer retention period. No records may be destroyed during 
the retention period without the written approval of the sponsor. No records may be 
transferred to another location or party without written notification to the sponsor. The 
investigator must ensure that the records continue to be stored securely for as long as they are 
maintained.


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When participant data are to be deleted, the investigator will ensure that all copies of such 
data are promptly and irrevocably deleted from all systems.
The investigator(s) will notify the sponsor or its agents immediately of any regulatory 
inspection notification in relation to the study.  Furthermore, the investigator will cooperate 
with the sponsor or its agents to prepare the investigator site for the inspection and will allow 
the sponsor or its agent, whenever feasible, to be present during the inspection.  The 
investigator site and investigator will promptly resolve any discrepancies that are identified 
between the study data and the participant's medical records.  The investigator will promptly 
provide copies of the inspection findings to the sponsor or its agent.  Before response 
submission to the regulatory authorities, the investigator will provide the sponsor or its 
agents with an opportunity to review and comment on responses to any such findings.
10.1.7. Source Documents
Source documents provide evidence for the existence of the participant and substantiate the 
integrity of the data collected. Source documents are filed at the investigator site.
Data reported on the CRF or entered in the electronic CRF (eCRF) that are transcribed from 
source documents must be consistent with the source documents or the discrepancies must be 
explained. The investigator may need to request previous medical records or transfer 
records, depending on the study. Also, current medical records must be available.
Definition of what constitutes source data can be found in the study monitoring plan.
10.1.8. Study and Site Closure
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 contract 
research organization (CRO) if requested to do so by the responsible IRB/EC or if such 
termination is required to protect the health of study participants.
Reasons for the early closure of a study site by the sponsor may include but are not limited 
to:

Failure of the investigator to comply with the protocol, the requirements of the 
IRB/EC or local health authorities, the sponsor's procedures, or GCP guidelines;

Inadequate recruitment of participants by the investigator;

Discontinuation of further study intervention development.


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Study termination is also provided for in the clinical study agreement.  If there is any conflict 
between the contract and this protocol, the contract will control as to termination rights.
10.1.9. Publication Policy
The results of this study may be published or presented at scientific meetings by the 
investigator after publication of the overall study results or 1 year after end of the study (or 
study termination), whichever comes first. 
The investigator agrees to refer to the primary publication in any subsequent publications 
such as secondary manuscripts, and submits all manuscripts or abstracts to the sponsor 
30 days before submission. This allows the sponsor to protect proprietary information and to 
provide comments and the investigator will, on request, remove any previously undisclosed 
confidential information before disclosure, except for any study- or Pfizer
intervention-related information necessary for the appropriate scientific presentation or 
understanding of the study results.
For all publications relating to the study, the investigator will comply with recognized ethical 
standards concerning publications and authorship, including those established by the 
International Committee of Medical Journal Editors.
The sponsor will comply with the requirements for publication of the overall study results 
covering all investigator sites.  In accordance with standard editorial and ethical practice, the 
sponsor will support publication of multicenter studies only in their entirety and not as 
individual site data.  In this case, a coordinating investigator will be designated by mutual 
agreement.
Authorship of publications for the overall study results will be determined by mutual 
agreement and in line with International Committee of Medical Journal Editors authorship 
requirements. 
If publication is addressed in the clinical study agreement, the publication policy set out in 
this section will not apply.
10.1.10. Sponsor’s Qualified Medical Personnel
The contact information for the sponsor's appropriately qualified medical personnel for the 
study is documented in the study contact list located in the study team on demand (SToD) 
system.  
To facilitate access to appropriately qualified medical personnel on study-related medical 
questions or problems, participants are provided with a contact card.  The contact card 
contains, at a minimum, protocol and investigational product identifiers, participant numbers, 
contact information for the investigator site, and contact details for a contact center in the 
event that the investigator site staff cannot be reached to provide advice on a medical 
question or problem originating from another healthcare professional not involved in the 
participant’s participation in the study.  The contact number can also be used by investigator 


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staff if they are seeking advice on medical questions or problems; however, it should be used 
only in the event that the established communication pathways between the investigator site 
and the study team are not available.  It is therefore intended to augment, but not replace, the 
established communication pathways between the investigator site and the study team for 
advice on medical questions or problems that may arise during the study.  The contact 
number is not intended for use by the participant directly, and if a participant calls that 
number, he or she will be directed back to the investigator site.


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10.2. Appendix 2: Clinical Laboratory Tests
The following safety laboratory tests will be performed at times defined in the SoA section of 
this protocol.  Additional laboratory results may be reported on these samples as a result of 
the method of analysis or the type of analyzer used by the clinical laboratory; or as derived 
from calculated values.  These additional tests would not require additional collection of 
blood.  Unscheduled clinical laboratory measurements may be obtained at any time during 
the study to assess any perceived safety concerns.
Table 4.
Protocol-Required Safety Laboratory Assessments
Hematology
Chemistry
Urinalysis
Other
Hemoglobin
Hematocrit
RBC count
MCV
MCH
MCHC
Platelet count
WBC count
Total neutrophils (Abs and
%)
Eosinophils (Abs and %)
Monocytes (Abs and %)
Basophils (Abs and %)
Lymphocytes (Abs and %)
Reticulocyte count %
Partial thromboplastin time 
(PTT)
Prothrombin time (PT)
BUN/urea and creatinine
Glucose (fasting)
Calcium
Sodium
Potassium
Chloride
Total CO2 (bicarbonate)
AST, ALT
Total bilirubin
Alkaline phosphatase
Uric acid
Albumin
Total protein
Serum myoglobind
Lipid profilesc
Cardiac troponin-I 
(cTn-I), CK and CK-MBd
pH
Glucose (qual)
Protein (qual)
Blood (qual)
Ketones
Nitrites
Leukocyte esterase
Urobilinogen
Urine bilirubin
Microscopye
Color and clarity
Specific gravity
Urine Culturef
At screening only:

FSHa

Pregnancy test 
(-hCG)b

Hepatitis B surface 
antigen, HepBc Abd

Hepatitis C antibody
or HCV RNAd

HIVd

QuantiFERON® TB 
Gold testd
Abbreviations: Abs = absolute; ALT = alanine aminotransferase; AST = aspartate aminotransferase; 
-hCG = beta-human chorionic gonadotropin; BUN = blood urea nitrogen; CO2 = carbon dioxide; 
FSH = follicle-stimulating hormone; MCH = mean corpuscular hemoglobin; MCHC = mean corpuscular 
hemoglobin concentration; MCV = mean corpuscular volume; qual = qualitative; RBC = red blood cell; 
WBC = white blood cell.
a.
In females who are amenorrheic for at least 12 consecutive months, for confirmation of 
postmenopausal status only.
b.
Local urine testing will be standard for the protocol unless serum testing is required by local 
regulation or institutional review board/ethics committee (IRB/EC).  Serum or urine -hCG for female 
participants of childbearing potential.
c.
Lipid Profile includes fasting total cholesterol, LDL, HDL, triglycerides and may include fasting 
apolipoprotein A-1 and B and other lipoprotein tests potentially including particle size measurements. 
d.
At screening only, additional tests may be performed during the study at the investigator’s discretion, 
as indicated by signs and symptoms of ongoing AEs.
e.
To be performed if urine dipstick is positive for blood, protein, nitrites, or leukocyte esterase; 
f.
If urine microscopic examination is suggestive of urinary tract infection (eg, due to the presence of 
neutrophils); or if deemed clinically appropriate by the PI.
Investigators must document their review of each laboratory safety report.


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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 (ie, not related to progression of 
underlying disease).

Exacerbation of a chronic or intermittent preexisting condition including either an 
increase in frequency and/or intensity of the condition.

New conditions detected or diagnosed after study intervention administration even 
though it may have been present before the start of the study.

Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction.

Signs, symptoms, or the clinical sequelae of a suspected overdose of either study 
intervention or a concomitant medication. Overdose per se will not be reported as 
an AE/SAE unless it is an intentional overdose taken with possible 
suicidal/self-harming intent. Such overdoses should be reported regardless of 
sequelae.
Events NOT Meeting the AE Definition

Any clinically significant abnormal laboratory findings or other abnormal safety 
assessments which are associated with the underlying disease, unless judged by the 
investigator to be more severe than expected for the participant’s condition.


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


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
This definition is not intended to include experiences of relatively minor medical 
significance such as uncomplicated headache, nausea, vomiting, diarrhea, 
influenza, and accidental trauma (eg, sprained ankle) which may interfere with or 
prevent everyday life functions but do not constitute a substantial disruption.
e.
Is a congenital anomaly/birth defect
f.
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:

Examples of such events include invasive or malignant cancers, intensive treatment 
in an emergency room or at home for allergic bronchospasm, blood dyscrasias or 
convulsions that do not result in hospitalization, or development of drug 
dependency or drug abuse.
10.3.3. Recording/Reporting and Follow-up of AEs and/or SAEs
AE and SAE Recording/Reporting
The table below summarizes the requirements for recording adverse events on the CRF 
and for reporting serious adverse events on the Clinical Trial (CT) Serious Adverse Event 
(SAE) Report Form to Pfizer Safety.  These requirements are delineated for 3 types of 
events: (1) SAEs; (2) nonserious adverse events (AEs); and (3) exposure to the 
investigational product under study during pregnancy or breastfeeding, and occupational 
exposure. 
It should be noted that the CT SAE Report Form for reporting of SAE information is not 
the same as the AE page of the CRF.  When the same data are collected, the forms must be 
completed in a consistent manner.  AEs should be recorded using concise medical 
terminology and the same AE term should be used on both the CRF and the CT SAE 
Report Form for reporting of SAE information.


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


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
Moderate: An event that causes sufficient discomfort and interferes with normal 
everyday activities.

Severe: An event that prevents normal everyday activities. An AE that is assessed 
as severe should not be confused with an SAE. Severe is a category utilized for 
rating the intensity of an event; and both AEs and SAEs can be assessed as severe.
An event is defined as “serious” when it meets at least 1 of the predefined outcomes as 
described in the definition of an SAE, NOT when it is rated as severe.
Assessment of Causality

The investigator is obligated to assess the relationship between study intervention 
and each occurrence of each AE/SAE.

A “reasonable possibility” of a relationship conveys that there are facts, evidence, 
and/or arguments to suggest a causal relationship, rather than a relationship cannot 
be ruled out.

The investigator will use clinical judgment to determine the relationship.

Alternative causes, such as underlying disease(s), concomitant therapy, and other 
risk factors, as well as the temporal relationship of the event to study intervention 
administration will be considered and investigated.

The investigator will also consult the investigator’s brochure (IB) and/or product 
information, for marketed products, in his/her assessment.

For each AE/SAE, the investigator must document in the medical notes that he/she 
has reviewed the AE/SAE and has provided an assessment of causality.

There may be situations in which an SAE has occurred, and the investigator has 
minimal information to include in the initial report to the sponsor. However, it is 
very important that the investigator always make an assessment of causality 
for every event before the initial transmission of the SAE data to the sponsor.

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.


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
If the investigator does not know whether or not the investigational product caused 
the event, then the event will be handled as “related to investigational product” 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 professionals.

If a participant dies during participation in the study or during a recognized 
follow-up period, the investigator will provide Pfizer Safety with a copy of any 
postmortem findings including histopathology.

New or updated information will be recorded in the originally completed CRF.

The investigator will submit any updated SAE data to the sponsor within 24 hours 
of receipt of the information.
10.3.4. Reporting of SAEs
SAE Reporting to Pfizer Safety via 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.
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.


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
If the electronic system is unavailable, then the site will use the paper SAE data 
collection tool (see next section) in order to report the event within 24 hours.

The site will enter the SAE data into the electronic system as soon as the data
become available.

After the study is completed at a given site, the electronic data collection tool will 
be taken off-line to prevent the entry of new data or changes to existing data.

If a site receives a report of a new SAE from a study participant or receives updated 
data on a previously reported SAE after the electronic data collection tool has been 
taken off-line, then the site can report this information on a paper SAE form (see 
next section) or to Pfizer Safety by telephone.


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10.4. Appendix 4: Contraceptive Guidance and Collection of Pregnancy Information
10.4.1. Male Participant Reproductive Inclusion Criteria
Male participants are eligible to participate if they agree to the following requirements during 
the intervention period and for at least 28 days after the last dose of study intervention, which
corresponds to the time needed to eliminate study intervention(s):

Refrain from donating sperm.
PLUS either:

Be abstinent from heterosexual intercourse with a female of childbearing potential as 
their preferred and usual lifestyle (abstinent on a long-term and persistent basis) and 
agree to remain abstinent.
OR

Must agree to use a male condom when engaging in any activity that allows for 
passage of ejaculate to another person.

In addition to male condom use, a highly effective method of contraception may be 
considered in WOCBP partners of male participants (refer to the list of highly 
effective methods below in Section 10.4.4).
10.4.2. Female Participant Reproductive Inclusion Criteria
A female participant is eligible to participate if she is not pregnant or breastfeeding, and at 
least 1 of the following conditions applies:

Is not a WOCBP (see definitions below in Section 10.4.3).
OR

Is a WOCBP and using a contraceptive method that is highly effective (with a failure 
rate of <1% per year), preferably with low user dependency, as described below 
during the intervention period and for at least 28 days after the last dose of study 
intervention, which corresponds to the time needed to eliminate any study 
intervention(s). If the primary form of contraception is an estrogen containing 
hormone method, then the women or her partner must additionally use a barrier 
method. 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. A barrier method must be used with all highly effective methods that are 
user dependent listed below.  Participants enrolled in Canadian sites must use at least 
2 forms of contraception regardless of the user dependency of the method(s), 


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including at least 1 form of highly effective contraception and 1 form of effective 
contraception.
10.4.3. Woman of Childbearing Potential (WOCBP)
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. Premenarchal.  
2. Premenopausal female with 1 of the following:

Documented hysterectomy;

Documented bilateral salpingectomy;

Documented bilateral oophorectomy.
For individuals with permanent infertility due to an alternate medical cause other than 
the above, (eg, mullerian agenesis, androgen insensitivity), investigator discretion 
should be applied to determining study entry.
Note: Documentation for any of the above categories can come from the site 
personnel’s review of the participant’s medical records, medical examination, or 
medical history interview.  The method of documentation should be recorded in the 
participant’s medical record for the study.
3. Postmenopausal female:

A postmenopausal state is defined as age 60 years or older or no menses for 
12 months without an alternative medical cause. 

A high follicle-stimulating hormone (FSH) level in the postmenopausal range 
may be used to confirm a postmenopausal state in women not using hormonal 
contraception or hormone replacement therapy (HRT). 

Females 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.


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10.4.4. Contraception Methods
Highly Effective Methods That Have Low User Dependency
1. Implantable progestogen-only hormone contraception associated with inhibition of 
ovulation and a barrier method.
2. Intrauterine device (IUD).
3. Intrauterine hormone-releasing system (IUS).
4. Bilateral tubal occlusion.
5. Vasectomized partner.

Vasectomized partner is a highly effective contraceptive method provided that the 
partner is the sole sexual partner of the WOCBP and the absence of sperm has 
been confirmed.  If not, an additional highly effective method of contraception 
should be used.  The spermatogenesis cycle is approximately 90 days.
Highly Effective Methods That Are User Dependent 
1. Combined (estrogen- and progestogen-containing) hormonal contraception associated 
with inhibition of ovulation and a barrier method if using hormonal contraceptive 
agent:

oral;

intravaginal;

transdermal.
2. Progestogen-only hormone contraception associated with inhibition of ovulation and 
a barrier method:

oral;

injectable.
3. Sexual abstinence:

Sexual abstinence is considered a highly effective method only if defined as 
refraining from heterosexual intercourse during the entire period of risk associated 
with the study intervention.  The reliability of sexual abstinence needs to be 
evaluated in relation to the duration of the study and the preferred and usual 
lifestyle of the participant. If during the study the subject decides to become 


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sexually active they must inform the study site and start using one of the effective 
contraception method described in this section. 
Effective methods to be used with all highly effective contraceptive methods that are user 
dependent listed above: 
4. Male or female condom with or without spermicide.
5. Cervical cap, diaphragm, or sponge with spermicide.
Collection of Pregnancy Information
For both unapproved/unlicensed products and for marketed products, an exposure during 
pregnancy (EDP) occurs if:

A female becomes, or is found to be, pregnant either while receiving or having been 
exposed (eg, because of treatment or environmental exposure) to the investigational 
product; or the female becomes or is found to be pregnant after discontinuing and/or 
being exposed to the investigational product;

An example of environmental exposure would be a case involving direct contact 
with a Pfizer product in a pregnant woman (eg, a nurse reports that she is pregnant 
and has been exposed to chemotherapeutic products).

A male has been exposed (eg, because of treatment or environmental exposure) to the 
investigational product prior to or around the time of conception and/or is exposed 
during his partner’s pregnancy.
If a participant or participant’s partner becomes or is found to be pregnant during the 
participant’s treatment with the investigational product, 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.  In addition, the investigator must submit 
information regarding environmental exposure to a Pfizer product in a pregnant woman (eg, a 
participant reports that she is pregnant and has been exposed to a cytotoxic product by 
inhalation or spillage) to Pfizer Safety using the EDP supplemental form.  This must be done 
irrespective of whether an AE has occurred and within 24 hours of awareness of the 
exposure.  The information submitted should include the anticipated date of delivery (see 
below for information related to termination of pregnancy).
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 


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preprocedure test findings are conclusive for a congenital anomaly and the findings are 
reported).
If the outcome of the pregnancy meets the criteria for an SAE (ie, ectopic pregnancy, 
spontaneous abortion, intrauterine fetal demise, neonatal death, or congenital anomaly [in a 
live-born baby, a terminated fetus, an intrauterine fetal demise, or a neonatal death]), the 
investigator should follow the procedures for reporting SAEs.
Additional information about pregnancy outcomes that are reported to Pfizer Safety as SAEs 
follows: 

Spontaneous abortion includes 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 investigational product. 
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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10.5. Appendix 5: Genetics
Use/Analysis of DNA

Genetic variation may impact a participant’s response to study intervention, 
susceptibility to, and severity and progression of disease.  Therefore, where local 
regulations and IRBs/ECs allow, a blood sample will be collected for DNA analysis.

Genetic research may consist of the analysis of 1 or more candidate genes or the 
analysis of genetic markers throughout the genome or analysis of the entire genome 
(as appropriate).

The samples may be analyzed as part of a multistudy assessment of genetic factors 
involved in the response to PF-06651600 or study interventions of this class to 
understand treatments for the disease(s) under study or the disease(s) themselves.

The results of genetic analyses may be reported in the clinical study report (CSR) or 
in a separate study summary or may be used for internal decision making without 
being included in a study report.

The sponsor will store the DNA samples in a secure storage space with adequate 
measures to protect confidentiality. 

The samples will be retained as indicated:

Samples for specified genetic analysis (see Section 8.8) will be stored for up to 
15 years or other period as per local requirements.

Samples for banking (see Section 8.7.2 and 8.8.4) will be stored indefinitely or 
other period as per local requirements.

Participants may withdraw their consent for the storage and/or use of their banked 
biospecimens at any time by making a request to the investigator; in this case, any 
remaining material will be destroyed.  Data already generated from the samples will 
be retained to protect the integrity of existing analyses.

Banked biospecimens will be labeled with a code.  The key between the code and the 
participant’s personally identifying information (eg, name, address) will be held at the 
study site and will not be provided to the sample bank.


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


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Rises in AST/ALT and TBili separated by more than a few weeks should be assessed 
individually based on clinical judgment; any case where uncertainty remains as to whether it 
represents a potential Hy’s law case should be reviewed with the sponsor.  
The participant should return to the investigator site and be evaluated as soon as possible, 
preferably within 48 hours from awareness of the abnormal results.  This evaluation should 
include laboratory tests, detailed history, and physical assessment. 
In addition to repeating measurements of AST and ALT and TBili for suspected cases of 
Hy’s law, additional laboratory tests should include albumin, creatine kinase (CK), direct and 
indirect bilirubin, gamma-glutamyl transferase (GGT), prothrombin time (PT)/international 
normalized ratio (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 (either by itself or as a coformulated 
product in prescription or over-the-counter medications), recreational drug, supplement 
(herbal) use and consumption, family history, sexual history, travel history, history of contact 
with a jaundiced person, surgery, blood transfusion, history of liver or allergic disease, and 
potential occupational exposure to chemicals, should be collected.  Further testing for acute 
hepatitis A, B, C, D, and E infection and liver imaging (eg, biliary tract) and collection of 
serum sample for acetaminophen 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 liver function test (LFT) abnormalities has yet been found.  Such 
potential DILI (Hy’s law) cases are to be reported as SAEs, irrespective of availability 
of all the results of the investigations performed to determine etiology of the LFT 
abnormalities.
A potential DILI (Hy’s law) case becomes a confirmed case only after all results of 
reasonable investigations have been received and have excluded an alternative etiology.


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10.7. Appendix 7: ECG Findings of Potential Clinical Concern
ECG Findings That May Qualify as Adverse Events (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 premature ventricular complexes (PVCs), triplets, or short intervals 
(<30 seconds) of consecutive ventricular complexes.
ECG Findings That May Qualify as Serious Adverse Events (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 patients 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 patients 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 (rate 
<40 bpm), accelerated idioventricular rhythm (40< x <100), and 
monomorphic/polymorphic ventricular tachycardia >100 bpm (such as torsades de 
pointes).

Type II second-degree (Mobitz II) AV block.

Complete (third-degree) heart block.
ECG Findings That Qualify as Serious Adverse Events

Change in pattern suggestive of new myocardial infarction.

Sustained ventricular tachyarrhythmias (>30 seconds’ duration).

Second- or third-degree AV block requiring pacemaker placement.

Asystolic pauses requiring pacemaker placement.

Atrial flutter or fibrillation with rapid ventricular response requiring cardioversion.

Ventricular fibrillation/flutter.

At the discretion of the investigator, any arrhythmia classified as an adverse 
experience.
The enumerated list of major events of potential clinical concern are recommended as “alerts” or 
notifications from the core ECG laboratory to the investigator and Pfizer study team, and not to be 
considered as all inclusive of what to be reported as AEs/SAEs.


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10.8. Appendix 8: 2010 ACR/EULAR Classification Criteria for Rheumatoid Arthritis
(RA)
Presented below are the 2010 American College of Rheumatology (ACR)/European League 
Against Rheumatism (EULAR) classification criteria for RA. 
Target population (Who should be tested?) must have:
1. Have at least 1 joint with definite clinical synovitis (swelling).*
2. With the synovitis not better explained by another disease.†
Classification criteria for RA (score-based algorithm: add score of categories A–D;
a score of ≥6/10 is needed for classification of a patient as having definite RA):‡
A. Joint involvement§
SCORE (A) ______
1 large joint¶
0
2-10 large joints 
1
1-3 small joints (with or without involvement of large joints)#
2
4-10 small joints (with or without involvement of large joints) 
3
>10 joints (at least 1 small joint)**
5
B. Serology (at least 1 test result is needed for classification)††
SCORE (B) ______
Negative RF and negative ACPA 
0
Low-positive RF or low-positive ACPA 
2
High-positive RF or high-positive ACPA 
3
C. Acute-phase reactants (at least 1 test result is needed for classification)‡‡
SCORE (C) ______
Normal CRP and normal ESR 
0
Abnormal CRP or abnormal ESR 
1
D. Duration of symptoms§§
SCORE (D) ______
<6 weeks
0
≥6 weeks
1
TOTAL SCORE (A+B+C+D) ___________


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A TOTAL Score of ≥6/10 is needed for classification of a patient as having definite RA)‡
* The criteria are aimed at classification of newly presenting patients.  In addition, patients with erosive disease 
typical of rheumatoid arthritis (RA) with a history compatible with prior fulfillment of the 2010 criteria 
should be classified as having RA.  Patients with longstanding disease, including those whose disease is 
inactive (with or without treatment) who, based on retrospectively available data, have previously fulfilled the 
2010 criteria should be classified as having RA.
† Differential diagnoses vary among patients with different presentations, but may include conditions such as 
systemic lupus erythematosus, psoriatic arthritis, and gout.  If it is unclear about the relevant differential 
diagnoses to consider, an expert rheumatologist should be consulted.
‡ Although patients with a score of <6/10 are not classifiable as having RA, their status can be reassessed and 
the criteria might be fulfilled cumulatively over time.
§ Joint involvement refers to any swollen or tender joint on examination, which may be confirmed by imaging 
evidence of synovitis.  Distal interphalangeal joints, first carpometacarpal joints, and first 
metatarsophalangeal joints are excluded from assessment.  Categories of joint distribution are classified 
according to the location and number of involved joints, with placement into the highest category possible 
based on the pattern of joint involvement.
¶ “Large joints” refers to shoulders, elbows, hips, knees, and ankles.
# “Small joints” refers to the metacarpophalangeal joints, proximal interphalangeal joints, second through fifth 
metatarsophalangeal joints, thumb interphalangeal joints, and wrists.
** In this category, at least 1 of the involved joints must be a small joint; the other joints can include any 
combination of large and additional small joints, as well as other joints not specifically listed elsewhere 
(eg, temporomandibular, acromioclavicular, sternoclavicular, etc.).
†† Negative refers to IU values that are less than or equal to the upper limit of normal (ULN) for the laboratory 
and assay; low-positive refers to IU values that are higher than the ULN but ≤3 times the ULN for the 
laboratory and assay; high-positive refers to IU values that are >3 times the ULN for the laboratory and assay.  
Where rheumatoid factor (RF) information is only available as positive or negative, a positive result should 
be scored as low-positive for RF.  ACPA= anti-citrullinated protein antibody.
‡‡ Normal/abnormal is determined by local laboratory standards.  CRP = C-reactive protein; ESR = erythrocyte 
sedimentation rate.
§§ Duration of symptoms refers to patient self-report of the duration of signs or symptoms of synovitis 
(eg, pain, swelling, tenderness) of joints that are clinically involved at the time of assessment, regardless of 
treatment status.


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10.9. Appendix 9: Criteria for Classification of Functional Status in Rheumatoid 
Arthritis
Class I: Completely able to perform usual activities of daily living (self-care, vocational, and 
avocational).
Class II: Able to perform usual self-care and vocational activities but limited in avocational 
activities.
Class III: Able to perform usual self-care activities but limited in vocational and avocational 
activities.
Class IV: Limited in ability to perform usual self-care, vocational, and avocational activities.
Usual self-care activities including dressing, feeding, bathing, grooming, and toileting.  
Avocational (recreational and/or leisure) and vocational (work, school, homemaking) 
activities are patient-desired and age- and sex-specific.


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10.10. Appendix 10: Disease Activity Score DAS (DAS28-CRP), 
 
Assessments
The formula for calculation of DAS28-CRP uses the following 4 components:
•
Swollen Joints (0–28);
•
Tender Joints (0–28);
•
hsCRP (high sensitivity C-reactive protein);
•
Patient’s Global Assessment (PtGA) of Arthritis (0 – 100 mm VAS).
DAS28-CRP= 0.56 sqrt (DAS 28 tender joint count) + 0.28 sqrt (DAS 28 swollen joint 
count) + 0.36 ln (CRP [mg/L] +1) + 0.014 (PtGA [mm]) + 0.96.
CCI
CCI


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10.11. Appendix 11: Prohibited Concomitant Medications
Prohibited Concomitant Medications
Please note that this list addresses only CYP3A4 inhibitors and inducers, CYP3A 
substrates and BCRP and Pgp substrates.  This is not an all-inclusive list.  Study 
personnel should stay current and consult with their pharmacy to exclude all concomitant 
medications that are either moderate to potent CYP3A inhibitors or inducers or sensitive or 
moderate sensitive CYP3A4 substrates or BCRP or Pgp substrates with narrow therapeutic 
index.
Moderate to Potent CYP3A Inhibitors*
Moderate to Potent CYP3A 
Inducers**
Amprenavir
Indinavir#
Avasimibe#
Amiodarone 
Itraconazole#
Bosentan
Aprepitant
Ketoconazole#
Barbiturates
Atazanavir
Lopinavir#
Carbamazepine#
Boceprevir
Mibefradil#
Efavirenz 
Casopitant
Mifepristone (RU486)
Etravirine
Cimetidine
Nefazodone#
Mitotane#
Ciprofloxacin
Nelfinavir#
Modafinil
Clarithromycin#
Norfloxacin
Nafcillin
Cobicistat#
Posaconazole#
Phenobarbital#
Conivaptan#
Ritonavir#
Phenytoin#
Darunavir
Saquinavir#
Rifabutin#
Diethyldithiocarbamate
Schisandra sphenanthera
Rifampin #
Diltiazem
Telaprevir
St. John’s Wort#
Dronedarone
Telithromycin#
Talviraline
Elvitegravir#
Tipranavir#
Erythromycin
Tofisopam
Fluconazole
Troleandomycin#
Fluvoxamine
Verapamil
Imatinib
Voriconazole#
Danoprevir
Crizotinib
Grapefruit Juice***
Faldepravir
Idelalisib
Netupitant
Nilotinib
Isavuconazole
CYP3A4 Substrates##
CYP3A4 Substrates with NTI
Pgp Substrates
Aprepitant
Argatroban
Digoxin
Eliglustat
Alfentanil
Pimozide
Astemizole
BCRP Substrates
Conivaptan
Cisapride
Rosuvastatin
Darunavir
Cyclosporine
Glecaprevir
Dasatinib
Diergotamine
Pibrentasvir
Dronedarone
Ergotamine
Ebastine
Fentanyl
Indinavir
Quinidine
Lomitapide
Terfenadine
Nisoldipine
Valproate
Rilpivirine


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Saquinavir
Sirolimus
Tacrolimus
Tipranavir
Tolvaptan
* 
All prohibited drugs that are CYP3A inhibitors require at least a 7 day or 5 half-lives (whichever is 
longer) washout prior to the first dose of study drug.  Note: Amiodarone requires discontinuation at 
least 290 days (~5 half-lives, half-life averages ~58 days) prior to the first dose of study drug.
** All prohibited drugs that are CYP3A inducers require at least a 28 day or 5 half-lives (whichever is 
longer) washout prior to the first dose of study drug.
# 
Notated as potent inhibitors or inducers. 
##
The label recommends to avoid (or contraindicate) use of these concomitant medication with 
moderate CYP3A4 inhibitors (eg, PF-06651600). 
***It is recommended that study participants avoid consumption of grapefruit juice exceeding 8 ounces 
(~240 ml) total in a day while in the study.
In a situation where appropriate medical care of a subject requires the use of a prohibited CYP3A 
inhibitor or inducer: Moderate to potent inhibitors and inducers of CYP3A are not permitted in the study 
EXCEPT in emergency situations requiring no more than one day of administration.  Note: Amiodarone 
and mitotane are not permitted for any duration due to their long half-lives.  Topical (including skin or 
mucous membranes) application of antimicrobial and antifungal medications is permitted.
Concomitant Medications to be Used with Caution or Dose Reduction
CYP3A4 Substrates (Use with caution or dose reduction)$
Alprozolam
Midazolam
Atorvastatin
Naloxegol
Colchicine
Quetiapine
Tadalafil
Sildenafil
Alfentanil
Simvastatin
Avanafil
Triazolam
Budesonide
Vardenafil
Buspirone
Fentanyl
Eletriptan
Tramadol
Eplerenone
Oxycodone
Everolimus
Hydrocodone
Felodipine
Codeine
Ibrutinib
Dihydrocodeine
Lovastatin
Buprenorphine
Lurasidone
Methadone
Maraviroc
Rivaroxaban§
$ The label allows to use concomitant medication with moderate CYP3A4 inhibitors with caution or dose 
adjustment. Also, the drug will not affect PF-06651600 exposure (either no effect or weak CYP3A4 
inhibitor).
§ The label recommends to avoid use of the drug in multiple conditions (for example, avoid use in patients 
with CrCl 15 to <80 mL/min who are receiving concomitant combined P-gp and moderate CYP3A4 
inhibitors). Clinical judgement should be used in co-administration.


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10.12. Appendix 12: Oral Corticosteroid Equivalents
The following is a summary of corticosteroid equivalents. 
Oral corticosteroids – participants already taking oral corticosteroids must be on a stable dose 
of ≤7.5 mg/day of prednisone or equivalent for at least 4 weeks prior to first dose of study 
drug.  Tapering or discontinuation of the corticosteroid treatment is only allowed after 
Week 12, unless required for toxicity, and should be performed slowly at the discretion of the 
investigator.
Compound
Equivalent Dose (mg)
Prednisone
7.5
Prednisolone
7.5 
6-methylprednisolone
6 
Triamcinolone
6
Betamethasone
1.1
Dexamethasone
1.1
Hydrocortisone
30
Cortisone
37.5
Deflazacort
10.7-11
Cloprednol
3.75
Prednylidene
7.5
Note: these dose equivalents apply to oral administration.


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10.13. Appendix 13: Alternative Measures During Public Emergencies
The alternative study measures described in this section are to be followed during public 
emergencies, including the COVID-19 pandemic. This appendix applies for the duration of 
the COVID-19 pandemic globally and will become effective for other public emergencies 
only upon written notification from Pfizer. 
Use of these alternative study measures are expected to cease upon the return of business as 
usual circumstances (including the lifting of any quarantines and travel bans/advisories). 
10.13.1. Telehealth Visits
In the event that in-clinic study visits cannot be conducted, every effort should be made to 
follow-up on the safety of study participants at scheduled visits per the SoA or unscheduled 
visits. Telehealth visits may be used to continue to assess participant safety and collect data 
points. Telehealth includes the exchange of healthcare information and services via 
telecommunication technologies (eg, audio, video, video-conferencing software) remotely, 
allowing the participant and the investigator to communicate on aspects of clinical care, 
including medical advice, reminders, education, and safety monitoring. The following 
assessments must be performed during a telehealth visit:

Review and record study intervention(s), including compliance and missed doses.

Review and record any AEs and SAEs since the last contact.  Refer to Section 8.3.

Review and record any new concomitant medications or changes in concomitant 
medications since the last contact.

Review and record contraceptive method and results of pregnancy testing (as 
available). Confirm that the participant is adhering to the contraception method(s) 
required in the protocol. Refer to Appendix 4 and Section 10.13.2 of this appendix 
regarding pregnancy tests.

In situations where participants are unable to attend sites for protocol required 
pregnancy testing, the participant should if possible visit a local laboratory for 
pregnancy testing (where allowable by law or local guidance). If this is not 
possible, the study site should make every effort to develop a plan to provide a 
home urine pregnancy testing kit with a sensitivity of at least 25 IU/mL to be 
performed by the participant at home. The site should document the pregnancy 
test outcome in a source document and enter the result into the study database 
and/or CRF as required.
Study participants must be reminded to promptly notify site staff about any change in their 
health status.


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10.13.2. Laboratory Testing
If a study participant is unable to visit the site for protocol-specified safety laboratory 
evaluations, testing may be conducted at a local laboratory if permitted by local regulations.
The local laboratory may be a standalone institution or within a hospital. The following 
safety laboratory evaluations may be performed at a local laboratory:  
Hematology
Chemistry
Urinalysis
Other
Hemoglobin
Hematocrit
RBC count
MCV
MCH
MCHC
Platelet count
WBC count
Total neutrophils (Abs and %)
Eosinophils (Abs and %)
Monocytes (Abs and %)
Basophils (Abs and %)
Lymphocytes (Abs 
and %)Reticulocyte count %
Partial thromboplastin time (PTT)
Prothrombin time (PT)
BUN/urea and 
creatinine
Glucose (fasting)
Calcium
Sodium
Potassium
Chloride
Total 
CO2 (bicarbonate)
AST, ALT
Total bilirubin
Alkaline 
phosphatase
Uric acid
Albumin
Total protein
Lipid profilesb
Serum myoglobinc
Cardiac troponin-I 
(cTn-I), CK and 
CK-MBc
pH
Glucose (qual)
Protein (qual)
Blood (qual)
Ketones
Nitrites
Leukocyte esterase
Urobilinogen
Urine bilirubin
Microscopyd
Color and clarity
Specific gravity
Urine culturee
Pregnancy test (-hCG)a
C-Reactive Protein 
(hsCRP)
a.
Local urine testing will be standard for the protocol unless serum testing is required by local regulation 
or institutional review board/ethics committee (IRB/EC).  Serum or urine -hCG for female 
participants of childbearing potential.
b.
Lipid Profile includes fasting total cholesterol, LDL, HDL, triglycerides and may include fasting 
apolipoprotein A-1 and B and other lipoprotein tests potentially including particle size measurements. 
c.
At screening only; additional tests may be performed during the study at the investigator’s discretion, 
as indicated by signs and symptoms of ongoing AEs.
d.
Only if urine dipstick is positive for blood, protein, nitrites, or leukocyte esterase
e.
If urine microscopic examination is suggestive of urinary tract infection (eg, due to the presence of neutrophils); or 
if deemed clinically appropriate by the PI.
If a local laboratory is used, qualified study site personnel must order, receive, and review 
results. Site staff must collect the local laboratory reference ranges and certifications/
accreditations for filing at the site. Laboratory test results are to be provided to the site staff 
as soon as possible. The local laboratory reports should be filed in the participant’s source 
documents/medical records. Relevant data from the local laboratory report should 
be recorded on the CRF. 
If a participant requiring pregnancy testing cannot visit a local laboratory for pregnancy 
testing, a home urine pregnancy testing kit with a sensitivity of at least 25 IU/mL may be 
used by the participant to perform the test at home, if compliant with local regulatory 
requirements. The pregnancy test outcome should be documented in the participant’s source 


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documents/medical records and relevant data recorded on the CRF. Confirm that the 
participant is adhering to the contraception method(s) required in the protocol.
10.13.3. Electrocardiograms
If the participant is unable to visit the study site for ECGs, the participant may visit an 
alternative facility to have the ECGs performed. Qualified study site personnel must order, 
receive, and review results. 
10.13.4. Study Intervention
If the safety of a trial participant is at risk because they cannot complete required evaluations 
or adhere to critical mitigation steps, then discontinuing that participant from study 
intervention must be considered.
IP may be shipped by courier to study participants if permitted by local regulations and in 
accordance with storage and transportation requirements for the IP. Pfizer does not permit 
the shipment of IP by mail. The tracking record of shipments and the chain of custody of IP 
must be kept in the participant’s source documents/medical records.
10.13.5. Adverse Events and Serious Adverse Events
If a participant has COVID-19 during the study, this should be reported as an adverse event 
(AE) or serious adverse events (SAE) and appropriate medical intervention provided. 
Temporary discontinuation of the study intervention may be medically appropriate until the 
participant has recovered from COVID-19. 
It is recommended that the investigator discuss temporary or permanent discontinuation of 
study intervention with the study medical monitor. 
10.13.6. Independent Oversight Committees
In case of an interruption in the study conduct due to COVID-19 the frequency of the IRC 
meeting may be adjusted to reflect availability of personnel on the committee, rate of 
randomization and the accrual of new participant and new emergent safety data.


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10.14. Appendix 14: Abbreviations
The following is a list of abbreviations that may be used in the protocol. 
Abbreviation
Term
AA
Alopecia Areata
Abs
Absolute
ACR
American College of Rheumatology
ACPA
anti-citrullinated protein antibodies 
ADA
antidrug antibodies
AE
adverse event
ALT
alanine aminotransferase
ANCOVA
analysis of covariance
API
active pharmaceutical ingredient 
AST
aspartate aminotransferase
AUC
area under the curve
AUCtau
area under the concentration-time curve over dosing interval tau
AV
atrioventricular
BA
Bioavailability
BBS
Biospecimen Banking System
BCRP
Breast Cancer Resistance Protein 
BE
Bioequivalence
BIC
Bayesian Information Criterion
BID
twice a day
β-hCG
beta-human chorionic gonadotropin
BP
blood pressure
bpm
beats per minute
BUN
blood urea nitrogen
CD
Crohn’s Disease 
CFB
change from baseline
CFR
Code of Federal Regulations
CIOMS
Council for International Organizations of Medical Sciences
CK
creatine kinase
CKD-EPI
Chronic Kidney Disease Epidemiology Collaboration
CK-MB
Creatine kinase MB
Cmax
maximum observed concentration
CMC
Chemistry, Manufacturing, and Controls
CMV
cytomegalovirus
CO2
carbon dioxide (bicarbonate)
CONSORT
Consolidated Standards of Reporting Trials
COVID-19
coronavirus disease 2019
CRF
case report form
CRO
contract research organization
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Abbreviation
Term
CRP
C reactive protein
CRU
clinical research unit
CSF
cerebrospinal fluid
CSR
clinical study report
csDMARDs
Conventional synthetic DMARDs
CT
clinical trial
CTCAE
Common Terminology Criteria for Adverse Events
cTn-I
cardiac troponin-I
CVA
Cerebrovascular accident 
CV
Cardiovascular
CYP
Cytochrome p
DAMPs
damage associated molecular patterns 
DAS
Disease Activity Score
DCE-MRI
dynamic contrast enhanced-MRI 
DCT
data collection tool
DDI
drug-drug interaction 
DILI
drug-induced liver injury
DMARD
Disease-modifying antirheumatic drugs 
DMC
data monitoring committee
DNA
deoxyribonucleic acid
DO
Doctor of Osteopathic
DRE
disease-related event
DU
dispensable unit
DVT
Deep vein thrombosis
EC
ethics committee
EBV
Epstein-Barr Virus
ECG
Electrocardiogram
eCRF
electronic case report form
E-DMC
external data monitoring committee 
EDP
exposure during pregnancy
EDR
extemporaneous dispensing record
EFD
embryo-fetal developmental 
eGFR
estimated glomerular filtration rate
ELISA
enzyme-linked immunosorbent assay
EMA
European Medicines Agency
EOS
End of the study
ESR
erythrocyte sedimentation rate
EU
European Union
EudraCT
European Clinical Trials Database
EULAR
European League Against Rheumatism
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Abbreviation
Term
FDA
Food and drug Administration
FSH
follicle-stimulating hormone
FU
follow up
GCP
Good Clinical Practice
GFR
glomerular filtration rate
GGT
gamma-glutamyl transferase
GI
gastrointestinal 
GLP
Good Laboratory Practice 
HbA1c
hemoglobin A1c
HBcAb
hepatitis B core antibody
HBsAb 
hepatitis B surface antibody
HBsAg 
hepatitis B surface antigen
HCVAb
hepatitis C antibody
HCV
hepatitis C virus
HIPAA
Health Insurance Portability and Accountability Act
HDL
High density lipoprotein
HEENT 
head, eyes, ears, nose and throat
HIV
human immunodeficiency virus
HRT
hormone replacement therapy
HS
hidradenitis suppurative
hsCRP
high-sensitivity C-reactive protein
IA
interim analysis
IB
investigator’s brochure
IC50
50% inhibitory concentration
IC90
90% inhibitory concentration
ICD
informed consent document
ICH
International Council for Harmonisation
ID
Identification
IGRA 
Interferon-Gamma Release Assay
IL
Interleukin
ILD
Interstitial Lung Disease
IOC
Independent Oversight Committee
IMP
Investigational Medicinal Product
IND
investigational new drug
INR
international normalized ratio
IP
investigational product
IP Manual or IPM
Investigational Product Manual
IR 
Inadequate response
IRAK4
interleukin -1 receptor associated kinase 4 
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Abbreviation
Term
IRB
institutional review board
IRC
Internal Review Committee
IRT
Interactive Response Technology
IUD
intrauterine device
IUS
intrauterine hormone-releasing system
IVRS
Integrated Voice Response System
IWR
interactive Web-based response
JAK
Janus kinases 
LBBB
left bundle branch block
LDA
Low disease activity
LFT
liver function test
MACE
major adverse cardiovascular events
MCH
mean corpuscular hemoglobin
MCHC
mean corpuscular hemoglobin concentration
MCV
mean corpuscular volume
mITT
modified intent to treat
mm
millimeter
MMRM
Mixed Model Repeated Measures
MnB
Neisseria meningitidis serogroup B
MR
modified release
MRI
magnetic resonance imaging
msec
Millisecond
MTX
methotrexate
MTX-IR
inadequate response to MTX
N/A
not applicable
NAb
neutralizing antibodies
NMSC
Non melanoma skin cancer
NIMP
noninvestigational medicinal product
NOAEL
no-observed-adverse-effect level
NSAID
nonsteroidal anti-inflammatory drug
NTI
narrow therapeutic index
PBMC
peripheral blood mononuclear cell
PCD
primary completion date
PD
pharmacodynamic(s)
PE
Pulmonary embolism
PFS
prefilled syringe
PhGA 
Physician Global Assessment
PI
Principal Investigator
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Abbreviation
Term
PK
pharmacokinetic(s)
PRO
Patient reported outcome
PT
prothrombin time
PT/INR
Prothrombin Time International Normalized Ratio
PtGA 
patient global assessment 
PTT
partial thromboplastin time 
PVC
premature ventricular complex
QD
Once daily
QRS
ventricular depolarization
QTc
corrected QT
QTcF
corrected QT (Fridericia method)
qual
Qualitative
RA
Rheumatoid arthritis
RAMRIQ
Rheumatoid Arthritis MRI Quantification 
RAMRIS
Rheumatoid Arthritis MRI Score  
RBC
red blood cell
RF
rheumatoid factor
RNA
ribonucleic acid
SAD
single ascending dose
SAE
serious adverse event
SAP
statistical analysis plan
SALT
severity of alopecia tool
SARS-CoV-2
severe acute respiratory syndrome coronavirus 2
SC
subcutaneous
Scr
serum creatinine
SDAI
simplified disease activity index
SoA
schedule of activities
SoC
standard of care
SOP
standard operating procedure
SRSD
single reference safety document
SJC
Swollen Joint Count 
SToD
study team on demand
SUSAR
suspected unexpected serious adverse reaction
TB
Tuberculosis
TBili
total bilirubin
TEAEs
treatment-emergent adverse events
TEC
tyrosine kinase expressed in hepatocellular carcinoma
TIR
toll/interleukin-1 receptor 
TJC
Tender/Painful Joint Count 
TLR
Toll Like Receptor
TNF
tumor necrosis factor
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Abbreviation
Term
TNF
tumor necrosis factor alpha
TNFi
TNF inhibitors 
TRIF
Toll/interleukin-1 receptor domain-containing adapter inducing 
IFN
TYK2
tyrosine kinase 2 
TXK
tyrosine protein kinase that is encoded in humans by TXK gene
UC
Ulcerative Colitis 
ULN
upper limit of normal
US
United States
USPI
US Product Insert
VAS
visual analog scale
VTE
venous thromboembolic events
WBC
white blood cell
WHO
World Health Organization
WOCBP
women of childbearing potential
XR
Extended Release


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11. REFERENCES
1.
Banholzer ML, Wandel C, Barrow P, et al. Clinical trial considerations on male 
contraception and collection of pregnancy information from female partner: update. 
Clin Transl Med 2016;5(1):23-37.
2.
Guangyong Zou, A Modified Poisson Regression Approach to Prospective Studies with 
Binary Data, American Journal of Epidemiology, Volume 159, Issue 7, 1 April 2004, 
Pages 702–706.
3.
Karaman MW, Herrgard S, Treiber DK, et al. A quantitative analysis of kinase inhibitor 
selectivity. Nat Biotechnol 2008; 26:127-32.
4.
Meyer DM, Jesson MI. Anti-inflammatory activity and neutrophil reductions mediated 
by the JAK1/JAK3 inhibitor, CP-690,550, in rat adjuvant-induced arthritis. J Inflamm 
(Lond) 2010;7:41.
5.
O’ Shea JJ, Kontzias A, Yamaoka K et al. Janus kinase inhibitors in autoimmune 
diseases. Ann Rheum Dis 2013;72 (Apr):111-5.
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SAP_001.pdf: 
Protocol B7921023 (PF-06650833, PF-06651600, Tofacitinib) Statistical Analysis Plan
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Protocol B7921023
A 24-WEEK RANDOMIZED, DOUBLE-BLIND, PARALLEL GROUP, ACTIVE 
COMPARATOR, MULTICENTER STUDY TO ASSESS THE EFFICACY AND 
SAFETY OF PF-06650833, PF-06651600, AND TOFACITINIB ALONE AND IN 
COMBINATION IN PARTICIPANTS WITH MODERATELY-SEVERELY ACTIVE 
RHEUMATOID ARTHRITIS WITH AN INADEQUATE RESPONSE TO 
METHOTREXATE
Statistical Analysis Plan 
(SAP)
Version: 2.0
Date: March 1, 2022


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TABLE OF CONTENTS
TABLE OF CONTENTS...........................................................................................................2
LIST OF TABLES.....................................................................................................................3
LIST OF FIGURES ...................................................................................................................4
1. VERSION HISTORY............................................................................................................5
2. INTRODUCTION .................................................................................................................7
2.1. Study Objectives, Endpoints and Estimands.............................................................7
2.2. Study Design ...........................................................................................................12
3. ENDPOINTS AND BASELINE VARIABLES: DEFINITIONS AND 
CONVENTIONS ................................................................................................................14
3.1. Efficacy Endpoints ..................................................................................................14
3.1.1. Clinician Reported Outcomes (ClinRO).....................................................15
3.1.2. Patient-Reported Outcomes (PRO).............................................................15
3.1.3. Selected Laboratory Measurements (LAB)................................................16
3.1.4. Imaging Measurements (IMG) ...................................................................16
3.1.5. Continuous Composite Measures of Efficacy: DAS28-CRP, DAS28-
ESR, CDAI, SDAI...........................................................................................17
3.1.6. Binary Composite Measures of Efficacy....................................................17
3.2. Baseline Variables...................................................................................................19
3.3. Safety Endpoints .....................................................................................................19
3.4. 
 PD Endpoints..............................................................................................19
4. ANALYSIS SETS ...............................................................................................................20
5. GENERAL METHODOLOGY AND CONVENTIONS....................................................20
5.1. Hypotheses and Decision Rules ..............................................................................20
5.2. Analyses of Continuous Data..................................................................................21
5.3. Analyses of Binary Data .........................................................................................21
5.4. Analysis of Safety Data...........................................................................................22
6. ANALYSES AND SUMMARIES ......................................................................................22
6.1. Efficacy Analyses....................................................................................................22
6.2. Baseline and Other Summaries and Analyses.........................................................24
6.2.1. Baseline Summaries....................................................................................24
6.2.2. Study Conduct and Participant Disposition................................................24
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6.2.3. Study Intervention Compliance..................................................................24
6.2.4. Concomitant Medications and Nondrug Treatments..................................24
6.3. Safety Summaries and Analyses .............................................................................25
6.3.1. Adverse Events...........................................................................................25
6.3.2. Laboratory Data..........................................................................................25
6.3.3. Vital Signs ..................................................................................................25
6.3.4. Physical Examination .................................................................................25
6.3.5. Electrocardiogram Analyses.......................................................................25
6.5. Analysis of PD and Biomarker Endpoints ..............................................................26
6.6. Analysis of MRI Endpoints.....................................................................................26
6.7. Additional Analyses ................................................................................................26
7. INTERIM ANALYSES.......................................................................................................27
7.1.1. Data Monitoring Committee.......................................................................27
8. REFERENCES ....................................................................................................................28
9. APPENDICES .....................................................................................................................29
9.1. Appendix 1. Definition and Use of Visit Windows in Reporting ...........................29
LIST OF TABLES
Table 1.
Summary of Major Changes in SAP Amendments ....................................5
Table 2.
Characterization of the Estimands..............................................................8
Table 3.
List of Study Objectives, Endpoints and Estimands...................................9
Table 4.
ClinRO, PRO and LAB Outcomes ...........................................................17
Table 5.
Continuous Composite Outcomes ............................................................17
Table 6.
Remission (REM) and Low Disease Activity Thresholds........................18
Table 7.
Analysis Sets.............................................................................................20
Table 8.
Analyses of Continuous Data ...................................................................21
Table 9.
Analyses of Binary Data...........................................................................22
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Table 10.
Analyses of Continuous Efficacy Endpoints ............................................23
Table 11.
Analyses of Binary Efficacy Endpoints....................................................24
Table 12.
Definition of Visit Windows ....................................................................29
Table 13.
Input Parameters for MMRM Analysis ....................................................31
Table 14.
Input Parameters for Analyses of Binary Outcomes ................................32
LIST OF FIGURES
Figure 1.
Study Design Schematic...........................................................................14


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1. VERSION HISTORY
This statistical analysis plan (SAP) for Study B7921023 is based on the protocol 
Amendment 3 dated by February 10, 2022.
Table 1.
Summary of Major Changes in SAP Amendments
SAP
Version
Change
Rationale
2
The updated evaluations of treatment efficacy use 
the “treatment policy” approach. The approach 
compares treatment efficacy across the treatment 
groups irrespective of the participant's compliance 
with the study treatment and use of concomitant 
medications.  
This change affected sections 2.1, 5.2, 5.3, 6.1,
6.5, 6.6, 6.7.
The update makes the 
analyses identical to the 
studies that are expected in 
the forthcoming Phase 3 
study and other concurrent 
studies in the literature.  
2
The details of notation and definitions of 
estimands are updated.
This change affected sections 2.1,5.2,5.3,6.1, 
6.5,6.6,6.7.
The update improves the 
match between the 
statistical terminology and 
the terminology in the 
recent statistical literature.
2
Added supportive estimands to evaluate 
sensitivity of the results of primary and key 
secondary analyses to the adjustment of efficacy 
comparisons for poor compliance and use of 
concomitant medications.
This change affected sections 2.1, 5.2, 5.3, 6.1,
The analysis explores the
robustness of the primary 
and key secondary analyses 
to the confounding effects 
of poor compliance and use 
of concomitant medications. 
2
Incorporated exact (rather than asymptotic) 
statistical inference methods for a comparison of 
binary outcomes.
This change affected sections 5.3, 6.1,
The update ensures a 
validity of the analyses at 
the visits where proportion 
of responders is low.
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2
For each of the visits and treatment arms we will 
estimate the proportions of subjects in the mITT 
data set that were removed from the sensitivity 
data set because of the potential influence on poor 
compliance, use of prohibited concomitant 
medication or any of these reasons. 
This change affected section 6.7.
Confirm the expected 
balance of proportions of 
potentially confounding 
intercurrent events across 
the treatment arms.
2
Additional comparisons for the E1 analysis of 
DAS28-CRP at week 12, analyses E2 and E3 for 
the ratio and difference of DAS28-CRP remission 
rates at week 24 and E3 analyses of ACR 20, 
ACR 50, ACR 70 and ACR 90 responder rates at 
week 24.
• A comparison of the treatment effect 
between the combination treatment arm 
PF-06650833 +TOFACITINIB and 
monotherapy arm PF-06650833 and the 
comparison of the combination arm 
PF-06650833 + PF06651600 with each of 
the mono-therapy treatment arms 
(PF-06650833 and PF06651600). 
•
An estimation of the treatment effects of 
primary interest (each of the combination 
treatment arms versus tofacitinib) for the 
subset of anti-TNF naïve patients.
This change affected section 6.7.
The results of these analyses 
may be included into the 
CSR.
2
Changed label of longitudinal analysis of 
covariance from LANCOVA to MMRM (The
abbreviation for Mixed Model for Repeated 
Measures).
This change affected sections 5.2,
Retain consistency with the 
Protocol.
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2. INTRODUCTION
This SAP provides the detailed methodology for summary and statistical analyses of the data 
collected in Study B7921023. 
2.1. Study Objectives, Endpoints and Estimands
A definition of an estimand includes four components (ICH, 2019, Mallinckrodt et al, 
2020).1,2
1. The population targeted by the scientific question.
2. The endpoint (variable) to be obtained for each patient.
3. The population-level summary for the variable that provides a basis for a comparison 
between treatment conditions and metric for a comparison between the treatment 
groups.
4. How to account for the intercurrent events (ICEs). The intercurrent events are defined 
as the post-randomization events that alter the course of the randomized treatment.
We will use 5 different estimands presented in the Table 2. These estimands are 
characterized by the different definition of the key features above. We will use the estimand 
from the group E1-E3 corresponding to a particular study objective as the main estimand and 
the estimands E1*, E2* as supportive. The goal of the estimands E1* and E2* is to confirm a 
qualitative similarity of the results of primary and key secondary analyses based on the 
different approaches to the adjustment of the analyses for the presence of the intercurrent 
events. 
The estimands E1-E3 rely on the “treatment policy” approach to the efficacy comparison 
across the treatment groups. The approach compares treatment efficacy across the treatment 
groups irrespective of the participant's compliance with study treatment and use of 
concomitant medications. No intercurrent events are included into the definition of these 
estimands and therefore no accounting for the intercurrent events is required. The estimands 
E1*, E2* classify the events of poor compliance to the randomized treatment or use of 
concomitant medications as the intercurrent events and use “hypothetical” strategy for 
accounting for these events. This strategy aims at the mitigation of the confounding of the 
comparison of the efficacy of randomized treatment by the intercurrent events. The 
estimands E1* and E2* will be used for the support of the primary and key secondary 
objective of the study.
We will also report the additional supportive analyses of continuous and binary outcomes 
based on the cross-sectional, visit specific summaries. These summaries are based on the data 
observed at a particular visit (also baseline observations for change from baseline). The 
analyses may be viewed as an estimation of the treatment effect in the population of subjects 
who stay in the study up to a given study visit. 


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In our presentation we will use labels E1, E1*, E2, E2*, E3 for the analyses which have as 
their target the estimands presented in the Table 2 and labels D1, D2, D3 for the descriptive 
analyses.
The qualitative similarity of the results of these different analyses is expected to support the 
conclusion based on the results of primary and key secondary analyses. 
Table 2.
Characterization of the Estimands
Notation 
for the 
Estimand
Population 
targeted by the 
Scientific 
Question
Type of 
Endpoint  
Population-level 
Summary for a 
given Treatment
Metric for a 
Comparison 
between the 
Treatment Groups
Account for the 
ICE
E1
All treated study 
participants
Continuous
Mean change from 
baseline 
Difference of mean
values
None  
E2
All treated study 
participants
Binary
Mean probability of 
response
Ratio of 
probabilities of 
response.
None  
E3 
All treated study 
participants
Binary
Probability of 
response
Difference of 
probabilities of 
response
None  
E1*
All treated study 
participants
Continuous
Mean change from 
baseline
Difference of mean
values
Censoring of 
observations
(visits within a 
subject) 
potentially 
affected by the 
ICE
E2*
All treated study 
participants
Binary
Mean probability of 
response
Ratio of 
probabilities of 
response.
Censoring of 
observations 
(visits within a 
subject) 
potentially 
affected by the 
ICE
The correspondence between the study objectives, endpoints and estimands is shown in 
Table 3.


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Table 3.
List of Study Objectives, Endpoints and Estimands
Objectives
Endpoints
Key Estimand
[Supportive 
estimand]
Primary
Primary
Primary

To compare the efficacy of each of 
2 treatment combination arms to 
tofacitinib alone at Week 12 

Change from baseline DAS28-CRP at
week 12.
E1 [E1*]
Key Secondary
Key Secondary
Key Secondary

To compare the remission rates for 
each of 2 treatment combinations 
arms to tofacitinib alone at 
Week 24

DAS28-CRP remission at Week 24.
E2 [E2*]
Secondary
Secondary
Secondary

To assess the safety of 
PF-06650833, PF-06651600, and 
tofacitinib alone and of the 
combinations of PF-06650833 with 
PF-06651600 and tofacitinib
Most of the safety outcomes are defined by 
the Sponsor’s standards. These outcomes 
include 

Incidence and severity of adverse events
(AEs), serious adverse events (SAEs), 
and withdrawals due to adverse events.

Change from baseline in clinical 
laboratory values (chemistry, 
hematology parameters).

Change from baseline in vital signs 
(blood pressure, pulse rate and 
temperature measurements),ECG-based 
parameters.

Incidences of severe and opportunistic 
infection AEs; herpes virus infection 
AEs; clinically significant categorical 
increases in hepatic enzymes Aspartate 
aminotransferase (AST), and Alanine 
aminotransferase (ALT) and total 
bilirubin, and potential cases meeting 
Hy’s Law criteria for increased risk of 
drug-induced liver injury (DILI); major 
adverse cardiovascular events (MACE), 
including pulmonary embolism (PE) and 
deep vein thrombosis (DVT), 
Cerebrovascular accident (CVA); 
Adverse events (AEs) for decreased 
renal function, acute kidney injury, 
clinically significant increases in serum 
creatinine (Scr) and decreases in 

There is no 
defined 
estimand for 
these endpoints.  
They will be 
analyzed using 
Pfizer data 
standards as 
applicable.


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estimated glomerular filtration rate 
(eGFR).
The additions include the parameters of the 
audiometry test
Secondary
Secondary
Secondary
•
To explore other signs of clinical 
efficacy of all treatment arms at 
week 12 and 24
•
Change from baseline in DAS28-CRP at 
week 24.
•
Change from baseline in Tender/Painful 
and Swollen Joint Count at Week 12 and 
Week 24.
•
Change from baseline in Physician’s 
Global Assessment (PhGA) of Arthritis 
at Week 12 and Week 24. 
•
American College of Rheumatology 
(ACR 20, ACR 50, ACR 70, and 
ACR 90) responder rates at Week 12 
and Week 24. 
•
E1 for 
continuous 
endpoints.
•
E3 for binary 
endpoints.  
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•
To explore treatment-related 
pharmacodynamic (PD) activity in 
all treatment arms
•
Change from baseline in concentration 
of anti-citrullinated protein antibodies 
(ACPA).
•
Change from baseline of rheumatoid 
factor (RF).
•
Change from baseline of Interferon 
Gamma-Induced Protein 10 (IP-10).
•
To evaluate the effects of 
PF-06650833, PF-06651600, and 
tofacitinib alone and in 
combination on joint inflammation 
assessed by magnetic resonance 
imaging (MRI), in a subset of 
participants
•
Change from baseline for each of 
multiple MRI-based endpoints collected 
for the study participant.
2.2. Study Design
This is a Phase 2, 24-week, multicenter, randomized, double-blind, 5-arm, parallel group, 
active comparator study to evaluate the efficacy and safety profiles of 2 combinations of 
investigational products (IPs): PF-06650833 co-administered with PF-06651600 
(PF-06650833 + PF-06651600) and PF-06650833 co-administered with tofacitinib 
(PF-06650833 + tofacitinib), as well as the efficacy and safety of each IP individually in the 
absence of background MTX in participants with moderately - severely active RA who have 
had an inadequate response to MTX (MTX-IR). Both PF-06650833 and tofacitinib will be 
administered as modified release (MR) tablets to allow for once daily administration. The 
primary objective is to demonstrate superiority of at least 1 combination to tofacitinib 
monotherapy as measured by CFB in DAS28-CRP at Week 12. A key secondary endpoint is 
to assess the remission rates of the combinations and individual IPs at Week 24, as defined 
by DAS28-CRP <2.6. The study is powered to show statistical superiority of the 
combinations to tofacitinib monotherapy at Week 12.
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After an up to 28-day screening period, eligible participants will enter a 24-week active 
treatment period after being randomly assigned to one of the 5 treatment groups shown in 
Figure 1 below.
All doses will be administered orally once daily in a fasted state (about 4 hours after the last 
and 1.5 hours before the next meal). In order to maintain the blind and minimize bias, all 
participants will receive the same number and types of tablets each day as a mix of active and 
placebo tablets. MTX (and folate/folinic acid taken with MTX) will be discontinued at the 
time of randomization and washed out during the active treatment phase. The MTX washout 
is intended to reduce the potential for excessive immune suppression and additive safety 
liability.
No changes in the background concomitant steroid dose is allowed during the study.  During 
the active dosing period, no “rescue” treatment is pre-specified. However, limited - duration 
increases in permitted analgesic medication (acetaminophen/paracetamol, nonsteroidal 
anti-inflammatory drugs [NSAIDs], opiates) will be permitted for acute worsening of arthritis 
pain (see Permitted Concomitant Medications, Protocol Sections 6.5.1 and 6.5.2).  
Up to approximately 450 participants are planned to be randomized globally into the study to 
ensure at least up to approximately 370 participants complete at least 12 weeks of active 
dosing (assuming a dropout rate of approximately 18%). Participants will be in this study for 
a total of approximately 32 weeks which includes an up to 28-day screening period, a 
24-week active treatment period, and a 4-week drug-free follow-up period.


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Figure 1.
Study Design Schematic
3. ENDPOINTS AND BASELINE VARIABLES: DEFINITIONS AND 
CONVENTIONS
3.1. Efficacy Endpoints
The characterization of the treatment efficacy at a given visit relies on the four classes of 
outcomes
•
Clinician Reported Outcomes (ClinRO);
•
Patient-Reported Outcomes (PRO);
•
Laboratory Measurements (LAB);
•
Imaging Measurements (IMG).
The endpoints are designated as primary, secondary, 
in Table 2 in Section 2.1. 
This section further defines the components of the composite endpoints. 
24 Weeks
ACR20 non-responders after 12 
Weeks required to be discontinued
12 Weeks
4 Weeks 
FU
<28 days 
Screening
Rand/
Stop
MTX
PF-06650833 400 mg MR + PF-06651600 100 mg; N =100
PF-06650833 400 mg MR + Tofacitinib 11 mg MR; N = 100
Tofacitinib 11 mg MR; N = 100
PF-06650833 400 mg MR; N = 75
PF-06651600 100 mg; N = 75
All doses are orally administered once daily under fasted conditions.
Non-responders (defined as not meeting ACR20 response criteria) by Week 12 (or later) are to be discontinued from study.
MR=modified release; MTX=methotrexate; Rand=randomization; FU=follow-up; ACR=American College of Rheumatology.
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3.1.1. Clinician Reported Outcomes (ClinRO)
The outcomes include:
•
Counts of Tender/Painful Joints (TJC28, TJC68) among the pre-defined sets of 
28 (TJC28) and 68 (TJC68) joints. The 28-joints set is the subset of 68 joints set. 
Higher scores indicate higher level of disability.
•
Counts of Swollen Joints (SJC28, SJC66) among the pre-defined sets of 28 (SJC28) 
and 66 (SJC66) joints. The 28-joints set is the subset of 66 joints set. Higher scores
indicate higher level of disability.
•
Physician Global Assessment Score (PhGA) is defined as a value within (0-100 mm 
or 0-10 cm) visual analog scale. Higher scores indicate higher level of disability.
3.1.2. Patient-Reported Outcomes (PRO)
The outcomes include:
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3.1.3. Selected Laboratory Measurements (LAB)
The following laboratory measurements used in the computation of the efficacy endpoints are 
included below:

CRP- concentration of high sensitivity C-reactive protein (mg/L). The normal range is 
0.08-3.1 mg/L. Higher values of CRP indicate higher levels of inflammation.

ESR- Erythrocyte Sedimentation Rate (mm/hr). The normal range is 0 to 
22 mm/hr for men and 0 to 29 mm/hr for women. Higher values of ESR indicate 
higher level of inflammation.
3.1.4. Imaging Measurements (IMG)
The MRI imaging endpoints come from the dynamic contrast-enhanced MRI (DCE-MRI), 
RA MRI scoring system (RAMRIS) and automated quantitative RA MRI system (RAMRIQ)

The DCE-MRI method provides 5 measurements of interest: Volume of enhancing
synovium, Mean Ktrans, Median Ktrans, Median AUCBN (90), and Median Ve. Each 
of these values will be reported for 4 different subregions (metacarpophalangeal 
joints, wrist joint, hand, wrist and metacarpophalangeal joints) resulting in 
20 endpoints for a study participant at each visit.

The RAMRIS method provides 5 measurements/scores: bone erosion, synovitis,
osteitis/bone marrow edema, tenosynovitis, and joint space narrowing. Bone erosions, 
Synovitis and Joint space narrowing will be summarized as combined wrist and MCP 
locations. Osteitis/bone marrow edema scores will be shown for the combined wrist 
and MCP locations in addition to MCP joint locations and wrist locations. 
Tenosynovitis scores will be shown for the combined wrist and finger joint locations
in addition to finger joint locations and wrist locations. This results in 9 endpoints for 
a study participant at each visit.

The RAMRIQ method provides 4 measurements/scores: bone erosion, synovitis, 
osteitis/bone marrow edema, and tenosynovitis. Bone erosions and synovitis will be 
summarized as combined wrist and MCP locations. Osteitis/bone marrow edema 
scores will be shown for the combined wrist and MCP locations in addition to MCP 
joint locations and wrist locations. Tenosynovitis scores will be shown for the 
combined wrist and finger joint locations in addition to finger joint locations and 
wrist locations. This results in 8 endpoints for a study participant at each visit.
Table 4 lists ClinRO, PRO and LAB measurements used in the evaluation of the treatment
efficacy. 


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Table 4.
ClinRO, PRO and LAB Outcomes
Outcome
Desirable Score (indicates lower
level of disability/inflammation)
Group
TJC28, TJC68
Low
ClinRO
SJC28, SJC66
Low
ClinRO
CRP
Low
LAB
Some of the ClinRO and PRO outcomes and LAB measurements listed in the Table 4 are 
used for forming composite variables. If any of the component of the score is missing, then 
the composite score is assigned to a missing value.
3.1.5. Continuous Composite Measures of Efficacy: DAS28-CRP, DAS28-ESR, CDAI, 
SDAI
Table 5.
Continuous Composite Outcomes
Variable 
Calculation 
DAS28-CRP
0.56√ܶܬܥ28 ൅0.28√ܵܬܥ28 ൅0.36݈݊ሺܥܴܲ, ݉݃/݈൅1ሻ൅0.014ܲݐܩܣሺ݉݉ሻ൅0.96
DAS28-ESR
0.56√ܶܬܥ28 ൅0.28√ܵܬܥ28 ൅0.70݈݊ሺܧܴܵ,
௠௠
௛௥ሻ
൅0.014ܲݐܩܣሺ݉݉ሻ
CDAI
ܶܬܥ28 ൅ܵܬܥ28 ൅ܲݐܩܣሺܿ݉ሻ൅݄ܲܩܣሺܿ݉ሻ
SDAI
ܶܬܥ28 ൅ܵܬܥ28 ൅ܲݐܩܣሺܿ݉ሻ൅݄ܲܩܣሺܿ݉ሻ൅ܥܴܲሺ݉݃/݀ܮሻ
The variables CDAI and SDAI denote Clinical Disease Activity Index and Simplified 
Disease Activity Index, respectively. For all composite outcomes, higher scores correspond 
to higher disease severity.
3.1.6. Binary Composite Measures of Efficacy
The following binary measures of efficacy will be evaluated.
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3.1.6.1. ACR20, ACR50, ACR70, ACR90 outcomes
For a given level of response of x% (x=20,50,70,90) the study participant will be declared a 
responder if the following three criteria are satisfied:
1. A decrease by x% or more from the baseline in the number of tender joints (TJC68).
2. A decrease by x% or more from the baseline in the number of swollen joints (SJC66).
3. A decrease by x% or more from the baseline in three of the following five variables 
(see Table 3)
a.
PhGA
b. PAAP
c.
PtGA
d. HAQ-DI
e.
CRP or ESR
Also, the decrease in either of the lab measures CRP or ESR is sufficient for satisfying 
requirement 3e.
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3.2. Baseline Variables
Unless specifically stated otherwise, the baseline value is defined as the last non-missing 
measurement collected prior to the first administration of study drug at Day 1.
Baseline value will be used as a covariate in statistical models for change from baseline in 
efficacy endpoints to adjust for baseline disease severity.
3.3. Safety Endpoints
Most of the safety outcomes are defined by the Sponsor’s standards. These outcomes include 
•
Incidence and severity of adverse events (AEs), serious adverse events (SAEs), and 
withdrawals due to adverse events.
•
Clinical laboratory values (chemistry, hematology parameters).
•
Vital signs (blood pressure, pulse rate and temperature measurements),ECG-based 
parameters.
•
Incidences of severe and opportunistic infection AEs; herpes virus infection AEs;
clinically significant categorical increases in hepatic enzymes Aspartate 
aminotransferase (AST), and Alanine aminotransferase (ALT) and total bilirubin, and 
potential cases meeting Hy’s Law criteria for increased risk of drug-induced liver 
injury (DILI); major adverse cardiovascular events (MACE), including pulmonary 
embolism (PE) and deep vein thrombosis (DVT), Cerebrovascular accident (CVA); 
Adverse events (AEs) for decreased renal function, acute kidney injury, clinically 
significant increases in serum creatinine (Scr) and decreases in estimated glomerular 
filtration rate (eGFR).
The additions include the parameters of the audiometry test.
An adverse event (AE) is considered a Treatment-Emergent Adverse Event (TEAE) if the 
event started during the effective duration of treatment. All events that start on or after the 
first dosing day for B7921023 will be flagged as TEAEs. The algorithm will not consider any 
events that started prior to the first dose date. If an AE starts on the same day as the first dose 
date, it will be considered treatment emergent unless the CRF data indicates otherwise via 
explicitly recording time for AE onset which was occurred before the first treatment dosing.
3.4.
 PD Endpoints
The 
/PD endpoints include:
•
Concentrations of anti-citrullinated protein antibodies (ACPA), rheumatoid factor 
(RF) and IP-10;
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•
4. ANALYSIS SETS
For purposes of analysis, the following analysis sets are defined.
Table 7.
Analysis Sets
Data Set 
Description
Modified Intent to Treat 
(mITT)
All participants randomly assigned to investigational product 
who take at least 1 dose of investigational product. Participants 
will be analysed according to the randomized intervention.
Sensitivity Set
(SNS)
All participants randomly assigned to investigational product 
who take at least 1 dose of investigational product. It is a 
subset of mITT data set where the observations that may be
affected by the poor compliance or use of concomitant 
medications are excluded. Participants will be analysed 
according to the randomized intervention.
Safety Set
All participants randomly assigned to investigational product 
who take at least 1 dose of investigational product. Participants 
will be analysed according to the intervention they actually 
received.
PD Data Set 
(PD)
All participants randomly assigned to investigational product 
and who take at least 1 dose of investigational product and 
have at least 1 of PD parameters of interest.
Appendix 1 shows how to assign observations to the discrete set of study visits based on the
observation time. 
5. GENERAL METHODOLOGY AND CONVENTIONS
Final analyses will occur after database lock after Last Participant Last Visit (LPLV).
5.1. Hypotheses and Decision Rules
The primary clinical hypothesis is that mean decrease at week 12 in DAS28-CRP score in 
one or both combo arms 
 
exceeds the mean decrease in the reference (tofacitinib) treatment arm. The null hypothesis is 
that the mean decrease in DAS28-CRP score at week 12 is identical in the control 
(Tofacitinib arm) and combination arms. There are no multiplicity adjustments planned for 
this study.
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5.2. Analyses of Continuous Data
The estimands E1 and E1* are described in the Section 2.1. The analysis for the estimand E1 
is based on the mITT data set while the analysis for the estimand E1* is based on the 
sensitivity data set. We denote the analyses of interest by the names of the corresponding 
estimands and use the name D1 for the descriptive analysis. The analyses names, data sets 
and analyses methods are listed in the Table 8.
Table 8.
Analyses of Continuous Data
Analysis Name
Data Set
Analytic Approach 
E1
mITT
MMRM
E1* 
Sensitivity data set (SNS)
MMRM
D1 
mITT
Descriptive statistics
For the E1 and E1* analyses we will use the MMRM (Mixed Model for Repeated Measures) 
estimator while the usual descriptive estimator will be used for estimating E1*. The MMRM
analysis will use the change from baseline value of the continuous variable as an outcome and 
treatment, scheduled study visit, baseline value of the variable of interest, treatment by visit 
interaction and baseline by visit interaction as fixed effects. The model will use the 
unstructured covariance matrix. The MMRM model is described in multiple textbooks 
including the books by Fitzmaurice, Laird and Ware (2011)4 and by Mallinckrodt and 
Lipkovich (2017).3
 
 
The p-values and 90% confidence intervals will be reported for the E1 analysis of primary
and secondary efficacy outcomes for the comparisons of combination arms with tofacitinib 
arm. Only the confidence intervals with 90% coverage will be used for all other analyses of 
continuous outcomes.
5.3. Analyses of Binary Data
The estimands E2, E2*, and E3 are described in the Section 2.1. The analyses for the 
estimands E2, E3, are based on the mITT data set while the analysis for the estimand E2* is 
based on the sensitivity data set. We denote the analyses of interest by the names of the 
corresponding estimands and denote the analyses based on descriptive statistics by D2, D3. 
The analyses names, data sets and analyses methods are listed in the Table 9. 
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Table 9.
Analyses of Binary Data
Analysis 
Name
Data Set
Analytic Approach 
E2 
mITT
BSC + CZ (ratio of probabilities) + NRI
E2* 
Sensitivity data set (SNS)
BSC + CZ (ratio of probabilities) + NRI
E3  
mITT
BSC + CZ (difference of probabilities) + NRI
D2
mITT
BSC + CZ (ratio of probabilities) + NOIMP
D3 
mITT
BSC + CZ (difference of probabilities) + NOIMP
*BSC+CZ= Blyth-Still-Casella + Chan and Zhang, NRI- non-responder imputation, NOIMP-no 
imputation.
We will use the Blyth-Still-Casella (Blyth and Still (1983)5 and Casella (1986)6) method for 
the estimation of the probability of response at a given visit and a given treatment arm and 
Chan and Zhang (Chan and Zhang, 1999)7 method for comparison of the probability of 
response across the treatment arms. For the E2, E2* and E3 analyses we will use the 
non-responder imputation treating missing value of the binary outcome as non-response with 
the exception of the two special cases of the reason for missing data. These special reasons 
for missing data include missingness related to the COVID infection (either patient illness or 
COVID-related problem of attending the visit) and missingness when subject attended the 
visit but some of the components for the calculation of the outcome (eg, ACR20) are 
missing. The observations that are missing for these special reasons will be excluded from 
the calculation of the probabilities of response at a given visit. 
The p-values and 90% confidence intervals will be reported for the E2 and E3 analysis of key 
secondary and secondary efficacy outcomes for the comparisons of combination arms with 
tofacitinib arm. Only the confidence intervals with 90% coverage will be used for all other 
analyses of binary outcomes.
5.4. Analysis of Safety Data
Safety data will be summarized based on observed-case data by treatment arm.
6. ANALYSES AND SUMMARIES
6.1. Efficacy Analyses
The tables below summarize analyses of continuous and binary efficacy endpoints.


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Table 10.
Analyses of Continuous Efficacy Endpoints
N
Observations
Group
E1
D1
E1*
1
DAS28-CRP at week 12
X
X
X
2
TJC28,
ClinRo
X
X
3
TJC68
ClinRo
X
X
4
SJC 28
ClinRo
X
X
5
SJC 68
ClinRo
X
X
6
PhGA
ClinRo
X
X
15
DAS28-CRP
COMP-CONTI
X
X
The analysis #1 for primary outcome will include data collected up to and including week 12
and will report the summaries for week 12 visit. All other analyses will include all collected 
data and will report summaries at all study visits.
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Table 11.
Analyses of Binary Efficacy Endpoints
N
Observations
Group
E2
D2
E2*
E3
D3
1
DAS28-CRP remission rate at week 24
X
X
X
2
ACR 20 
ACR
X
X
3
ACR 50
ACR
X
X
4
ACR 70
ACR
X
X
5
ACR 90
ACR
X
X
6.2. Baseline and Other Summaries and Analyses
6.2.1. Baseline Summaries
Demographics and baseline characteristics will be summarized for each arm and total
according to Pfizer standards.
6.2.2. Study Conduct and Participant Disposition
Participant’s evaluation, disposition, discontinuation will be summarized according to Pfizer 
standards.
6.2.3. Study Intervention Compliance
A participant will be considered compliant with the dosing regimen if they receive at least 
80% of the expected number of doses in accordance with the protocol. The number and 
percentage of participants who are compliant with the dosing regimen, number of dosing 
days and number of applications, and amount of intervention used will be summarized.
6.2.4. Concomitant Medications and Nondrug Treatments
Prior drug and non-drug treatment, concomitant drug and non-drug treatment will be 
summarized according to Pfizer standards.
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6.3. Safety Summaries and Analyses
All safety analyses will be performed on the safety analysis set population (Section 4).
The safety data will be summarized in accordance with Pfizer Data Standards. All safety data 
will be summarized descriptively through appropriate data tabulations, descriptive statistics, 
categorical summaries, and graphical presentations.
6.3.1. Adverse Events
Overall standard AE endpoints for this study are:

Incidence of TEAEs;

Incidence of SAEs;

Incidence of AEs leading to discontinuation;

Incidence of special interest AEs: severe and opportunistic infection, herpes virus 
infection, MACE including PE and DVT, CVA, and decreased renal function, and 
acute kidney injury.
6.3.2. Laboratory Data
To determine if there are any clinically significant laboratory abnormalities, the safety 
laboratory tests will be assessed against the criteria specified in the protocol. The assessment 
will consider whether each participant’s baseline test result is within or outside the laboratory 
reference range for the laboratory parameter. Absolute value, changes from baseline and 
percent changes from baseline in laboratory data will be summarized. The number (%) of 
subjects with abnormal AST, ALT, and alkaline phosphatase (>2 × ULN), and bilirubin 
(>1.5 × ULN) and the number (%) of subjects with abnormal AST, ALT, and alkaline 
phosphatase (>2 × baseline) will also be presented. Baseline of safety laboratory tests will be 
the last pre-dose measurement. 
6.3.3. Vital Signs
Vital signs will be summarized for treatment arm in accordance with the Pfizer reporting 
standards.
6.3.4. Physical Examination
Physical examination data (including incidence of clinically significant changes in physical 
examination from baseline) will be summarized for treatment arm in accordance with the
Pfizer reporting standards.
6.3.5. Electrocardiogram Analyses
Parameters of electrocardiogram analyses (including PR, QRS, QT, QTC) will be 
summarized according to Pfizer’s reporting standards.  


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6.5. Analysis of PD and Biomarker Endpoints
Concentrations of ACPA, RF, IP-10, hsCRP, and ESR will be analyzed using E1 and D1 
methods. The log-transformation of the endpoints will be explored if needed for achievement 
symmetry of the distributions
6.6. Analysis of MRI Endpoints
Each of the 37 endpoints listed in Section 3.1.4 will be analyzed by the E1 and D1 methods. 
The log-transformation of the endpoints will be explored if needed for achievement 
symmetry of the distributions. 
6.7. Additional Analyses
For the E1 analysis of DAS28-CRP at week 12, analyses E2 and E3 for the ratio and 
difference of DAS28-CRP remission rates at week 24 and E3 analyses of ACR 20, ACR 50, 
ACR 70 and ACR 90 responder rates at week 24 we may implement additional comparisons.
•
A comparison of the treatment effect between the combination treatment arm 
PF-06650833 +TOFACITINIB and monotherapy arm PF-06650833 and the 
comparison of the combination arm PF-06650833 + PF06651600 with each of the 
mono-therapy treatment arms (PF-06650833 and PF06651600). 
•
An estimation of the treatment effects of primary interest (each of the combination 
treatment arms versus tofacitinib) for the subset of anti-TNF naïve patients.
Also, for each of the visits and treatment arms we will estimate the proportions of subjects in 
the mITT data set that were removed from the sensitivity data set because of the potential 
influence on these observations of poor compliance , use of prohibited concomitant 
medication or any of these reasons. The Blyth-Still-Casella method will be used for the 
estimation.
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7. INTERIM ANALYSES
One or more interim analyses (IA) may be performed for internal business decision-making 
or sample size re-estimation (there is no intention a priori to terminate the study or a 
treatment arm based on the results of the IA).  The final number and timing of any IA, if 
performed, will be defined by the sponsor.
If an IA is performed, an Interim Analysis Committee/Executive Committee will be 
constituted that will include members of senior Pfizer leadership. Before any interim analysis 
is initiated, the details of the objectives, decision criteria, dissemination plan, and method of 
maintaining the study blind as per Pfizer’s SOPs will be documented and approved in an 
Interim Analysis Committee/Executive Committee charter. In addition, the analysis details 
must be documented and approved in an interim analysis SAP or final SAP. The study team 
will remain blinded to all interim results.
7.1.1. Data Monitoring Committee
An Independent Oversight Committee (IOC) will be constituted and be responsible for 
review of unblinded safety and laboratory data on a regularly scheduled, periodic basis
(eg, after 25%, 50% and 75% of participants have been randomized, and periodically 
thereafter), as well as on an ad hoc basis at the request of the study team. The IOC may also 
have access to unblinded efficacy data from any interim analyses (if performed) for ongoing 
assessment of overall benefit: risk. For this study, the IOC will be an Internal Review 
Committee (IRC) comprised of Sponsor personnel (at least one of whom is medically 
qualified and one of whom is a clinical statistician) not directly involved in study conduct or 
in interactions with site personnel or participants.
The IRC will be responsible for ongoing monitoring of safety of participants in the study 
according to the Charter. Any recommendations made by the IRC to alter the conduct of the 
study will be forwarded to the Executive Committee for final decisions. Pfizer will forward 
such decisions, which may include summaries of aggregate analyses of endpoint events and 
of safety data that are not endpoints, to regulatory authorities, as appropriate.


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8. REFERENCES
1.
ICH Harmonized Guideline E9 (R1), Estimands and sensitivity analysis in clinical 
trials. Step 4 version. November 20, 2019.
2.
Mallinckrodt C., Molenberghs G., Lipkovich I., Ratitich B. Estimands, estimators and 
sensitivity analysis in clinical trials, 2020.
3.
Mallinckrodt C, Lipkovich I. Analyzing Longitudinal Clinical Trial Data: A Practical 
Guide; 2017.
4.
Fitzmaurice GM, Laird NM, Ware JH. Applied Longitudinal Analysis, 2nd edition. 
Hoboken, NJ: Wiley Interscience; 2011.
5.
Blyth CR, Still HA. Binomial confidence intervals. J Am Stat Assoc 1983;78:108-16.
6.
Casella G. Refining binomial confidence intervals. Can J Stat 1986;14:113-29.
7.
Chan IS, Zhang Z. Test-based exact confidence intervals for the difference of two 
binomial proportions. Biometrics 1999;55:1202-9.


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9. APPENDICES
9.1. Appendix 1. Definition and Use of Visit Windows in Reporting
Visit windows will be used for efficacy variables, and for any safety data that 
display/summarize by study visit. For other endpoints (eg, vital signs, physical 
examinations), visit windows will be applied for summary statistics by study visits if
required.
Table 12.
Definition of Visit Windows
Visit Label
Target Day
Definition [Day window]
Screening
Days -28 to Day 0
Baseline
Day 1, Baseline
Day 1
Week 2
15
Days 2 to 22
Week 4
29
Days 23 to 43
Week 8
57
Days 44 to 71
Week 12
85
Days 72 to 99
Week 16
113
Days 100 to 127
Week 20
141
Days 128 to 155
Week 24
169
Days 156 to 183
Follow Up/End of Study
Week 28
Days 184 to -
For the lab values, if the calculated study day for the labelled baseline visit is not study Day 1
but falls within 28 days before the start of the study dosing, then that data should be used for 
the baseline instead of leaving baseline missing.
For the other values, if the calculated study day for the labelled baseline visit is not study 
Day 1, but falls before the start of the study dosing, then that data should be used for the 
baseline instead of leaving baseline missing.
If two or more visits fall into the same window, keep the one closest to the Target Day. If 
two visits are equaled distant from the Target Day in absolute value, the later visit should be 
used.


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